A shortcoming of conventional assays used for the study of HIV-1-specific antibodies is that they often fail to detect activities associated with complement activation and Fc receptor binding that could influence virus replication in vivo. Complement-activating antibodies enhance the formation of complement-coated HIV-1 that resists complement lysis and binds complement receptors (CR) on a variety of cell types, including follicular dendritic cells, monocytes, macrophages, B lymphocyte and red blood cells. Antibody-coated virus may further interact with monocytes and macrophages through Fc receptors (FcR) independently of complement. Each of theses activities may be regulated by the immunoglobulin class and subclass and could influence HIV-1 replication in vivo by; 1) increasing virus entry or post-entry replication leading to infection-enhancement, 2) expanding tropism to cells that have little or no CD4 antigen on their surface, 3) trapping complement-opsonized virus on the surface of follicular dendritic cells and 4) clearing virus through the mononuclear phagocytic system. We will study immunologic mechanisms of complement activation and interactions of HIV-1 with CR and FcR during acute primary infection as a unique setting in which to explore their possible contribution to virus replication or clearance. One approach will be to determine whether complement activation in vivo correlates with immunological, virological and clinical profiles. Additional studies will characterize the appearance of circulating HIV-1 immune complexes and will assess whether their biochemical content and biological properties are predicted by serologic correlates. IgA, IgM and IgG production will be assessed to determine their timing of appearance and virus antigen specificity/ IgG will be further delineated with respect to subclasses. Antibodies will be assessed for complement activation using patient isolates and autologous sera in quantitative immunoassays. Infection- enhancement will be evaluated in assays that detect both complement- dependent and -independent mechanisms of antibody-enhanced HIV-1 infection. These studies will provide critical information on serological correlates of HIV-1 pathogenesis that predict interactions with CR and FcR involved in wither virus spread or in control of plasma viremia.
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