CD8+ T cells in HIV: The impact of responses to consensus HIV epitopes and their natural variants and implications for differential disease progression
For three decades, CD8+ T cells have been implicated in the control of HIV, ever since early studies revealed that a temporal correlation exists between the emergence of CD8+ T cells and the decline of viral loads in HIV infection. Subsequently, a large body of research focusing on the impact of CD8+ T cell responses on HIV has been produced. The central aim of this thesis was to investigate the relationship between CD8+ T cells and control of HIV, with a focus on the differences in CD8+ T cell responses to consensus HIV epitopes and their naturally occurring variants, as well as CD8+ T cell-mediated infection inhibition in disease progression groups. Previous work has indicated that mutations in HIV epitopes of just one or two amino acids can have a drastic impact on the resulting CD8+ T cell response. Considering the extreme genetic diversity of the virus, understanding how CD8+ T cell responses differ to these common natural variants is essential when trying to elucidate what the best targets for an HIV vaccine would be. It was hypothesized that CD8+ T cell responses to consensus HIV epitopes, as a consequence of them being more common in nature, would be more frequent, polyfunctional, and proliferative than responses to their less common variants, as well as being associated with better disease outcomes. After assessing these functional parameters in response to four consensus HIV epitopes and their natural variants, this hypothesis was rejected, and it was determined that the consensus status of an epitope could not reliably dictate the resulting CD8+ T cell response. Rather, it seems more likely that the particular epitope being presented, combined with the HLA allele presenting it and the particular TCRs binding to it, have a much larger impact on the CD8+ T cell response. In the course of this study, the Gag TL9 T variant epitope was identified as stimulating a CD8+ T cell response that is considered to be beneficial in HIV infection. Responses to this epitope were also associated with higher CD4 counts, which, taken together, suggests that this epitope has potential for further research as an HIV vaccine target. In the spectrum of HIV infection, there is a significant amount of heterogeneity in disease progression, whereby some individuals progress to disease more slowly, and others, more rapidly. The mechanisms by which this differential disease progression occurs are not completely understood. It was hypothesized that CD8+ T cells from individuals who progress to disease more slowly (long term non- progressors) would be able to inhibit p24 production in-vitro to a higher degree than CD8+ T cells from individuals who progress more rapidly or at a normal rate (RP/NP). This hypothesis was confirmed, as CD8+ T cells from LTNP individuals were significantly better at inhibiting both secreted and intracellular p24 levels than CD8+ T cells from RP/NPs in an in vitro viral inhibition assay. Overall, these studies confirm that CD8+ T cells are important in control of HIV, as indicated by an increased capacity to inhibit p24 in LTNP individuals. However, it is also clear from this work that the role that CD8+ T cells play in HIV infection is complex, and the responses to HIV epitopes can vary greatly.
HIV, CD8+ T cells, Kenya, Immunology, Viral inhibition