Role of polyfunctional and proliferative CD8+ T cell responses in HIV-1 infection

The limited success of HIV vaccine candidates to date highlights our need to better characterize protective cell-mediated immunity. Understanding correlates CD8+ T cell protection against HIV infection and progressive disease is essential for informing effective vaccine development, design and evaluation. CD8+ T cell responses with a robust polyfunctional and proliferative component are strongly linked to better disease outcomes. However, the specificity of polyfunctional and proliferative CD8+ T cell responses has not been thoroughly investigated. Additionally, the specificity of memory subsets and their connection to polyfunctionality and proliferation responses has not been adequately assessed. We address these gaps in knowledge and provide a better understanding of the fine specificity of HIV-specific CD8+ T cell responses. We hypothesize that the epitopes recognized by central memory (TCM) and effector memory (TEM) CD8+ T cells, defined by functional attributes, differ in chronic HIV-1 infection. Additionally, we hypothesize that polyfunctional and proliferative responses will better correlate with protection in HIV disease progression. The qualities of CD8+ T cell responses were evaluated using polyfunctional flow cytometry measuring both functional and phenotypic attributes of both TEM and TCM subsets in HIV infected individuals. We evaluated the quality and evolution of CD8+ T cell responses in HIV infected individuals shortly after seroconversion through to the chronic phase of infection, finding that early polyfunctional responses may result in better HIV disease outcomes. Additionally, we show that epitope-specificity differs between short-term cytokine/chemokine secretion and long-term proliferative assays. Importantly, we show that, at a cohort level, particular epitopes preferentially elicit specific qualities of CD8+ T cell responses in preference to others. This research improves our understanding of HIV pathogenesis and indicates that we can identif