During the clinically latent phase of HIV-1 infection, spleen and lymph nodes (secondary lymphoid organs) are major virus reservoirs. However, it is unclear how HIV-1 reaches these sites following initial systemic infection or entry via mucosal surfaces. Dendritic cells and Langerhans cells (DC/LH) are the most potent antigen presenting cells (APC). DC/LH comprise a leukocyte lineage distinct from monocytes and macrophages. DC/LH are thought to play a key role in uptake and transmission of virus to the secondary lymphoid organs, but little is known about this very early infection period. Data from rhesus monkeys suggest that Langerhans cells can be infected by simian immunodeficiency virus (SIV) through direct mucosal transmission and may provide a sanctuary site during early SIV infection. In vitro and in vivo data in humans indicate HIV-1 uptake and efficient transmission by DC/LH., but the extent of active virus replication in the cells remains to be clarified. The overall goal of this proposal is to elucidate the interaction of HIV-1 and SIV with DC/LH, in vitro and in vivo.
The Specific Aims are to: 1. Examine the biology of HIV-1 transmission from DC/LH to T cells in vitro The studies will model conditions in vivo which may influence virus spread from DC/LH to T cells in culture. Modulations of virus transmission by cytokines and CD8+ T cells will be examined. 2. Confirm key findings in vitro using SIV an primate DC. Key experiments from the culture studies of HIV-1 will be repeated by using SIV and primate and human leukocytes. Major findings will be confirmed to validate the SIV model as relevant. No problems are anticipated because of the parallels between SIV and HIV-1 infection. 3. Study infection of DC/LH by HIV-1 in vivo in preliminary studies, HIV-1 infection of DC/LH in clinical material will be studied taking advantage of a novel monoclonal antibody (mAb) specific for human and primate DC/LH. Studies which cannot be addressed in humans will be conducted in primates infected by SIV. 4. Study mucosal DC/LH in SIV infection in vivo To test the role of DC/LH - early following mucosal lentiviral infection, rhesus monkeys will be challenged with cell free virus. These studies will examine neonatal transmission of SIV (oral) and adult transmission of SIV (vaginal). In situ studies will determine tissue localization and infection of primate DC/LH. Since DC/LH are likely to be the first cells in contract with virus after mucosal SIV or HIV-1 exposure, the proposed studies will increase the understanding of mucosal transmission of HIV-1 and SIV. Most importantly these studies will provide insight into viral and/or cellular determinants for efficient mucosal entry and virus transmission.
