The innate immune effector cell response against HIV-1

Since being identified as the cause of AIDS in 1983, HIV-1 infection has reached pandemic proportions. Despite public awareness about prevention, the growing incidence of HIV-1 infection and the limitations of current antiretroviral therapy underscore the imperative need for a vaccine. Understanding the basis of an immune response that controls infection or provides sterilizing immunity remains a major goal in the search for effective vaccines or immunotherapies. Research into correlates of immunity to HIV-1 have largely focused on CD8+ T cells or neutralising antibodies (NAbs) but to date these responses have not proved effective in containing viral replication in vaccinees who become infected. Natural killer cells (NKs), monocytes (MCs), and neutrophils (PMNs) are cells of the innate immune system with intrinsic cytotoxic function that can be enhanced by antibodies (Abs) in what is termed antibody-dependent cellular cytotoxicity (ADCC). In my studies I investigated the production of PMNs from human stem cells, the elimination of HIV-1 infected cells by these effector cells, the modulation of cellular cytotoxicity by Ab, and characterized how Abs facilitate a potent ADCC response. I developed a novel flow cytometry assay to measure cytotoxic activity against HIV-1 infected CD4+ T cells. Using this, effector cells were shown to have different cytotoxic capacities which were enhanced by Ab. Comparing ADCC mediated by patient serum revealed that higher levels correlated with IgG binding to infected cells. I observed no correlation between serum-mediated ADCC and markers of disease progression including patient status, viral RNA load, CD4+ T cell count, or NAb titers. The data presented here have implications for acquisition and control of early HIV-1 infection by NKs, MCs, and PMNs prior to activation of an adaptive immune response, at later stages in the presence of HIV-1-specific Abs, and are relevant to vaccine-induced anti- HIV-1 Ab-based effector mechanisms.This thesis is not currently available in ORA