Dr Lucy Dorrell
|Technology Exchange:||Cell sorting, Cellular immunology, Flow cytometry, Microscopy (Confocal) and Vaccine production and evaluation|
|Scientific Themes:||Immunology & Infectious Disease|
|Keywords:||hiv, t cell, vaccine, clinical trial, viral vector and antiretroviral|
The goal of our research is to understand the mechanisms that determine successful containment of HIV and how these can be exploited in the development of vaccines and T cell-based therapies. Our work encompasses studies at the single cell level, patient cohorts and clinical trials.
We are currently focusing on the following areas of investigation:
New approaches to reducing HIV reservoirs
Natural immune responses keep HIV under control to some degree in most people but are unable to prevent disease progression. ART stops viral replication but is not able to eliminate cells that harbour dormant (the latent reservoir) HIV. New approaches are needed to eliminate this viral reservoir. We are testing ART in combination with vaccines and other agents in clinical trials. The vaccines comprise a conserved region immunogen, HIVconsv, delivered by replication-defective chimpanzee adenovirus and MVA vectors. These trials are among the first to evaluate latent HIV reservoirs before and after vaccination. In addition, in collaboration with Immunocore Ltd, Oxon, we are investigating the potency of novel engineered immune-mobilising T cell receptors-based drugs (‘ImmTAVs’) that are designed to clear HIV-infected cells.
Immunological correlates of HIV control
We demonstrated that ex vivo CD8+ T cell viral inhibitory activity measured in HIV-positive patients is correlated with viral load set-point and is predictive of the rate of HIV disease progression. A critical next step in the development of preventive and therapeutic vaccines is to define the components of an HIV immunogen that could induce CD8+ T cells with broad and potent inhibitory capacity. Through collaboration with the NIAID-funded HIV Vaccine Trials Network and Duke University NC, we have shown that targeting of selected vulnerable regions within the HIV proteome by CD8+ T cells is strongly associated with their capacity to inhibit HIV replication in vitro.
This work has paved the way for new imaging studies of HIV-immune cell interactions using the first ever containment level 3 high-resolution microscopy facility at the Weatherall Institute of Molecular Medicine.
Prevention of co-infections
As HIV-positive people are living longer, prevention of comorbidities has become a priority. PEACHI is an EU FP7-funded project to develop vaccines for prevention of hepatitis C and HIV co-infections. The PEACHI consortium brings together expertise in the HIV and HCV fields, with European partners from academia (Oxford, St. James Hospital Dublin, Kantosspital St Gallen) and industry (GSK and Okairos) (www.peachi.eu). We are planning a series of vaccine trials to evaluate vaccinations with HIV and/or HCV immunogens, each delivered by replication-defective chimpanzee adenovirus and MVA vectors, in healthy volunteers and in HIV-positive HCV-uninfected patients on ART. We will also test next-generation viral vectored vaccines employing an HCV immunogen fused to HLA class II invariant chain. These clinical studies will be complemented by comprehensive immunomonitoring with the goal of identifying possible immune correlates that could be tested in future efficacy trials.
We are starting a new project to develop new multi-genotype vaccines for therapy of human papilloma virus (HPV) infections that are responsible for cervical cancer (0.5 million cases per year worldwide) and other anogenital cancers. We exploit the same potent viral vectors for delivery of a novel HPV immunogen that have proven safe and immunogenic for HIV and HCV.
|Prof Tomas Hanke||Jenner Institute||University of Oxford||United Kingdom|
|Prof Brian J Angus FRCP||Tropical Medicine||University of Oxford||United Kingdom|
|Dr Cameron Holloway||University of Oxford||United Kingdom|
|Prof Stefan Neubauer FMedSci FRCP (RDM)||Cardiovascular Medicine||University of Oxford||United Kingdom|
|Dr Christian Brander||Fundacio irsiCaixa||Spain|
|Dr Persephone Borrow||NDM Research Building||University of Oxford||United Kingdom|
|Dr Benedikt M Kessler||Target Discovery Institute||University of Oxford||United Kingdom|
|Prof Johnson Mak||Deakin University||Australia|
|Dr Arturo Reyes-Sandoval||Jenner Institute||University of Oxford||United Kingdom|
|Prof Ellie (Eleanor) Barnes||Experimental Medicine Division||University of Oxford||United Kingdom|
Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro. Hide abstract
Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection. Hide abstract
The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions. Hide abstract
HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. Hide abstract
The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10(-2) to 8×10(-5), and by nearly two-fold (p<0.001) at the optimal MOI tested (10(-2)). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs. Hide abstract
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. Hide abstract
JOURNAL OF INFECTIOUS DISEASES, 206 (4), pp. 552-561. | Read more2012. Antiviral Inhibitory Capacity of CD8+ T cells Predicts the Rate of CD4+ T-Cell Decline in HIV-1 Infection
Science, 324 (5932), pp. 1264-1265. | Read more2009. A step ahead on the HIV collaboratory.
Affordable therapeutic strategies that induce sustained control of human immunodeficiency virus type 1 (HIV-1) replication and are tailored to the developing world are urgently needed. Since CD8(+) and CD4(+) T cells are crucial to HIV-1 control, stimulation of potent cellular responses by therapeutic vaccination might be exploited to reduce antiretroviral drug exposure. However, therapeutic vaccines tested to date have shown modest immunogenicity. In this study, we performed a comprehensive analysis of the changes in virus-specific CD8(+) and CD4(+) T-cell responses occurring after vaccination of 16 HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara-vectored vaccine expressing the consensus HIV-1 clade A Gag p24/p17 sequences and multiple CD8(+) T-cell epitopes during highly active antiretroviral therapy. We observed significant amplification and broadening of CD8(+) and CD4(+) gamma interferon responses to vaccine-derived epitopes in the vaccinees, without rebound viremia, but not in two unvaccinated controls followed simultaneously. Vaccine-driven CD8(+) T-cell expansions were also detected by tetramer reactivity, predominantly in the CD45RA(-) CCR7(+) or CD45RA(-) CCR7(-) compartments, and persisted for at least 1 year. Expansion was associated with a marked but transient up-regulation of CD38 and perforin within days of vaccination. Gag-specific CD8(+) and CD4(+) T-cell proliferation also increased postvaccination. These data suggest that immunization with MVA.HIVA is a feasible strategy to enhance potentially protective T-cell responses in individuals with chronic HIV-1 infection. Hide abstract
Harnessing T cells for HIV-1 control and elimination
Currently, the only effective treatment option for people with HIV-1 infection is a lifelong combination antiretroviral drug regimen (ART) . A stable reservoir of latently infected long-lived CD4+ T cells is established during primary infection and persists despite suppression of viraemia by ART. Understanding how to combine drug treatments and immune-based interventions to eliminate this reservoir is now a major priority for the field. The relationship between virus-specific CD8+ T cell ...