register interest

Professor Christophe Fraser

Research Area: Genetics and Genomics
Scientific Themes: Immunology & Infectious Disease and Genetics & Genomics
Keywords: HIV, Antibiotic resistance, Mathematical modelling, Pathogen genetics and Evolution
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Professor Christophe Fraser is Senior Group Leader in Pathogen Dynamics at the Big Data Institute. The group studies aims to better understand infectious disease dynamics, and so contribute to designing better disease prevention strategies. The group uses a combination of mathematical modelling, pathogen genetics, and evolution, and works closely with clinicians, epidemiologists and public health practitioners.  Current areas of particular interest are in HIV, and in antibiotic resistance. 

There are no collaborations listed for this principal investigator.

Blanquart F, Lehtinen S, Fraser C. 2017. An evolutionary model to predict the frequency of antibiotic resistance under seasonal antibiotic use, and an application to Streptococcus pneumoniae. Proc Biol Sci, 284 (1855), pp. 20170679-20170679. | Show Abstract | Read more

The frequency of resistance to antibiotics in Streptococcus pneumoniae has been stable over recent decades. For example, penicillin non-susceptibility in Europe has fluctuated between 12% and 16% without any major time trend. In spite of long-term stability, resistance fluctuates over short time scales, presumably in part due to seasonal fluctuations in antibiotic prescriptions. Here, we develop a model that describes the evolution of antibiotic resistance under selection by multiple antibiotics prescribed at seasonally changing rates. This model was inspired by, and fitted to, published data on monthly antibiotics prescriptions and frequency of resistance in two communities in Israel over 5 years. Seasonal fluctuations in antibiotic usage translate into small fluctuations of the frequency of resistance around the average value. We describe these dynamics using a perturbation approach that encapsulates all ecological and evolutionary forces into a generic model, whose parameters quantify a force stabilizing the frequency of resistance around the equilibrium and the sensitivity of the population to antibiotic selection. Fitting the model to the data revealed a strong stabilizing force, typically two to five times stronger than direct selection due to antibiotics. The strong stabilizing force explains that resistance fluctuates in phase with usage, as antibiotic selection alone would result in resistance fluctuating behind usage with a lag of three months when antibiotic use is seasonal. While most antibiotics selected for increased resistance, intriguingly, cephalosporins selected for decreased resistance to penicillins and macrolides, an effect consistent in the two communities. One extra monthly prescription of cephalosporins per 1000 children decreased the frequency of penicillin-resistant strains by 1.7%. This model emerges under minimal assumptions, quantifies the forces acting on resistance and explains up to 43% of the temporal variation in resistance.

Le Vu S, Ratmann O, Delpech V, Brown AE, Gill ON, Tostevin A, Fraser C, Volz EM. 2018. Comparison of cluster-based and source-attribution methods for estimating transmission risk using large HIV sequence databases. Epidemics, 23 pp. 1-10. | Show Abstract | Read more

Phylogenetic clustering of HIV sequences from a random sample of patients can reveal epidemiological transmission patterns, but interpretation is hampered by limited theoretical support and statistical properties of clustering analysis remain poorly understood. Alternatively, source attribution methods allow fitting of HIV transmission models and thereby quantify aspects of disease transmission. A simulation study was conducted to assess error rates of clustering methods for detecting transmission risk factors. We modeled HIV epidemics among men having sex with men and generated phylogenies comparable to those that can be obtained from HIV surveillance data in the UK. Clustering and source attribution approaches were applied to evaluate their ability to identify patient attributes as transmission risk factors. We find that commonly used methods show a misleading association between cluster size or odds of clustering and covariates that are correlated with time since infection, regardless of their influence on transmission. Clustering methods usually have higher error rates and lower sensitivity than source attribution method for identifying transmission risk factors. But neither methods provide robust estimates of transmission risk ratios. Source attribution method can alleviate drawbacks from phylogenetic clustering but formal population genetic modeling may be required to estimate quantitative transmission risk factors.

Corander J, Fraser C, Gutmann MU, Arnold B, Hanage WP, Bentley SD, Lipsitch M, Croucher NJ. 2017. Frequency-dependent selection in vaccine-associated pneumococcal population dynamics. Nat Ecol Evol, 1 (12), pp. 1950-1960. | Show Abstract | Read more

Many bacterial species are composed of multiple lineages distinguished by extensive variation in gene content. These often cocirculate in the same habitat, but the evolutionary and ecological processes that shape these complex populations are poorly understood. Addressing these questions is particularly important for Streptococcus pneumoniae, a nasopharyngeal commensal and respiratory pathogen, because the changes in population structure associated with the recent introduction of partial-coverage vaccines have substantially reduced pneumococcal disease. Here we show that pneumococcal lineages from multiple populations each have a distinct combination of intermediate-frequency genes. Functional analysis suggested that these loci may be subject to negative frequency-dependent selection (NFDS) through interactions with other bacteria, hosts or mobile elements. Correspondingly, these genes had similar frequencies in four populations with dissimilar lineage compositions. These frequencies were maintained following substantial alterations in lineage prevalences once vaccination programmes began. Fitting a multilocus NFDS model of post-vaccine population dynamics to three genomic datasets using Approximate Bayesian Computation generated reproducible estimates of the influence of NFDS on pneumococcal evolution, the strength of which varied between loci. Simulations replicated the stable frequency of lineages unperturbed by vaccination, patterns of serotype switching and clonal replacement. This framework highlights how bacterial ecology affects the impact of clinical interventions.

Mostowy RJ, Croucher NJ, De Maio N, Chewapreecha C, Salter SJ, Turner P, Aanensen DM, Bentley SD, Didelot X, Fraser C. 2017. Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination. Mol Biol Evol, 34 (10), pp. 2537-2554. | Show Abstract | Read more

Diversity of the polysaccharide capsule in Streptococcus pneumoniae-main surface antigen and the target of the currently used pneumococcal vaccines-constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium's ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination.

Cobey S, Baskerville EB, Colijn C, Hanage W, Fraser C, Lipsitch M. 2017. Host population structure and treatment frequency maintain balancing selection on drug resistance. J R Soc Interface, 14 (133), pp. 20170295-20170295. | Show Abstract | Read more

It is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modelled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact.

Li LM, Grassly NC, Fraser C. 2017. Quantifying Transmission Heterogeneity Using Both Pathogen Phylogenies and Incidence Time Series. Mol Biol Evol, 34 (11), pp. 2982-2995. | Show Abstract | Read more

Heterogeneity in individual-level transmissibility can be quantified by the dispersion parameter k of the offspring distribution. Quantifying heterogeneity is important as it affects other parameter estimates, it modulates the degree of unpredictability of an epidemic, and it needs to be accounted for in models of infection control. Aggregated data such as incidence time series are often not sufficiently informative to estimate k. Incorporating phylogenetic analysis can help to estimate k concurrently with other epidemiological parameters. We have developed an inference framework that uses particle Markov Chain Monte Carlo to estimate k and other epidemiological parameters using both incidence time series and the pathogen phylogeny. Using the framework to fit a modified compartmental transmission model that includes the parameter k to simulated data, we found that more accurate and less biased estimates of the reproductive number were obtained by combining epidemiological and phylogenetic analyses. However, k was most accurately estimated using pathogen phylogeny alone. Accurately estimating k was necessary for unbiased estimates of the reproductive number, but it did not affect the accuracy of reporting probability and epidemic start date estimates. We further demonstrated that inference was possible in the presence of phylogenetic uncertainty by sampling from the posterior distribution of phylogenies. Finally, we used the inference framework to estimate transmission parameters from epidemiological and genetic data collected during a poliovirus outbreak. Despite the large degree of phylogenetic uncertainty, we demonstrated that incorporating phylogenetic data in parameter inference improved the accuracy and precision of estimates.

Blanquart F, Wymant C, Cornelissen M, Gall A, Bakker M, Bezemer D, Hall M, Hillebregt M, Ong SH, Albert J et al. 2017. Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe. PLoS Biol, 15 (6), pp. e2001855. | Show Abstract | Read more

HIV-1 set-point viral load-the approximately stable value of viraemia in the first years of chronic infection-is a strong predictor of clinical outcome and is highly variable across infected individuals. To better understand HIV-1 pathogenesis and the evolution of the viral population, we must quantify the heritability of set-point viral load, which is the fraction of variation in this phenotype attributable to viral genetic variation. However, current estimates of heritability vary widely, from 6% to 59%. Here we used a dataset of 2,028 seroconverters infected between 1985 and 2013 from 5 European countries (Belgium, Switzerland, France, the Netherlands and the United Kingdom) and estimated the heritability of set-point viral load at 31% (CI 15%-43%). Specifically, heritability was measured using models of character evolution describing how viral load evolves on the phylogeny of whole-genome viral sequences. In contrast to previous studies, (i) we measured viral loads using standardized assays on a sample collected in a strict time window of 6 to 24 months after infection, from which the viral genome was also sequenced; (ii) we compared 2 models of character evolution, the classical "Brownian motion" model and another model ("Ornstein-Uhlenbeck") that includes stabilising selection on viral load; (iii) we controlled for covariates, including age and sex, which may inflate estimates of heritability; and (iv) we developed a goodness of fit test based on the correlation of viral loads in cherries of the phylogenetic tree, showing that both models of character evolution fit the data well. An overall heritability of 31% (CI 15%-43%) is consistent with other studies based on regression of viral load in donor-recipient pairs. Thus, about a third of variation in HIV-1 virulence is attributable to viral genetic variation.

Rutstein SE, Ananworanich J, Fidler S, Johnson C, Sanders EJ, Sued O, Saez-Cirion A, Pilcher CD, Fraser C, Cohen MS et al. 2017. Clinical and public health implications of acute and early HIV detection and treatment: a scoping review. J Int AIDS Soc, 20 (1), pp. 21579. | Show Abstract | Read more

INTRODUCTION: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. METHODS: We searched PubMed, in addition to hand-review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low- and middle-income countries (LMICs) published in the last fifteen years. RESULTS AND DISCUSSION: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease-of-use, suitability for application and distribution in LMIC, and throughput for high-volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI - evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point-of-care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre-exposure prophylaxis outcomes by avoiding treatment initiation for HIV-seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. CONCLUSIONS: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale-up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point-of-care diagnostics, and efficacious and effective first-line regimens.

Garske T, Cori A, Ariyarajah A, Blake IM, Dorigatti I, Eckmanns T, Fraser C, Hinsley W, Jombart T, Mills HL et al. 2017. Heterogeneities in the case fatality ratio in the West African Ebola outbreak 2013-2016. Philos Trans R Soc Lond B Biol Sci, 372 (1721), pp. 20160308-20160308. | Show Abstract | Read more

The 2013-2016 Ebola outbreak in West Africa is the largest on record with 28 616 confirmed, probable and suspected cases and 11 310 deaths officially recorded by 10 June 2016, the true burden probably considerably higher. The case fatality ratio (CFR: proportion of cases that are fatal) is a key indicator of disease severity useful for gauging the appropriate public health response and for evaluating treatment benefits, if estimated accurately. We analysed individual-level clinical outcome data from Guinea, Liberia and Sierra Leone officially reported to the World Health Organization. The overall mean CFR was 62.9% (95% CI: 61.9% to 64.0%) among confirmed cases with recorded clinical outcomes. Age was the most important modifier of survival probabilities, but country, stage of the epidemic and whether patients were hospitalized also played roles. We developed a statistical analysis to detect outliers in CFR between districts of residence and treatment centres (TCs), adjusting for known factors influencing survival and identified eight districts and three TCs with a CFR significantly different from the average. From the current dataset, we cannot determine whether the observed variation in CFR seen by district or treatment centre reflects real differences in survival, related to the quality of care or other factors or was caused by differences in reporting practices or case ascertainment.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.

Cori A, Donnelly CA, Dorigatti I, Ferguson NM, Fraser C, Garske T, Jombart T, Nedjati-Gilani G, Nouvellet P, Riley S et al. 2017. Key data for outbreak evaluation: building on the Ebola experience. Philos Trans R Soc Lond B Biol Sci, 372 (1721), pp. 20160371-20160371. | Show Abstract | Read more

Following the detection of an infectious disease outbreak, rapid epidemiological assessment is critical for guiding an effective public health response. To understand the transmission dynamics and potential impact of an outbreak, several types of data are necessary. Here we build on experience gained in the West African Ebola epidemic and prior emerging infectious disease outbreaks to set out a checklist of data needed to: (1) quantify severity and transmissibility; (2) characterize heterogeneities in transmission and their determinants; and (3) assess the effectiveness of different interventions. We differentiate data needs into individual-level data (e.g. a detailed list of reported cases), exposure data (e.g. identifying where/how cases may have been infected) and population-level data (e.g. size/demographics of the population(s) affected and when/where interventions were implemented). A remarkable amount of individual-level and exposure data was collected during the West African Ebola epidemic, which allowed the assessment of (1) and (2). However, gaps in population-level data (particularly around which interventions were applied when and where) posed challenges to the assessment of (3). Here we highlight recurrent data issues, give practical suggestions for addressing these issues and discuss priorities for improvements in data collection in future outbreaks.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.

Ratmann O, Wymant C, Colijn C, Danaviah S, Essex M, Frost SDW, Gall A, Gaiseitsiwe S, Grabowski M, Gray R et al. 2017. HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences. AIDS Res Hum Retroviruses, 33 (11), pp. 1083-1098. | Show Abstract | Read more

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3,985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2,833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

Doekes HM, Fraser C, Lythgoe KA. 2017. Effect of the Latent Reservoir on the Evolution of HIV at the Within- and Between-Host Levels. PLoS Comput Biol, 13 (1), pp. e1005228. | Show Abstract | Read more

The existence of long-lived reservoirs of latently infected CD4+ T cells is the major barrier to curing HIV, and has been extensively studied in this light. However, the effect of these reservoirs on the evolutionary dynamics of the virus has received little attention. Here, we present a within-host quasispecies model that incorporates a long-lived reservoir, which we then nest into an epidemiological model of HIV dynamics. For biologically plausible parameter values, we find that the presence of a latent reservoir can severely delay evolutionary dynamics within a single host, with longer delays associated with larger relative reservoir sizes and/or homeostatic proliferation of cells within the reservoir. These delays can fundamentally change the dynamics of the virus at the epidemiological scale. In particular, the delay in within-host evolutionary dynamics can be sufficient for the virus to evolve intermediate viral loads consistent with maximising transmission, as is observed, and not the very high viral loads that previous models have predicted, an effect that can be further enhanced if viruses similar to those that initiate infection are preferentially transmitted. These results depend strongly on within-host characteristics such as the relative reservoir size, with the evolution of intermediate viral loads observed only when the within-host dynamics are sufficiently delayed. In conclusion, we argue that the latent reservoir has important, and hitherto under-appreciated, roles in both within- and between-host viral evolution.

Didelot X, Fraser C, Gardy J, Colijn C. 2017. Genomic Infectious Disease Epidemiology in Partially Sampled and Ongoing Outbreaks. Mol Biol Evol, 34 (4), pp. 997-1007. | Show Abstract | Read more

Genomic data are increasingly being used to understand infectious disease epidemiology. Isolates from a given outbreak are sequenced, and the patterns of shared variation are used to infer which isolates within the outbreak are most closely related to each other. Unfortunately, the phylogenetic trees typically used to represent this variation are not directly informative about who infected whom-a phylogenetic tree is not a transmission tree. However, a transmission tree can be inferred from a phylogeny while accounting for within-host genetic diversity by coloring the branches of a phylogeny according to which host those branches were in. Here we extend this approach and show that it can be applied to partially sampled and ongoing outbreaks. This requires computing the correct probability of an observed transmission tree and we herein demonstrate how to do this for a large class of epidemiological models. We also demonstrate how the branch coloring approach can incorporate a variable number of unique colors to represent unsampled intermediates in transmission chains. The resulting algorithm is a reversible jump Monte-Carlo Markov Chain, which we apply to both simulated data and real data from an outbreak of tuberculosis. By accounting for unsampled cases and an outbreak which may not have reached its end, our method is uniquely suited to use in a public health environment during real-time outbreak investigations. We implemented this transmission tree inference methodology in an R package called TransPhylo, which is freely available from https://github.com/xavierdidelot/TransPhylo.

Lehtinen S, Blanquart F, Croucher NJ, Turner P, Lipsitch M, Fraser C. 2017. Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage. Proc Natl Acad Sci U S A, 114 (5), pp. 1075-1080. | Show Abstract | Read more

Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

Ratmann O, Hodcroft EB, Pickles M, Cori A, Hall M, Lycett S, Colijn C, Dearlove B, Didelot X, Frost S et al. 2017. Phylogenetic Tools for Generalized HIV-1 Epidemics: Findings from the PANGEA-HIV Methods Comparison. Mol Biol Evol, 34 (1), pp. 185-203. | Show Abstract | Read more

Viral phylogenetic methods contribute to understanding how HIV spreads in populations, and thereby help guide the design of prevention interventions. So far, most analyses have been applied to well-sampled concentrated HIV-1 epidemics in wealthy countries. To direct the use of phylogenetic tools to where the impact of HIV-1 is greatest, the Phylogenetics And Networks for Generalized HIV Epidemics in Africa (PANGEA-HIV) consortium generates full-genome viral sequences from across sub-Saharan Africa. Analyzing these data presents new challenges, since epidemics are principally driven by heterosexual transmission and a smaller fraction of cases is sampled. Here, we show that viral phylogenetic tools can be adapted and used to estimate epidemiological quantities of central importance to HIV-1 prevention in sub-Saharan Africa. We used a community-wide methods comparison exercise on simulated data, where participants were blinded to the true dynamics they were inferring. Two distinct simulations captured generalized HIV-1 epidemics, before and after a large community-level intervention that reduced infection levels. Five research groups participated. Structured coalescent modeling approaches were most successful: phylogenetic estimates of HIV-1 incidence, incidence reductions, and the proportion of transmissions from individuals in their first 3 months of infection correlated with the true values (Pearson correlation > 90%), with small bias. However, on some simulations, true values were markedly outside reported confidence or credibility intervals. The blinded comparison revealed current limits and strengths in using HIV phylogenetics in challenging settings, provided benchmarks for future methods' development, and supports using the latest generation of phylogenetic tools to advance HIV surveillance and prevention.

International Ebola Response Team, Agua-Agum J, Ariyarajah A, Aylward B, Bawo L, Bilivogui P, Blake IM, Brennan RJ, Cawthorne A, Cleary E et al. 2016. Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study. PLoS Med, 13 (11), pp. e1002170. | Show Abstract | Read more

BACKGROUND: The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, mainly in Guinea (3,529), Liberia (5,343), and Sierra Leone (10,746). Here, we present analyses of data collected during the outbreak identifying drivers of transmission and highlighting areas where control could be improved. METHODS AND FINDINGS: Over 19,000 confirmed and probable Ebola cases were reported in West Africa by 4 May 2015. Individuals with confirmed or probable Ebola ("cases") were asked if they had exposure to other potential Ebola cases ("potential source contacts") in a funeral or non-funeral context prior to becoming ill. We performed retrospective analyses of a case line-list, collated from national databases of case investigation forms that have been reported to WHO. These analyses were initially performed to assist WHO's response during the epidemic, and have been updated for publication. We analysed data from 3,529 cases in Guinea, 5,343 in Liberia, and 10,746 in Sierra Leone; exposures were reported by 33% of cases. The proportion of cases reporting a funeral exposure decreased over time. We found a positive correlation (r = 0.35, p < 0.001) between this proportion in a given district for a given month and the within-district transmission intensity, quantified by the estimated reproduction number (R). We also found a negative correlation (r = -0.37, p < 0.001) between R and the district proportion of hospitalised cases admitted within ≤4 days of symptom onset. These two proportions were not correlated, suggesting that reduced funeral attendance and faster hospitalisation independently influenced local transmission intensity. We were able to identify 14% of potential source contacts as cases in the case line-list. Linking cases to the contacts who potentially infected them provided information on the transmission network. This revealed a high degree of heterogeneity in inferred transmissions, with only 20% of cases accounting for at least 73% of new infections, a phenomenon often called super-spreading. Multivariable regression models allowed us to identify predictors of being named as a potential source contact. These were similar for funeral and non-funeral contacts: severe symptoms, death, non-hospitalisation, older age, and travelling prior to symptom onset. Non-funeral exposures were strongly peaked around the death of the contact. There was evidence that hospitalisation reduced but did not eliminate onward exposures. We found that Ebola treatment units were better than other health care facilities at preventing exposure from hospitalised and deceased individuals. The principal limitation of our analysis is limited data quality, with cases not being entered into the database, cases not reporting exposures, or data being entered incorrectly (especially dates, and possible misclassifications). CONCLUSIONS: Achieving elimination of Ebola is challenging, partly because of super-spreading. Safe funeral practices and fast hospitalisation contributed to the containment of this Ebola epidemic. Continued real-time data capture, reporting, and analysis are vital to track transmission patterns, inform resource deployment, and thus hasten and maintain elimination of the virus from the human population.

Blanquart F, Grabowski MK, Herbeck J, Nalugoda F, Serwadda D, Eller MA, Robb ML, Gray R, Kigozi G, Laeyendecker O et al. 2016. A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda. Elife, 5 (NOVEMBER2016), | Show Abstract | Read more

Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals.

Lythgoe KA, Blanquart F, Pellis L, Fraser C. 2016. Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics. PLoS Biol, 14 (10), pp. e1002567. | Show Abstract | Read more

The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body's viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.

Lamers SL, Barbier AE, Ratmann O, Fraser C, Rose R, Laeyendecker O, Grabowski MK. 2016. HIV-1 Sequence Data Coverage in Central East Africa from 1959 to 2013 AIDS Research and Human Retroviruses, 32 (9), pp. 904-908. | Read more

2016. After Ebola in West Africa — Unpredictable Risks, Preventable Epidemics New England Journal of Medicine, 375 (6), pp. 587-596. | Read more

Cauchemez S, Nouvellet P, Cori A, Jombart T, Garske T, Clapham H, Moore S, Mills HL, Salje H, Collins C et al. 2016. Unraveling the drivers of MERS-CoV transmission. Proc Natl Acad Sci U S A, 113 (32), pp. 9081-9086. | Show Abstract | Read more

With more than 1,700 laboratory-confirmed infections, Middle East respiratory syndrome coronavirus (MERS-CoV) remains a significant threat for public health. However, the lack of detailed data on modes of transmission from the animal reservoir and between humans means that the drivers of MERS-CoV epidemics remain poorly characterized. Here, we develop a statistical framework to provide a comprehensive analysis of the transmission patterns underlying the 681 MERS-CoV cases detected in the Kingdom of Saudi Arabia (KSA) between January 2013 and July 2014. We assess how infections from the animal reservoir, the different levels of mixing, and heterogeneities in transmission have contributed to the buildup of MERS-CoV epidemics in KSA. We estimate that 12% [95% credible interval (CI): 9%, 15%] of cases were infected from the reservoir, the rest via human-to-human transmission in clusters (60%; CI: 57%, 63%), within (23%; CI: 20%, 27%), or between (5%; CI: 2%, 8%) regions. The reproduction number at the start of a cluster was 0.45 (CI: 0.33, 0.58) on average, but with large SD (0.53; CI: 0.35, 0.78). It was >1 in 12% (CI: 6%, 18%) of clusters but fell by approximately one-half (47% CI: 34%, 63%) its original value after 10 cases on average. The ongoing exposure of humans to MERS-CoV from the reservoir is of major concern, given the continued risk of substantial outbreaks in health care systems. The approach we present allows the study of infectious disease transmission when data linking cases to each other remain limited and uncertain.

Cornelissen M, Gall A, Vink M, Zorgdrager F, Binter Š, Edwards S, Jurriaans S, Bakker M, Ong SH, Gras L et al. 2017. From clinical sample to complete genome: Comparing methods for the extraction of HIV-1 RNA for high-throughput deep sequencing Virus Research, 239 pp. 10-16. | Read more

Heffernan A, Barber E, Thomas R, Fraser C, Pickles M, Cori A. 2016. Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa PLOS ONE, 11 (7), pp. e0158303-e0158303. | Read more

Croucher NJ, Mostowy R, Wymant C, Turner P, Bentley SD, Fraser C. 2016. Horizontal DNA Transfer Mechanisms of Bacteria as Weapons of Intragenomic Conflict. PLoS Biol, 14 (3), pp. e1002394. | Show Abstract | Read more

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated.

2016. Ebola Virus Disease among Male and Female Persons in West Africa New England Journal of Medicine, 374 (1), pp. 96-98. | Read more

Ratmann O, van Sighem A, Bezemer D, Gavryushkina A, Jurriaans S, Wensing A, de Wolf F, Reiss P, Fraser C. 2016. Sources of HIV infection among men having sex with men and implications for prevention Science Translational Medicine, 8 (320), pp. 320ra2-320ra2. | Read more

Pinsent A, Fraser C, Ferguson NM, Riley S. 2015. A systematic review of reported reassortant viral lineages of influenza A BMC Infectious Diseases, 16 (1), | Read more

Nouvellet P, Garske T, Mills HL, Nedjati-Gilani G, Hinsley W, Blake IM, Van Kerkhove MD, Cori A, Dorigatti I, Jombart T et al. 2015. The role of rapid diagnostics in managing Ebola epidemics Nature, 528 (7580), pp. S109-S116. | Read more

van Sighem A, Nakagawa F, De Angelis D, Quinten C, Bezemer D, de Coul EO, Egger M, de Wolf F, Fraser C, Phillips A. 2015. Estimating HIV Incidence, Time to Diagnosis, and the Undiagnosed HIV Epidemic Using Routine Surveillance Data Epidemiology, 26 (5), pp. 653-660. | Read more

Lipsitch M, Donnelly CA, Fraser C, Blake IM, Cori A, Dorigatti I, Ferguson NM, Garske T, Mills HL, Riley S et al. 2015. Potential Biases in Estimating Absolute and Relative Case-Fatality Risks during Outbreaks PLOS Neglected Tropical Diseases, 9 (7), pp. e0003846-e0003846. | Read more

Hollingsworth TD, Pilcher CD, Hecht FM, Deeks SG, Fraser C. 2015. High Transmissibility During Early HIV Infection Among Men Who Have Sex With Men-San Francisco, California. J Infect Dis, 211 (11), pp. 1757-1760. | Show Abstract | Read more

We estimate the relative transmission rate in early versus later infection among men who have sex with men (MSM) in San Francisco, California, by studying the characteristics of a sample of transmitters, recruited through newly diagnosed, recently infected MSM between 1996 and 2009. Of 36 transmitters identified, 9 were determined on the basis of testing history and serologic testing to have been recently infected. The unadjusted odds ratio of transmitting during early infection was 15.2 (95% confidence interval [CI], 6.3-33.4; P < .001); the odds ratio was 8.9 (95% CI, 4.1-19.4) after adjustment for self-reported antiretroviral treatment. This high transmissibility could be due to both high infectiousness and high rates of sex partner change or concurrent partnerships.

2015. Ebola Virus Disease among Children in West Africa New England Journal of Medicine, 372 (13), pp. 1274-1277. | Read more

Pillay D, Herbeck J, Cohen MS, Oliveira TD, Fraser C, Ratmann O, Brown AL, Kellam P. 2015. PANGEA-HIV: phylogenetics for generalised epidemics in Africa The Lancet Infectious Diseases, 15 (3), pp. 259-261. | Read more

Hayes R, Fidler S, Cori A, Fraser C, Floyd S, Ayles H, Beyers N, El-Sadr W. 2015. HIV Treatment-As-Prevention Research: Taking the Right Road at the Crossroads PLOS Medicine, 12 (3), pp. e1001800-e1001800. | Read more

2015. West African Ebola Epidemic after One Year — Slowing but Not Yet under Control New England Journal of Medicine, 372 (6), pp. 584-587. | Read more

Bonhoeffer S, Fraser C, Leventhal GE. 2015. High Heritability Is Compatible with the Broad Distribution of Set Point Viral Load in HIV Carriers PLOS Pathogens, 11 (2), pp. e1004634-e1004634. | Read more

Tong SYC, Holden MTG, Nickerson EK, Cooper BS, Köser CU, Cori A, Jombart T, Cauchemez S, Fraser C, Wuthiekanun V et al. 2015. Genome sequencing defines phylogeny and spread of methicillin-resistant Staphylococcus aureus in a high transmission setting. Genome Res, 25 (1), pp. 111-118. | Show Abstract | Read more

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial infection. Whole-genome sequencing of MRSA has been used to define phylogeny and transmission in well-resourced healthcare settings, yet the greatest burden of nosocomial infection occurs in resource-restricted settings where barriers to transmission are lower. Here, we study the flux and genetic diversity of MRSA on ward and individual patient levels in a hospital where transmission was common. We repeatedly screened all patients on two intensive care units for MRSA carriage over a 3-mo period. All MRSA belonged to multilocus sequence type 239 (ST 239). We defined the population structure and charted the spread of MRSA by sequencing 79 isolates from 46 patients and five members of staff, including the first MRSA-positive screen isolates and up to two repeat isolates where available. Phylogenetic analysis identified a flux of distinct ST 239 clades over time in each intensive care unit. In total, five main clades were identified, which varied in the carriage of plasmids encoding antiseptic and antimicrobial resistance determinants. Sequence data confirmed intra- and interwards transmission events and identified individual patients who were colonized by more than one clade. One patient on each unit was the source of numerous transmission events, and deep sampling of one of these cases demonstrated colonization with a "cloud" of related MRSA variants. The application of whole-genome sequencing and analysis provides novel insights into the transmission of MRSA in under-resourced healthcare settings and has relevance to wider global health.

Pelat C, Ferguson NM, White PJ, Reed C, Finelli L, Cauchemez S, Fraser C. 2014. Optimizing the Precision of Case Fatality Ratio Estimates Under the Surveillance Pyramid Approach American Journal of Epidemiology, 180 (10), pp. 1036-1046. | Read more

Jombart T, Aanensen DM, Baguelin M, Birrell P, Cauchemez S, Camacho A, Colijn C, Collins C, Cori A, Didelot X et al. 2014. OutbreakTools: a new platform for disease outbreak analysis using the R software. Epidemics, 7 pp. 28-34. | Show Abstract | Read more

The investigation of infectious disease outbreaks relies on the analysis of increasingly complex and diverse data, which offer new prospects for gaining insights into disease transmission processes and informing public health policies. However, the potential of such data can only be harnessed using a number of different, complementary approaches and tools, and a unified platform for the analysis of disease outbreaks is still lacking. In this paper, we present the new R package OutbreakTools, which aims to provide a basis for outbreak data management and analysis in R. OutbreakTools is developed by a community of epidemiologists, statisticians, modellers and bioinformaticians, and implements classes and methods for storing, handling and visualizing outbreak data. It includes real and simulated outbreak datasets. Together with a number of tools for infectious disease epidemiology recently made available in R, OutbreakTools contributes to the emergence of a new, free and open-source platform for the analysis of disease outbreaks.

Mostowy R, Croucher NJ, Hanage WP, Harris SR, Bentley S, Fraser C. 2014. Heterogeneity in the Frequency and Characteristics of Homologous Recombination in Pneumococcal Evolution PLoS Genetics, 10 (5), pp. e1004300-e1004300. | Read more

Kucharski A, Mills H, Pinsent A, Fraser C, Van Kerkhove M, Donnelly CA, Riley S. Distinguishing Between Reservoir Exposure and Human-to-Human Transmission for Emerging Pathogens Using Case Onset Data PLoS Currents, | Read more

Hayes R, Ayles H, Beyers N, Sabapathy K, Floyd S, Shanaube K, Bock P, Griffith S, Moore A, Watson-Jones D et al. 2014. HPTN 071 (PopART): Rationale and design of a cluster-randomised trial of the population impact of an HIV combination prevention intervention including universal testing and treatment – a study protocol for a cluster randomised trial Trials, 15 (1), pp. 57-57. | Read more

Cori A, Ayles H, Beyers N, Schaap A, Floyd S, Sabapathy K, Eaton JW, Hauck K, Smith P, Griffith S et al. 2014. HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model PLoS ONE, 9 (1), pp. e84511-e84511. | Read more

Cauchemez S, Fraser C, Van Kerkhove MD, Donnelly CA, Riley S, Rambaut A, Enouf V, van der Werf S, Ferguson NM. 2014. Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility The Lancet Infectious Diseases, 14 (1), pp. 50-56. | Read more

Pretorius C, Menzies NA, Chindelevitch L, Cohen T, Cori A, Eaton JW, Fraser C, Gopalappa C, Hallett TB, Salomon JA et al. 2014. The potential effects of changing HIV treatment policy on tuberculosis outcomes in South Africa AIDS, 28 pp. S25-S34. | Read more

Eaton JW, Menzies NA, Stover J, Cambiano V, Chindelevitch L, Cori A, Hontelez JAC, Humair S, Kerr CC, Klein DJ et al. 2014. Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models The Lancet Global Health, 2 (1), pp. e23-e34. | Read more

Li LM, Grassly NC, Fraser C. 2014. Genomic analysis of emerging pathogens: methods, application and future trends Genome Biology, 15 (11), | Read more

Jombart T, Cori A, Didelot X, Cauchemez S, Fraser C, Ferguson N. 2014. Bayesian reconstruction of disease outbreaks by combining epidemiologic and genomic data. PLoS Comput Biol, 10 (1), pp. e1003457. | Show Abstract | Read more

Recent years have seen progress in the development of statistically rigorous frameworks to infer outbreak transmission trees ("who infected whom") from epidemiological and genetic data. Making use of pathogen genome sequences in such analyses remains a challenge, however, with a variety of heuristic approaches having been explored to date. We introduce a statistical method exploiting both pathogen sequences and collection dates to unravel the dynamics of densely sampled outbreaks. Our approach identifies likely transmission events and infers dates of infections, unobserved cases and separate introductions of the disease. It also proves useful for inferring numbers of secondary infections and identifying heterogeneous infectivity and super-spreaders. After testing our approach using simulations, we illustrate the method with the analysis of the beginning of the 2003 Singaporean outbreak of Severe Acute Respiratory Syndrome (SARS), providing new insights into the early stage of this epidemic. Our approach is the first tool for disease outbreak reconstruction from genetic data widely available as free software, the R package outbreaker. It is applicable to various densely sampled epidemics, and improves previous approaches by detecting unobserved and imported cases, as well as allowing multiple introductions of the pathogen. Because of its generality, we believe this method will become a tool of choice for the analysis of densely sampled disease outbreaks, and will form a rigorous framework for subsequent methodological developments.

Fraser C, Lythgoe K, Leventhal GE, Shirreff G, Hollingsworth TD, Alizon S, Bonhoeffer S. 2014. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science, 343 (6177), pp. 1243727. | Show Abstract | Read more

Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

Cori A, Ferguson NM, Fraser C, Cauchemez S. 2013. A New Framework and Software to Estimate Time-Varying Reproduction Numbers During Epidemics American Journal of Epidemiology, 178 (9), pp. 1505-1512. | Read more

Lythgoe KA, Pellis L, Fraser C. 2013. Is HIV short-sighted? Insights from a multistrain nested model. Evolution, 67 (10), pp. 2769-2782. | Show Abstract | Read more

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus.

Robinson K, Fyson N, Cohen T, Fraser C, Colijn C. 2013. How the Dynamics and Structure of Sexual Contact Networks Shape Pathogen Phylogenies PLoS Computational Biology, 9 (6), pp. e1003105-e1003105. | Read more

Gras L, Geskus RB, Jurriaans S, Bakker M, van Sighem A, Bezemer D, Fraser C, Prins JM, Berkhout B, de Wolf F, ATHENA National Observational Cohort. 2013. Has the rate of CD4 cell count decline before initiation of antiretroviral therapy changed over the course of the Dutch HIV epidemic among MSM? PLoS One, 8 (5), pp. e64437. | Show Abstract | Read more

INTRODUCTION: Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline. METHODS: Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART, <100 CD4 cells/mm³, or AIDS) among therapy-naïve MSM HIV-1 seroconverters in the Netherlands. These models make different assumptions about the censoring process. RESULTS: All 3 models estimated lower median CD4 cell counts 9 months after seroconversion in later calendar years (623, 582, and 541 cells/mm³ for 1984-1995 [n = 111], 1996-2002 [n = 139], and 2003-2007 seroconverters [n = 356], respectively, shared-parameter model). Only the 2 joint-models found a trend for a steeper decline of CD4 cell counts with seroconversion in later calendar years (overall p-values 0.002 and 0.06 for the pattern-mixture and the shared-parameter model, respectively). In the shared-parameter model the median decline from 9 to 48 months was 276 cellsmm³ for 1984-1995 seroconverters and 308 cells/mm³ for 2003-2007 seroconverters (difference in slope, p = 0.045). CONCLUSION: Mixed-effects models underestimate the CD4 cell decline prior to starting ART. Joint-models suggest that CD4 cell count declines more rapidly in patients infected between 2003 and 2007 compared to patients infected before 1996.

Shepheard MA, Fleming VM, Connor TR, Corander J, Feil EJ, Fraser C, Hanage WP. 2013. Historical Zoonoses and Other Changes in Host Tropism of Staphylococcus aureus, Identified by Phylogenetic Analysis of a Population Dataset PLoS ONE, 8 (5), pp. e62369-e62369. | Read more

Alizon S, Fraser C. 2013. Within-host and between-host evolutionary rates across the HIV-1 genome Retrovirology, 10 (1), pp. 49-49. | Read more

Pybus OG, Fraser C, Rambaut A. 2013. Evolutionary epidemiology: Preparing for an age of genomic plenty Philosophical Transactions of the Royal Society B: Biological Sciences, 368 (1614), | Read more

Magiorkinis G, Sypsa V, Magiorkinis E, Paraskevis D, Katsoulidou A, Belshaw R, Fraser C, Pybus OG, Hatzakis A. 2013. Integrating phylodynamics and epidemiology to estimate transmission diversity in viral epidemics. PLoS Comput Biol, 9 (1), pp. e1002876. | Show Abstract | Read more

The epidemiology of chronic viral infections, such as those caused by Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV), is affected by the risk group structure of the infected population. Risk groups are defined by each of their members having acquired infection through a specific behavior. However, risk group definitions say little about the transmission potential of each infected individual. Variation in the number of secondary infections is extremely difficult to estimate for HCV and HIV but crucial in the design of efficient control interventions. Here we describe a novel method that combines epidemiological and population genetic approaches to estimate the variation in transmissibility of rapidly-evolving viral epidemics. We evaluate this method using a nationwide HCV epidemic and for the first time co-estimate viral generation times and superspreading events from a combination of molecular and epidemiological data. We anticipate that this integrated approach will form the basis of powerful tools for describing the transmission dynamics of chronic viral diseases, and for evaluating control strategies directed against them.

Shirreff G, Alizon S, Cori A, Günthard HF, Laeyendecker O, van Sighem A, Bezemer D, Fraser C. 2013. How effectively can HIV phylogenies be used to measure heritability? Evolution, Medicine, and Public Health, 2013 (1), pp. 209-224. | Read more

Pybus OG, Fraser C, Rambaut A. 2013. Evolutionary epidemiology: preparing for an age of genomic plenty. Philos Trans R Soc Lond B Biol Sci, 368 (1614), pp. 20120193. | Read more

Ratmann O, Donker G, Meijer A, Fraser C, Koelle K. 2012. Phylodynamic Inference and Model Assessment with Approximate Bayesian Computation: Influenza as a Case Study PLoS Computational Biology, 8 (12), pp. e1002835-e1002835. | Read more

van Sighem A, Vidondo B, Glass TR, Bucher HC, Vernazza P, Gebhardt M, de Wolf F, Derendinger S, Jeannin A, Bezemer D et al. 2012. Resurgence of HIV Infection among Men Who Have Sex with Men in Switzerland: Mathematical Modelling Study PLoS ONE, 7 (9), pp. e44819-e44819. | Read more

Lythgoe KA, Fraser C. 2012. New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels. Proc Biol Sci, 279 (1741), pp. 3367-3375. | Show Abstract | Read more

Over calendar time, HIV-1 evolves considerably faster within individuals than it does at the epidemic level. This is a surprising observation since, from basic population genetic theory, we would expect the genetic substitution rate to be similar across different levels of biological organization. Three different mechanisms could potentially cause the observed mismatch in phylogenetic rates of divergence: temporal changes in selection pressure during the course of infection; frequent reversion of adaptive mutations after transmission; and the storage of the virus in the body followed by the preferential transmission of stored ancestral virus. We evaluate each of these mechanisms to determine whether they are likely to make a major contribution to the mismatch in phylogenetic rates. We conclude that the cycling of the virus through very long-lived memory CD4(+) T cells, a process that we call 'store and retrieve', is probably the major contributing factor to the rate mismatch. The preferential transmission of ancestral virus needs to be integrated into evolutionary models if we are to accurately predict the evolution of immune escape, drug resistance and virulence in HIV-1 at the population level. Moreover, early infection viruses should be the major target for vaccine design, because these are the viral strains primarily involved in transmission.

de Silva E, Ferguson NM, Fraser C. 2012. Inferring pandemic growth rates from sequence data Journal of The Royal Society Interface, 9 (73), pp. 1797-1808. | Read more

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth D, Fraser C. 2012. 27 years of the HIV epidemic amongst men having sex with men in the Netherlands: An in depth mathematical model-based analysis (vol 2, pg 66, 2010) EPIDEMICS, 4 (3), pp. 170-170. | Read more

Eaton JW, Johnson LF, Salomon JA, Bärnighausen T, Bendavid E, Bershteyn A, Bloom DE, Cambiano V, Fraser C, Hontelez JAC et al. 2012. HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa PLoS Medicine, 9 (7), pp. e1001245-e1001245. | Read more

Cohen MS, Dye C, Fraser C, Miller WC, Powers KA, Williams BG. 2012. HIV Treatment as Prevention: Debate and Commentary—Will Early Infection Compromise Treatment-as-Prevention Strategies? PLoS Medicine, 9 (7), pp. e1001232-e1001232. | Read more

Delva W, Eaton JW, Meng F, Fraser C, White RG, Vickerman P, Boily M-C, Hallett TB. 2012. HIV Treatment as Prevention: Optimising the Impact of Expanded HIV Treatment Programmes PLoS Medicine, 9 (7), pp. e1001258-e1001258. | Read more

Truscott J, Fraser C, Cauchemez S, Meeyai A, Hinsley W, Donnelly CA, Ghani A, Ferguson N. 2012. Essential epidemiological mechanisms underpinning the transmission dynamics of seasonal influenza Journal of The Royal Society Interface, 9 (67), pp. 304-312. | Read more

Pellis L, Ferguson NM, Fraser C. 2011. Epidemic growth rate and household reproduction number in communities of households, schools and workplaces Journal of Mathematical Biology, 63 (4), pp. 691-734. | Read more

Shirreff G, Pellis L, Laeyendecker O, Fraser C. 2011. Transmission Selects for HIV-1 Strains of Intermediate Virulence: A Modelling Approach PLoS Computational Biology, 7 (10), pp. e1002185-e1002185. | Read more

Fraser C, Cummings DAT, Klinkenberg D, Burke DS, Ferguson NM. 2011. Influenza Transmission in Households During the 1918 Pandemic American Journal of Epidemiology, 174 (5), pp. 505-514. | Read more

Opatowski L, Fraser C, Griffin J, de Silva E, Van Kerkhove MD, Lyons EJ, Cauchemez S, Ferguson NM. 2011. Transmission Characteristics of the 2009 H1N1 Influenza Pandemic: Comparison of 8 Southern Hemisphere Countries PLoS Pathogens, 7 (9), pp. e1002225-e1002225. | Read more

Müller V, Fraser C, Herbeck JT. 2011. A Strong Case for Viral Genetic Factors in HIV Virulence Viruses, 3 (12), pp. 204-216. | Read more

Croucher NJ, Harris SR, Fraser C, Quail MA, Burton J, van der Linden M, McGee L, von Gottberg A, Song JH, Ko KS et al. 2011. Rapid pneumococcal evolution in response to clinical interventions. Science, 331 (6016), pp. 430-434. | Show Abstract | Read more

Epidemiological studies of the naturally transformable bacterial pathogen Streptococcus pneumoniae have previously been confounded by high rates of recombination. Sequencing 240 isolates of the PMEN1 (Spain(23F)-1) multidrug-resistant lineage enabled base substitutions to be distinguished from polymorphisms arising through horizontal sequence transfer. More than 700 recombinations were detected, with genes encoding major antigens frequently affected. Among these were 10 capsule-switching events, one of which accompanied a population shift as vaccine-escape serotype 19A isolates emerged in the USA after the introduction of the conjugate polysaccharide vaccine. The evolution of resistance to fluoroquinolones, rifampicin, and macrolides was observed to occur on multiple occasions. This study details how genomic plasticity within lineages of recombinogenic bacteria can permit adaptation to clinical interventions over remarkably short time scales.

Fraser C, Hollingsworth TD. 2010. Interpretation of correlations in setpoint viral load in transmitting couples. AIDS, 24 (16), pp. 2596-2597. | Read more

Baggaley RF, Fraser C. 2010. Modelling sexual transmission of HIV: testing the assumptions, validating the predictions Current Opinion in HIV and AIDS, 5 (4), pp. 269-276. | Read more

Colijn C, Cohen T, Fraser C, Hanage W, Goldstein E, Givon-Lavi N, Dagan R, Lipsitch M. 2010. What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae? Journal of The Royal Society Interface, 7 (47), pp. 905-919. | Read more

Van Kerkhove MD, Asikainen T, Becker NG, Bjorge S, Desenclos J-C, dos Santos T, Fraser C, Leung GM, Lipsitch M, Longini IM et al. 2010. Studies Needed to Address Public Health Challenges of the 2009 H1N1 Influenza Pandemic: Insights from Modeling PLoS Medicine, 7 (6), pp. e1000275-e1000275. | Read more

Hanage WP, Finkelstein JA, Huang SS, Pelton SI, Stevenson AE, Kleinman K, Hinrichsen VL, Fraser C. 2010. Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete Epidemics, 2 (2), pp. 80-84. | Read more

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Fraser C. 2010. 27 years of the HIV epidemic amongst men having sex with men in the Netherlands: an in depth mathematical model-based analysis. Epidemics, 2 (2), pp. 66-79. | Show Abstract | Read more

BACKGROUND: There has been increasing concern about a resurgent epidemic of HIV-1 amongst men having sex with men in the Netherlands, which has parallels with similar epidemics now occurring in many other countries. METHODS: A transmission model applicable to HIV-1 epidemics, including the use of antiretroviral therapy, is presented in a set of ordinary differential equations. The model is fitted by maximum likelihood to national HIV-1 and AIDS diagnosis data from 1980 to 2006, estimating parameters on average changes in unsafe sex and time to diagnosis. Robustness is studied with a detailed univariate sensitivity analysis, and a range of hypothetical scenarios are explored for the past and next decade. RESULTS: With a reproduction number around the epidemic threshold one, the HIV-1 epidemic amongst men having sex with men in the Netherlands is still not under control. Scenario analysis showed that in the absence of antiretroviral therapy limiting infectiousness in treated patients, the epidemic could have been more than double its current size. Ninety percent of new HIV transmissions are estimated to take place before diagnosis of the index case. Decreasing time from infection to diagnosis, which was 2.5 years on average in 2006, can prevent many future infections. CONCLUSIONS: Sexual risk behaviour amongst men having sex with men who are not aware of their infection is the most likely factor driving this epidemic.

Hollingsworth TD, Laeyendecker O, Shirreff G, Donnelly CA, Serwadda D, Wawer MJ, Kiwanuka N, Nalugoda F, Collinson-Streng A, Ssempijja V et al. 2010. HIV-1 transmitting couples have similar viral load set-points in Rakai, Uganda. PLoS Pathog, 6 (5), pp. e1000876. | Show Abstract | Read more

It has been hypothesized that HIV-1 viral load set-point is a surrogate measure of HIV-1 viral virulence, and that it may be subject to natural selection in the human host population. A key test of this hypothesis is whether viral load set-points are correlated between transmitting individuals and those acquiring infection. We retrospectively identified 112 heterosexual HIV-discordant couples enrolled in a cohort in Rakai, Uganda, in which HIV transmission was suspected and viral load set-point was established. In addition, sequence data was available to establish transmission by genetic linkage for 57 of these couples. Sex, age, viral subtype, index partner, and self-reported genital ulcer disease status (GUD) were known. Using ANOVA, we estimated the proportion of variance in viral load set-points which was explained by the similarity within couples (the 'couple effect'). Individuals with suspected intra-couple transmission (97 couples) had similar viral load set-points (p = 0.054 single factor model, p = 0.0057 adjusted) and the couple effect explained 16% of variance in viral loads (23% adjusted). The analysis was repeated for a subset of 29 couples with strong genetic support for transmission. The couple effect was the major determinant of viral load set-point (p = 0.067 single factor, and p = 0.036 adjusted) and the size of the effect was 27% (37% adjusted). Individuals within epidemiologically linked couples with genetic support for transmission had similar viral load set-points. The most parsimonious explanation is that this is due to shared characteristics of the transmitted virus, a finding which sheds light on both the role of viral factors in HIV-1 pathogenesis and on the evolution of the virus.

Shirreff G, Hollingsworth TD, Hanage WP, Fraser C. 2010. Modelling the between-host evolution of set-point viral load in HIV infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 14 pp. E79-E79. | Read more

Cauchemez S, Donnelly CA, Reed C, Ghani AC, Fraser C, Kent CK, Finelli L, Ferguson NM. 2009. Household Transmission of 2009 Pandemic Influenza A (H1N1) Virus in the United States New England Journal of Medicine, 361 (27), pp. 2619-2627. | Read more

Pellis L, Ferguson NM, Fraser C. 2009. Threshold parameters for a model of epidemic spread among households and workplaces Journal of The Royal Society Interface, 6 (40), pp. 979-987. | Read more

Truscott J, Fraser C, Hinsley W, Cauchemez S, Donnelly C, Ghani A, Ferguson N, Meeyai A. 2010. Quantifying the transmissibility of human influenza and its seasonal variation in temperate regions PLoS Currents, 1 pp. RRN1125-RRN1125. | Read more

Gras L, Jurriaans S, Bakker M, van Sighem A, Bezemer D, Fraser C, Lange J, Prins JM, Berkhout B, de Wolf F. 2009. Viral Load Levels Measured at Set-Point Have Risen Over the Last Decade of the HIV Epidemic in the Netherlands PLoS ONE, 4 (10), pp. e7365-e7365. | Read more

Goldstein E, Paur K, Fraser C, Kenah E, Wallinga J, Lipsitch M. 2009. Reproductive numbers, epidemic spread and control in a community of households Mathematical Biosciences, 221 (1), pp. 11-25. | Read more

Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins HE, Lyons EJ et al. 2009. Influenza: Making Privileged Data Public Response SCIENCE, 325 (5944), pp. 1072-1073. | Read more

Tang J, Hanage WP, Fraser C, Corander J. 2009. Identifying Currents in the Gene Pool for Bacterial Populations Using an Integrative Approach PLoS Computational Biology, 5 (8), pp. e1000455-e1000455. | Read more

Garske T, Legrand J, Donnelly CA, Ward H, Cauchemez S, Fraser C, Ferguson NM, Ghani AC. 2009. Assessing the severity of the novel influenza A/H1N1 pandemic BMJ, 339 (jul14 3), pp. b2840-b2840. | Read more

Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins HE, Lyons EJ et al. 2009. Pandemic potential of a strain of influenza A (H1N1): early findings. Science, 324 (5934), pp. 1557-1561. | Show Abstract | Read more

A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; >/=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.

Hanage WP, Fraser C, Tang J, Connor TR, Corander J. 2009. Hyper-Recombination, Diversity, and Antibiotic Resistance in Pneumococcus Science, 324 (5933), pp. 1454-1457. | Read more

Baggaley RF, Griffin JT, Chapman R, Hollingsworth TD, Nagot N, Delany S, Mayaud P, de Wolf F, Fraser C, Ghani AC, Weiss HA. 2009. Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load. AIDS, 23 (8), pp. 1005-1013. | Show Abstract | Read more

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted.

Lipsitch M, Colijn C, Cohen T, Hanage WP, Fraser C. 2009. No coexistence for free: Neutral null models for multistrain pathogens Epidemics, 1 (1), pp. 2-13. | Read more

Fraser C, Alm EJ, Polz MF, Spratt BG, Hanage WP. 2009. The Bacterial Species Challenge: Making Sense of Genetic and Ecological Diversity Science, 323 (5915), pp. 741-746. | Read more

Cited:

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Scopus

Ghani A, Baguelin M, Griffin J, Flasche S, van Hoek AJ, Cauchemez S, Donnelly C, Robertson C, White M, Truscott J et al. 2010. The early transmission dynamics of H1N1pdm influenza in the United Kingdom PLoS Currents, (JUN), | Show Abstract | Read more

We analyzed data on all laboratory-confirmed cases of H1N1pdm influenza in the UK to 10th June 2009 to estimate epidemiological characteristics. We estimated a mean incubation period of 2.05 days and serial interval of 2.5 days with infectivity peaking close to onset of symptoms. Transmission was initially sporadic but increased from mid-May in England and from early June in Scotland. We estimated 37% of transmission occurred in schools, 24% in households, 28% through travel abroad and the remainder in the wider community. Children under 16 were more susceptible to infection in the household (adjusted OR 5.80, 95% CI 2.99-11.82). Treatment with oseltamivir plus widespread use of prophylaxis significantly reduced transmission (estimated reduction 16%). Households not receiving oseltamivir within 3 days of symptom onset in the index case had significantly increased secondary attack rates (adjusted OR 3.42, 95% CI 1.51-8.55).

Pellis L, Ferguson NM, Fraser C. 2008. The relationship between real-time and discrete-generation models of epidemic spread Mathematical Biosciences, 216 (1), pp. 63-70. | Read more

Hollingsworth TD, Anderson RM, Fraser C. 2008. HIV-1 transmission, by stage of infection. J Infect Dis, 198 (5), pp. 687-693. | Show Abstract | Read more

BACKGROUND: The epidemiological impact of public health interventions targeted at reducing transmission of human immunodeficiency virus type 1 (HIV-1) during early or late-stage infection depends on the contribution of these disease stages to transmission within a particular epidemic. METHODS: Transmission hazards and durations of periods of high infectivity during primary, asymptomatic, and late-stage infection were estimated for HIV-1-serodiscordant heterosexual couples in Rakai, Uganda, by use of a robust probabilistic framework. RESULTS: Primary infection and late-stage infection were estimated to be 26 and 7 times, respectively, more infectious than asymptomatic infection. High infectiousness during primary infection was estimated to last for approximately 3 months after seroconversion, whereas high infectiousness during late-stage infection was estimated to be concentrated between 19 months and 10 months before death. CONCLUSIONS: Primary and late-stage HIV-1 infection are more infectious than previously estimated, but for shorter periods. In a homogeneous population, the asymptomatic stage of infection will typically contribute more to the net transmission of HIV-1 over the lifetime of an infected individual, because of its longer duration. The dependence of the relative contribution of infectious stages on patterns of sexual behavior and the phase of epidemics is discussed.

Grassly NC, Fraser C. 2008. Mathematical models of infectious disease transmission Nature Reviews Microbiology, 6 (6), pp. 477-487. | Read more

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Prins M, Geskus RB, Gras L, Coutinho RA, Fraser C. 2008. A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy. AIDS, 22 (9), pp. 1071-1077. | Show Abstract | Read more

OBJECTIVE: Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. DESIGN: We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. METHODS: We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. RESULTS: We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. CONCLUSION: We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Halloran ME, Ferguson NM, Eubank S, Longini IM, Cummings DAT, Lewis B, Xu S, Fraser C, Vullikanti A, Germann TC et al. 2008. Modeling targeted layered containment of an influenza pandemic in the United States Proceedings of the National Academy of Sciences, 105 (12), pp. 4639-4644. | Read more

Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. 2007. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A, 104 (44), pp. 17441-17446. | Show Abstract | Read more

The natural course of HIV-1 infection is characterized by a high degree of heterogeneity in viral load, not just within patients over time, but also between patients, especially during the asymptomatic stage of infection. Asymptomatic, or set-point, viral load has been shown to correlate with both decreased time to AIDS and increased infectiousness. The aim of this study is to characterize the epidemiological impact of heterogeneity in set-point viral load. By analyzing two cohorts of untreated patients, we quantify the relationships between both viral load and infectiousness and the duration of the asymptomatic infectious period. We find that, because both the duration of infection and infectiousness determine the opportunities for the virus to be transmitted, this suggests a trade-off between these contributions to the overall transmission potential. Some public health implications of variation in set-point viral load are discussed. We observe that set-point viral loads are clustered around those that maximize the transmission potential, and this leads us to hypothesize that HIV-1 could have evolved to optimize its transmissibility, a form of adaptation to the human host population. We discuss how this evolutionary hypothesis can be tested, review the evidence available to date, and highlight directions for future research.

Fraser C. 2007. Estimating Individual and Household Reproduction Numbers in an Emerging Epidemic PLoS ONE, 2 (8), pp. e758-e758. | Read more

Fraser C. 2007. Influenza Pandemic Vaccines: Spread Them Thin? PLoS Medicine, 4 (6), pp. e228-e228. | Read more

Gras L, Kesselring AM, Griffin JT, van Sighem AI, Fraser C, Ghani AC, Miedema F, Reiss P, Lange JMA, de Wolf F. 2007. CD4 Cell Counts of 800 Cells/mm3 or Greater After 7 Years of Highly Active Antiretroviral Therapy Are Feasible in Most Patients Starting With 350 Cells/mm3 or Greater JAIDS Journal of Acquired Immune Deficiency Syndromes, 45 (2), pp. 183-192. | Read more

Fraser C, Tomassini JE, Xi L, Golm G, Watson M, Giuliano AR, Barr E, Ault KA. 2007. Modeling the long-term antibody response of a human papillomavirus (HPV) virus-like particle (VLP) type 16 prophylactic vaccine Vaccine, 25 (21), pp. 4324-4333. | Read more

Turner KME, Hanage WP, Fraser C, Connor TR, Spratt BG. 2007. Assessing the reliability of eBURST using simulated populations with known ancestry BMC Microbiology, 7 (1), pp. 30-30. | Read more

Fraser C, Hanage WP, Spratt BG. 2007. Recombination and the Nature of Bacterial Speciation Science, 315 (5811), pp. 476-480. | Read more

Klinkenberg D, Fraser C, Heesterbeek H. 2006. The Effectiveness of Contact Tracing in Emerging Epidemics PLoS ONE, 1 (1), pp. e12-e12. | Read more

Hanage WP, Fraser C, Spratt BG. 2006. Sequences, sequence clusters and bacterial species Philosophical Transactions of the Royal Society B: Biological Sciences, 361 (1475), pp. 1917-1927. | Read more

Hanage WP, Spratt BG, Turner KME, Fraser C. 2006. Modelling bacterial speciation Philosophical Transactions of the Royal Society B: Biological Sciences, 361 (1475), pp. 2039-2044. | Read more

Grassly NC, Fraser C, Wenger J, Deshpande JM, Sutter RW, Heymann DL, Aylward RB. 2006. New Strategies for the Elimination of Polio from India Science, 314 (5802), pp. 1150-1153. | Read more

Grassly NC, Fraser C. 2006. Seasonal infectious disease epidemiology Proceedings of the Royal Society B: Biological Sciences, 273 (1600), pp. 2541-2550. | Read more

Wu JT, Riley S, Fraser C, Leung GM. 2006. Reducing the Impact of the Next Influenza Pandemic Using Household-Based Public Health Interventions PLoS Medicine, 3 (9), pp. e361-e361. | Read more

Ferguson NM, Cummings DAT, Fraser C, Cajka JC, Cooley PC, Burke DS. 2006. Strategies for mitigating an influenza pandemic Nature, 442 (7101), pp. 448-452. | Read more

Griffin JT, Fraser C, Gras L, de Wolf F, Ghani AC. 2006. The Effect on Treatment Comparisons of Different Measurement Frequencies in Human Immunodeficiency Virus Observational Databases American Journal of Epidemiology, 163 (7), pp. 676-683. | Read more

LEUNG GM, LIM WW, HO L-M, LAM T-H, GHANI AC, DONNELLY CA, FRASER C, RILEY S, FERGUSON NM, ANDERSON RM, HEDLEY AJ. 2006. Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups Epidemiology and Infection, 134 (02), pp. 211-211. | Read more

Hanage WP, Fraser C, Spratt BG. 2006. The impact of homologous recombination on the generation of diversity in bacteria Journal of Theoretical Biology, 239 (2), pp. 210-219. | Read more

Fidler S, Fraser C, Fox J, Tamm N, Griffin JT, Weber J. 2006. Comparative potency of three antiretroviral therapy regimes in primary HIV infection AIDS, 20 (2), pp. 247-252. | Read more

Fraser C. 2005. HIV recombination: what is the impact on antiretroviral therapy? Journal of The Royal Society Interface, 2 (5), pp. 489-503. | Read more

Ferguson NM, Donnelly CA, Hooper J, Ghani AC, Fraser C, Bartley LM, Rode RA, Vernazza P, Lapins D, Mayer SL, Anderson RM. 2005. Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients Journal of The Royal Society Interface, 2 (4), pp. 349-363. | Read more

Ferguson NM, Cummings DAT, Cauchemez S, Fraser C, Riley S, Meeyai A, Iamsirithaworn S, Burke DS. 2005. Strategies for containing an emerging influenza pandemic in Southeast Asia Nature, 437 (7056), pp. 209-214. | Read more

Fraser C, Hanage WP, Spratt BG. 2005. Neutral microepidemic evolution of bacterial pathogens Proceedings of the National Academy of Sciences, 102 (6), pp. 1968-1973. | Read more

Grassly NC, Fraser C, Garnett GP. 2005. Host immunity and synchronized epidemics of syphilis across the United States Nature, 433 (7024), pp. 417-421. | Read more

Ghani AC, Donnelly CA, Cox DR, Griffin JT, Fraser C, Lam TH, Ho LM, Chan WS, Anderson RM, Hedley AJ, Leung GM. 2005. Methods for estimating the case fatality ratio for a novel, emerging infectious disease. Am J Epidemiol, 162 (5), pp. 479-486. | Show Abstract | Read more

During the course of an epidemic of a potentially fatal disease, it is important that the case fatality ratio be well estimated. The authors propose a novel method for doing so based on the Kaplan-Meier survival procedure, jointly considering two outcomes (death and recovery), and evaluate its performance by using data from the 2003 epidemic of severe acute respiratory syndrome in Hong Kong, People's Republic of China. They compare this estimate obtained at various points in the epidemic with the case fatality ratio eventually observed; with two commonly quoted, naïve estimates derived from cumulative incidence and mortality statistics at single time points; and with estimates in which a parametric mixture model is used. They demonstrate the importance of patient characteristics regarding outcome by analyzing subgroups defined by age at admission to the hospital.

Donnelly CA, Fisher MC, Fraser C, Ghani AC, Riley S, Ferguson NM, Anderson RM. 2004. Epidemiological and genetic analysis of severe acute respiratory syndrome The Lancet Infectious Diseases, 4 (11), pp. 672-683. | Read more

Anderson RM, Fraser C, Ghani AC, Donnelly CA, Riley S, Ferguson NM, Leung GM, Lam TH, Hedley AJ. 2004. Epidemiology, transmission dynamics and control of SARS: the 2002-2003 epidemic Philosophical Transactions of the Royal Society B: Biological Sciences, 359 (1447), pp. 1091-1105. | Read more

Bocharov G, Ludewig B, Bertoletti A, Klenerman P, Junt T, Krebs P, Luzyanina T, Fraser C, Anderson RM. 2004. Underwhelming the immune response: Effect of slow virus growth on CD(8+) T-lymphocyte responses JOURNAL OF VIROLOGY, 78 (11), pp. 6079-6079. | Read more

Fraser C, Riley S, Anderson RM, Ferguson NM. 2004. Factors that make an infectious disease outbreak controllable Proceedings of the National Academy of Sciences, 101 (16), pp. 6146-6151. | Read more

Bocharov G, Ludewig B, Bertoletti A, Klenerman P, Junt T, Krebs P, Luzyanina T, Fraser C, Anderson RM. 2004. Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses. J Virol, 78 (5), pp. 2247-2254. | Show Abstract | Read more

The speed of virus replication has typically been seen as an advantage for a virus in overcoming the ability of the immune system to control its population growth. Under some circumstances, the converse may also be true: more slowly replicating viruses may evoke weaker cellular immune responses and therefore enhance their likelihood of persistence. Using the model of lymphocytic choriomeningitis virus (LCMV) infection in mice, we provide evidence that slowly replicating strains induce weaker cytotoxic-T-lymphocyte (CTL) responses than a more rapidly replicating strain. Conceptually, we show a "bell-shaped" relationship between the LCMV growth rate and the peak CTL response. Quantitative analysis of human hepatitis C virus infections suggests that a reduction in virus growth rate between patients during the incubation period is associated with a spectrum of disease outcomes, from fulminant hepatitis at the highest rate of viral replication through acute resolving to chronic persistence at the lowest rate. A mathematical model for virus-CTL population dynamics (analogous to predator [CTL]-prey [virus] interactions) is applied in the clinical data-driven analysis of acute hepatitis B virus infection. The speed of viral replication, through its stimulus of host CTL responses, represents an important factor influencing the pathogenesis and duration of virus persistence within the human host. Viruses with lower growth rates may persist in the host because they "sneak through" immune surveillance.

Garnett GP, Fraser C. 2003. Let it be sexual - selection, aggregation and distortion used to construct a case against sexual transmission International Journal of STD & AIDS, 14 (11), pp. 782-784. | Read more

Riley S. 2003. Transmission Dynamics of the Etiological Agent of SARS in Hong Kong: Impact of Public Health Interventions Science, 300 (5627), pp. 1961-1966. | Read more

Donnelly CA, Ghani AC, Leung GM, Hedley AJ, Fraser C, Riley S, Abu-Raddad LJ, Ho L-M, Thach T-Q, Chau P et al. 2003. Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong The Lancet, 361 (9371), pp. 1761-1766. | Read more

FRASER CHRISTOPHE, FERGUSON NEILM, DE WOLF FRANK, GHANI AZRAC, GARNETT GEOFFP, ANDERSON ROYM. 2002. Antigen-driven T-cell Turnover Journal of Theoretical Biology, 219 (2), pp. 177-192. | Read more

Ghani AC, Ferguson NM, Fraser C, Donnelly CA, Danner S, Reiss P, Lange J, Goudsmit J, Anderson RM, De Wolf F. 2002. Viral Replication Under Combination Antiretroviral Therapy: A Comparison of Four Different Regimens JAIDS Journal of Acquired Immune Deficiency Syndromes, 30 (2), pp. 167-176. | Read more

Fraser C, Ferguson NM, Anderson RM. 2001. Quantification of intrinsic residual viral replication in treated HIV-infected patients Proceedings of the National Academy of Sciences, 98 (26), pp. 15167-15172. | Read more

Frazer C, Ferguson NM, Wolf FD, Anderson RM. 2001. The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications Proceedings of the Royal Society B: Biological Sciences, 268 (1481), pp. 2085-2095. | Read more

Ferguson NM, Fraser C, Anderson RM. 2001. Viral dynamics and anti-viral pharmacodynamics: rethinking in vitro measures of drug potency Trends in Pharmacological Sciences, 22 (2), pp. 97-100. | Read more

Fraser C, Ferguson NM, Ghani AC, Prins JM, Lange JM, Goudsmit J, Anderson RM, de Wolf F. 2000. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS, 14 (6), pp. 659-669. | Show Abstract | Read more

BACKGROUND: Treatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells. OBJECTIVE: To analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis. DESIGN AND METHODS: A mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework. RESULTS: We show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir. CONCLUSIONS: Our analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.

Ferguson NM, deWolf F, Ghani AC, Fraser C, Donnelly CA, Reiss P, Lange JM, Danner SA, Garnett GP, Goudsmit J, Anderson RM. 1999. Antigen-driven CD4+ T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy. Proc Natl Acad Sci U S A, 96 (26), pp. 15167-15172. | Show Abstract | Read more

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.

Fraser C, Hollowood TJ. 1997. Semi-classical quantization in N = 4 supersymmetric Yang-Mills theory and duality Physics Letters B, 402 (1-2), pp. 106-112. | Read more

Fraser C, Hollowood TJ. 1997. On the weak coupling spectrum of N = 2 supersymmetric SU(n) gauge theory Nuclear Physics B, 490 (1-2), pp. 217-235. | Read more

Dorey N, Fraser C, Hollowood TJ, Kneipp MAC. 1996. S-duality in N = 4 supersymmetric gauge theories with arbitrary gauge group Physics Letters B, 383 (4), pp. 422-428. | Read more

Dudas G, Carvalho LM, Bedford T, Tatem AJ, Baele G, Faria NR, Park DJ, Ladner JT, Arias A, Asogun D et al. 2017. Virus genomes reveal factors that spread and sustained the Ebola epidemic. Nature, 544 (7650), pp. 309-315. | Show Abstract | Read more

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.

Lehtinen S, Blanquart F, Croucher NJ, Turner P, Lipsitch M, Fraser C. 2017. Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage. Proc Natl Acad Sci U S A, 114 (5), pp. 1075-1080. | Show Abstract | Read more

Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

Blanquart F, Grabowski MK, Herbeck J, Nalugoda F, Serwadda D, Eller MA, Robb ML, Gray R, Kigozi G, Laeyendecker O et al. 2016. A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda. Elife, 5 (NOVEMBER2016), | Show Abstract | Read more

Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals.

Lythgoe KA, Blanquart F, Pellis L, Fraser C. 2016. Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics. PLoS Biol, 14 (10), pp. e1002567. | Show Abstract | Read more

The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body's viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.

Croucher NJ, Mostowy R, Wymant C, Turner P, Bentley SD, Fraser C. 2016. Horizontal DNA Transfer Mechanisms of Bacteria as Weapons of Intragenomic Conflict. PLoS Biol, 14 (3), pp. e1002394. | Show Abstract | Read more

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated.

Ratmann O, van Sighem A, Bezemer D, Gavryushkina A, Jurriaans S, Wensing A, de Wolf F, Reiss P, Fraser C. 2016. Sources of HIV infection among men having sex with men and implications for prevention Science Translational Medicine, 8 (320), pp. 320ra2-320ra2. | Read more

Fraser C, Lythgoe K, Leventhal GE, Shirreff G, Hollingsworth TD, Alizon S, Bonhoeffer S. 2014. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science, 343 (6177), pp. 1243727. | Show Abstract | Read more

Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

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