Previously a new cellular system was identified, consisting of dendritic cells (DCs) and T cells from human skin that supports active replication of HIV in vitro. The skin is a useful model for the less accessible human mucosal tissues involved in HIV transmission. It was found that virus replication needs both DCs and T cells, which fuse to form virus-producing syncytia. DC-syncytia producing HIV proteins have now been identified in the adenoid mucosa of 13/13 HIV-infected individuals. Preliminary studies on the role of mucosal leukocytes in pathogenesis using the SIV-macaque system, has revealed similar observations to the HIV-human skin system. The DC-T cell mixtures isolated from macaque skin or oral mucosae support active replication of SIV in vitro. In a vaginally infected macaque, SIV-carrying cells were isolated from the tonsillar mucosa that formed virus-producing syncytia upon in vitro culture without added stimuli. Therefore, much like the HIV-infected individuals who have a productive infection in the tonsillar mucosa, so too does a monkey infected intravaginally with SIV. The SIV-macaque model will be used to identify cells that are critical for mucosal infection, systemic spread, and chronic replication of SIV. The hypothesis is that mucosal leukocytes will be pivotal in the replication of SIV especially DCs that contact CD4+ T cells (in vitro and in vivo). These studies cannot be performed in man and will identify cell-cell and cell-virus interactions crucial to SIV spread and replication. This proposal will address several issues: 1. Are mucosal DCs and T cells (versus blood and lymph node cells), needed for SIV replication in vitro? 2. What cells are involved in the spread of infection to blood and distal tissues following vaginal infection? 3. In what cells and tissues does SIV replication occur during the chronic phase of immunodeficiency? 4. What cell types, following infection with SIV in vitro, elicit infection in vivo upon reinfusion? 5. Are the tonsillar mucosae unusually susceptible sites for the onset of SIV infection? These studies will provide a better understanding of how infection is established in the mucosae during both sexual and perinatal transmission. Identifying the cells critical in the onset and spread of infection, as well as chronic virus replication, will direct the development of specific therapies that block infection and control virus replication.
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