Grant: Operating Grant

Approximately 5% of HIV-infected individuals can be classified as slow progressors (SP) because they remain healthy with normal CD4 counts for >7 years and/or control HIV viral load without treatment. Disappointing results from recent HIV vaccine trials has led to increased interest in studying how SP control HIV infection. This information may suggest therapies for HIV infected progressors so that they too can better control their infection. This knowledge may also suggest strategies for improving the design of effective vaccines for HIV. To this end a Canadian-wide cohort of HIV infected SP was recently set up with funding from CIHR and is currently recruiting and following SP. This cohort will be the source of samples for the research project submitted here. The project will study mechanisms underlying how Natural Killer (NK) cells influence the rate of HIV disease progression. NK cells are key players in innate immune responses to viruses such as HIV. Epidemiological studies have found that the co-expression of certain NK receptors called KIR and the molecules they recognize on neighboring cells (HLA) is associated with slower time to AIDS and viral load control. Indeed, certain KIR/HLA combinations are over-represented among SP. Our hypothesis is that the association between KIR/HLA and rate of HIV disease progression is related to how various KIR/HLA interactions determine the potency of NK activation. We have the expertise and tools to measure features of NK activation such as killing HIV infected targets and secreting factors called cytokines that suppress HIV replication. We will assess the requirements for activation of NK anti-viral function at the level of KIR/HLA interactions and how this translates into the distribution and potency of NK subsets with anti-viral activity when NK cells are stimulated with HLA negative target cells or autologous HIV infected CD4+ T cells.