The Impact of T Cell Immunity on HIV-1 Diversity

Despite intensive research there is still no effective HIV vaccine. There has been a recent international call to suspend clinical vaccine trials and to concentrate on the underlying molecular biology that determines how and why a vaccine might succeed. This project aims to address these fundamental issues.

HIV has the ability to adapt to its environment in a manner unprecedented in any other organism. This is reflected by the rapid development of resistance to antiviral drugs and by the development of mutations that camouflage the virus from the immune system. This project will demonstrate how, in a population of newly infected HIV positive individuals, the virus that has been transmitted will adapt to a key component of the immune system of the new host and simultaneously revert many of the mutations acquired during infection of the previous host. As patients progress to AIDS we hope to show how the immune system is no longer able to exert any selection pressure on the virus.

We will explore the key components of our immune system to see whether adaptation to one may be disadvantageous to others. If so, the impact of viral evolution on the efficacy of our immune system may be more significant than realised.

Aims
This project aims to determine the degree to which HIV is evolving at the population level to adapt to the human immune system.
Objectives
To explore the impact of HLA on the long-term evolution of HIV within a population.
o To define the evolution of HLA-associated genetic diversity from the time of infection until established chronic infection by tracking HIV sequence variation in a strictly defined group of several hundred seroconverters.
o To study how the onset of AIDS impacts on the fate of HLA-associated viral mutations.
To test whether identified polymorphisms facilitate adaptation to both HLA Class I subtypes and ‘supertypes‘.
o To assess the functional significance of identified polymorphisms using assays of HLA Class I binding and T cell activation.
o To identify cross-recognition of HIV-1 antigens by multiple HLA Class I subtypes according to the principle of ‘supertypes‘.
Design
This project will investigate a unique group of predominantly untreated HIV seroconverters that will represent the largest studied cohort of this sort to date. The study will involve both longitudinal and cross-sectional analyses. Stored samples will be tested retrospectively and those from newly recruited patients, prospectively.

Methodology
We have established collaborations to study four independent patient cohorts. Samples from HIV seroconverters will be tested retrospectively from St. Mary‘s Hospital in London (n=105) and from the Swiss HIV cohort (n=100). In addition, new patients will be recruited prospectively from the ‘Spartac‘ seroconverter cohort (total predicted n=450). Chronically infected HIV+ve patients will be recruited from the Free State ARV programme in South Africa (n>2000).

Longitudinal sequence analysis of viral RNA and proviral DNA by population and clonal sequencing will identify patterns of mutation and reversion and, specifically, the evolution of association of HIV polymorphisms with Class I HLA molecules. Bindi assess the interaction between variant peptides and HLA Class I molecules. Functional assays ( -interferon ELISpot) will be used to study the ability of variant peptides to induce an immune response.

Scientific and Medical Opportunities
The project will provide a detailed description of the HIV antigenic challenge. We will gain understanding of the population level evolution of HIV with inferences for changes in pathogenesis of the epidemic. The detailed sequence data will contribute towards understanding the HIV response to vaccine challenge - crucial information that is currently being demanded at an international level to enable the design of a sustainable vaccine.