HIV-1 immunity: Innate immune correlates and vaccine responses

HIV-1 infection represents one of the greatest threats to global health in the modern era. Efforts to develop a vaccine against HIV-1 have been hampered by a lack of knowledge regarding what type of immune response best affords protection from HIV-1 infection and subsequent disease progression. To elucidate immune mechanisms that may serve to protect individuals against HIV-1 infection and disease by mounting altered innate pro-inflammatory or antiviral responses, I investigated Toll-like receptor (TLR) function and genetic polymorphisms in cohorts of individuals with varying susceptibility to HIV-1 infection (exposed seronegative [ES] individuals) and variable courses of disease progression. I discovered that myeloid dendritic cells from ES individuals exhibited reduced responsiveness to LPS when compared to low-risk HIV-uninfected controls, and, separately, that a common non-synonymous TLR4 single-nucleotide polymorphism, D299G, was associated with higher viral loads in HIV-infected subjects. In addition, to determine how T-cell responses to an adenovirus-vector HIV-1 vaccine candidate are affected by pre-existing adenovirus-specific immunity, I developed a novel cytokine profiling assay to measure T-cell responses to both the gag transgene and Adenovirus serotype 5 (Ad5) vector in an MRKAd5 HIV-1 Gag phase I trial. I determined that pre-existing Ad5 immunity is a potent determinant of the HIV-specific vaccine-induced response, and that the presence of Ad5 neutralizing antibodies is not a useful predictor of cellular responses to the Ad5 vector. Altogether, my results demonstrate that variability among individual innate immune responses and pre-existing natural infections may contribute to the varying outcomes of exposure to HIV antigens, both in the context of natural infection and vaccination.