HIV-specific immunity Acute Infection Early disease (AIED)

An estimated 33 millions of individuals are currently infected with HIV worldwide; the majority of them lives in Sub-Saharan Africa and do not have access to antiretroviral treatment despite all efforts from the international community. Despite efforts made in the area of prevention and treatment, the virus is still continuing to infect people worldwide. It is therefore believed that a safe, effective and affordable vaccine is the best solution to the global HIV epidemic. Unfortunately, despite recent advances in our understanding of HIV-1 pathogenesis and immunology, this goal remains elusive. Vaccination started with Edward Jenner's success with smallpox immunization in 1796. Since then, a number of successful vaccines have been developed including, polio, measles, mumps, rubella, hepatitis B and influenza. The quest for an effective HIV-1 vaccine has proved to be very difficult because of specific characteristic of the virus, the lack of understanding of correlates of protection from infection and disease progression and the inadequacy of assays currently used to evaluate immune responses. This thesis focuses on characterizing the qualitative and quantitative features of HIV-specific T cell immune responses in individuals in primary infection as well as their fate in progressive HIV disease. The rationale for studying individuals in primary HIV infection is that events during this phase of infection are believed to set the stage for the subsequent course of infection. We first developed an ELISPOT assay able to detect both IFN-γ and IL-2 secretion simultaneously. This assay was used for the comprehensive screening and characterization of responses to the entire HIV proteome in individuals during primary and chronic infections. We showed that the dual color ELISPOT assay developed in our laboratory is capable of detecting 3 functional lymphocyte populations: single IFN-γ, dual IFN-γ/IL-2 and single IL-2 secreting cells. We demonstrated that this assay is sensitive, reproducible and able to detect both CD4+ and CD8+ T cell responses. We found that the breadth and magnitude of responses directed against the entire HIV proteome was not associated with control of viremia. Interestingly, we found an association between Gag p55-, and particularly Gag p24-specific responses, with concurrent and set point VL, for all 3 functional subsets detected. We also showed that the contribution of IFN-γ/IL-2 secreting cells to the total HIV-specific response as well as their proliferative capacity was reduced by the 2nd year of HIV infection. Taken together, we believe that the results presented in this thesis contribute to furthering our understanding of immune correlates of protection from disease progression. These results suggest that vaccine strategies designed to focus immune responses against Gag may have a better chance of controlling HIV viral replication to levels that slow disease progression and reduce HIV transmission both at the individual and the population levels.

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