The primary consequence of HIV-1 infection is profound disruption of host immunity. This is manifest as both immunosuppression (through depletion and dysfunction of CD4 helper-inducer lymphocytes) and abnormal immune activation. The latter is reflected in polyclonal B-lymphocyte activation, tilting the immune system toward a TH2-type response and away from the cellular immune or TH1 response that would be more beneficial for immune control of HIV-1 and for a patient's response to vaccines, including therapeutic vaccines. One result of this imbalance is hypergammaglobulinemia. We have observed continually high IgG levels in a group of HIV+ individuals despite receiving very effective antiretroviral therapy, and despite having sustained undetectable blood viral loads and normal numbers of CD4+ T lymphocytes for four years or more. The goal of the proposal is, therefore, to identify the causes of this persistent immune activation by HIV. I will characterize function, phenotype and cytokine profiles for both blood- and lymph node-derived B-lymphocytes, to determine what factors cause and sustain humoral immune activation in HIV-1 infection.
