Lucy Dorrell: How can we live with HIV?
NDM Research Building
Therapeutic HIV vaccines: Prior setbacks, current advances, and future prospects
|Laser scanning confocal microscopy image of human primary CD8+ T cells (magenta) forming a conjugate with an HIV-infected primary CD4+ T cell (p24 antigen - green) leading to cell death through upregulation of caspase-3 (red) in the infected cell. Image credit: Zoe Wallace, Nuffield Department of Medicine.|
Professor of Immunology
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.
Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study).
Mothe B. et al, (2019), EClinicalMedicine, 11, 65 - 80
MHC-II invariant chain adjuvanted chimpanzee adenoviral and MVA hepatitis C vaccines elicit unprecedented levels of anti-viral T-cell immune responses in humans
Esposito I. et al, (2019), JOURNAL OF HEPATOLOGY, 70, E3 - E4
MS-Rescue: A Computational Pipeline to Increase the Quality and Yield of Immunopeptidomics Experiments.
Andreatta M. et al, (2019), Proteomics, 19
Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors
López-Camacho C. et al, (2018), Nature Communications, 9
Mechanisms of Abrupt Loss of Virus Control in a Cohort of Previous HIV Controllers
Rosás-Umbert M. et al, (2018), Journal of Virology, 93