Complement-dependent trapping of HIV in lymphoid tissue

Research project P 14661 Complement-dependent trapping of HIV in lymphoid tissue Manfred P. DIETRICH 09.10.2000 Immunohistochemical studies of lymphoid tissue (LT) have shown that during HIV infection >98% of virions are extracellularly bound to follicular dendritic cells (FDC) in germinal centers (GC). HIV finally monopolizes FDC networks and transforms the FDC antigen repository into a highly infectious viral reservoir. Since the destruction of FDC network is characteristic for later stages of infection, the deposition of HIV in GC is generally accepted as a crucial event for the development of AIDS. Although the trapping process has been shown to be complement dependent, the mechanism of attachment was not determined in detail. We performed pilot stripping" experiments on LT cryosections and tonsillar cells isolated from HIV-positive individuals using blocking monoclonal antibodies (mAb) directed against complement receptors (CR) and their ligands, respectively. These experiments have shown that a large proportion of virions trapped in GC can be removed by blocking the CR2-C3d/iC3b interaction, suggesting that among the various CR the CR2 plays a central role for attachment of HIV in GC. To further investigate the mechanism of HIV deposition in lymphoid tissue we want to pursue the following 3 specific aims: First, we want to evaluate the contribution of particular human complement and Fc receptors and possibly of other factors to HIV trapping in vivo. Virus obtained from infected tissue by stripping will be characterised with respect to its surface (opsonins etc.) and teste d for its infectivity. Second, having analysed HIV detached frorn its natural reservoir, we plan to compare such virions with HIV generated invitro. Inthis way we expect to elucidate diverse opsonin patterns on virions, as well as their impact on cellular tropism and viral infectivity.. Finally, besides the human model of I-IIV infection we plan to perform similar experiments with. chimpanzees. Although HIV infection in chimpanzees was shown to be active and persistent, AIDS only rarely develops in these animals. This resistance of HIN-infected chimpanzees to AIDS correlates with maintenance of the LT architecture and with the lack of the virus deposition in GC. Therefore, we want to investigate the differences between tile human and chimpanzee immune system with special focus on complement receptor-ligand interactions in LT. The aim of this objective is to reveal the mechanism responsible for absence of HIV attachment in chimpanzee GC, and to exploit this knowledge for inhibition of HIV trapping in human lymphoid tissue.