Sexual transmission of HIV-1 in man begins when infected cells or cell-free virus in genital secretions contact a mucosal surface in the recipient. The events between local infection of the mucosa and systemic viremia with lymphadenopathy are largely unknown. In the application, the investigator concentrates on the biological processes linking the initial portal of infection to systemic virus spread from the local site of mucosal infection to the peripheral immune system. Rectal SIV infection of rhesus monkeys (M. mulatta) is used to model the biology of sexually transmitted HIV-1 infection in man. The animals model is crucial as it enables infection studies that are controlled for virus type, dose, and route of inoculation. The investigators hypothesize that spread from the mucosal site of infection to the peripheral immune system requires specific trafficking of infected cells from the mucosa to draining lymph node. A corollary to their hypothesis is that cell-free virus is less important for the initial step in virus dissemination. The abundant plasma viremia that is characteristic of acute infection in man and rhesus may result from a cell-associated infection that was established early in a lymph node and subsequently spread via blood to other immune tissues. The initial step of infected cells trafficking to lymph nodes is bypassed in the intravenous infection model and this may account for the more rapid disease progression in animals infected intravenously. Theses studies impact general understanding of the mechanisms involved in sexual transmission of HIV-1 in man by examining the key step between initial virus exposure and infection of peripheral immune system. They propose to use pertussis toxin (Ptx) to inhibit infected cell trafficking as an innovative experimental approach to examine the acute events following mucosal SIV exposure. Theses studies could be crucial for understanding the patterns of virus dissemination during the interval after acute infection and may revel key aspects of host immune responses that differentiate between mucosal and intravenous infection routes. It is the investigator's intent that results from these studies will help rationalize existing information about selection for unique virus variants during mucosal transmission, how this selection influences the pattern of host immune responses, the role of tissue-associated virus and the role of plasma virus during the acute infection interval. The investigators propose two specific aims: (1) Characterize host immune responses and patterns of early virus compartmentalization after intrarectal and intravenous SIV infection of rhesus monkeys. (2) Block cell trafficking to lymph nodes and evaluate the effects on intrarectal and intravenous SIV-challenge in rhesus macaques.
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