FOLLICULAR DENDRITIC CELLS AND IMMUNOSUPPRESSION IN AIDS

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Follicular dendritic cells (FDC) play a major role in immunoregulation and have recently been found to be a site of HIV deposition. FDC serve as long-term depots of Ag for induction and maintenance of anamnestic responses as well as contributing Ag independent signalling believed to be necessary for germinal center formation. In order for Ag (or infectious agents) to become associated with FDC, either specific Ab and/or complement activation is required. After one or both of these events have occurred, immune complexes or complement coated particles are formed and can be trapped on the dendritic surfaces of FDC. Shortly after trapping on FDC, germinal center formation occurs. These germinal centers are composed of highly activated and rapidly proliferating B (and CD4+ T) cells surrounding FDC. In HIV infection, viral particles quickly become associated with FDC in lymphoid follicles although the mechanism of this association has not been established. Once trapped on FDC, virus is localized to the germinal center area where susceptible cells reside in a highly activated state. Thus HIV localization on FDC apparently brings together all of the components needed for successful and productive infection of CD4 + T cells and keeps them together as long as the FDC are present. We hypothesize that FDC by virtue of trapped HIV and generation of costimulatory signals play a vital role In the pathogenesis of AIDS and propose to test this using both in vivo and in vitro models. The specific aims of this proposal are to: 1) determine if HIV can specifically target itself to FDC and if this targeting is accomplished by complement activation, specific Ab or a combination of both; 2) determine whether FDC bearing HIV can directly infect activated CD4 + T cells and to assess the contribution of HIV specific Ab on this infectious process; and 3) determine whether FDC and/or germinal center B cells can provide sufficient accessory cell function to promote productive infection of resting CD4 + T cells.