Aspects of CD8+ T cell and NK cell recognition that impact on MHC class I associations with HIV-1 disease progression

Over 50% of the 40 Million people estimated to be infected with HIV-1 live in sub-Saharan Africa alone. With only a small proportion of developing countries having access to the anti-retroviral therapies readily available in the Western world, an alternative approach is urgently required to control the spread of this virus. One promising strategy is the production of a vaccine to either prevent infection and/or augment immunity against HIV-1 during disease. Cells of the immune system, namely CD8+ T lymphocytes, effectively control the growth of HIV-1, and many vaccines in current clinical trials are designed to evoke CD8+ T cell mediated immunity.The interaction between this virus and the host s immune system is complex, however, and the level of viral control is variable in HIV-1 infected individuals. This, in turn, makes it difficult to design a truly effective HIV vaccine. Major Histocompatibility Complex (MHC) class I molecules represent important host factors that influence disease outcome - these molecules direct the CD8+ T cell responses against HIV-1, and therefore influence disease severity. By studying the fine details of diverse CD8+ T cell responses in distinct HIV-1 infected patient groups I hope to identify the reasons why some CD8+ T cell responses are more effective than others in controlling the replication of HIV-1. Certain MHC class I molecules also interact with different cells of the immune system, namely Natural Killer (NK) cells, and this also impacts on disease dynamics in HIV-1 infection. I also wish to study aspects of NK and MHC interactions that might explain this phenomenon, as this could influence the design and implementation of future vaccine regimens.

The natural history of HIV-1 infection is extremely heterogeneous, reflecting the complex interplay between viral and host genetic determinants that influence disease outcome. Of the major host factor influencing HIV-1 disease progression, the MHC class I loci is consistently described. MHC class I molecules select the repertoire of viral epitopes presented to CD8+ T cells and shape the immune response against HIV. Defining precise factors that explain influence of the MHC class I molecules on long term survival is crucial to our understanding of HIV-1-mediated disease pathogenesis, and to further the design of effective CD8+ T cell targeted vaccines and management of vaccination regimens.
The MHC class I molecules B*27 and B*57 represent favourable host genetic determinants that associate with slower disease progression. Whilst strong CD8+ T cell responses to a single and highly conserved immunodominant epitope account for the association of HLA B*27 with prolonged survival, the correlates relating HLA B*57 to favourable outcome are complex, and distinct B*57-restricted CD8+ T lymphocyte responses appear differentially effective in controlling HIV-1 replication. I wish to study features of CD8+ T cell recognition that might explain this phenomenon, including aspects of T cell receptor usage and biophysical parameters, in addition to qualitatively assessing individual B*57-restricted immune responses. I will also investigate whether the efficacy of B*57-restricted responses relates to features of antigen processing and presentation.
The influence of innate immune system on MHC class I associations with prolonged survival in HIV-1 infection has also be demonstrated, specifically, the synergistic association of a subset of MHC class I Bw4 molecules and an NK receptor from the Killer Inhibitory receptor (KIR) gene family called KIR3DS1. KIRs comprise a distinct group of MHC class I receptors, and are expressed on Natural Killer (NK) cells and a subset of T lymphocytes. They comprise both inhibitory and stimulatory receptors, of which KIR3DS1 is a putative stimulatory receptor, and allele of the inhibitory KIR3DL1 molecule. It is imperative that we define the relationship between KIR3DS1 and the associating MHC class I molecules, so as to understand natural disease pathogenesis and to elucidate whether the KIR haplotype of vaccine recipients should be considered when designing HIV-1 vaccine regimens. I aim to determine the ligand specificity of KIR3DS1, and to evaluate features of KIR3DS1 recognition that might explain its association with prolonged survival during HIV-1 infection.