This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Currently, more than 40 million people worldwide are persistently infected with HIV-1. Similar to HIV infection in humans, SIV infection in non-African primate species results in chronic disease that culminates in AIDS. The well-defined SlV infection of rhesus macaques is an excellent animal model system to assess HIV transmission and pathogenesis for several reasons. SIV infection In macaques closely resembles many aspects of HIV infection in humans including events associated with transmission, cellular tropism of the virus, viral replication patterns. disease progression, and the nature of the host immune response. Furthermore, the SIV/macaque model is important because knowledge of the time, route, and number of viral exposures Is known, the viral stock used to infect the macaques is well-characterized, and there is the ability to frequently sample important tissues (blood, lymph nodes, mucosal sites, etc) throughout infection. For HIV and SIV, the major mode of transmission for new infections is mucosal transmission, i.e. the virus has to pass through a mucosal membrane to infect the new host However, the probability to become infected from a mucosa] encounter is actually quite low. A variety of factors contribute to this low probability, including inhibitory proteins at mucosal surfaces, the difficulty to pass an intact mucosal membrane and the probability for the virus to find a suitable target cell to Infect Initially as soon as it passes the membrane. Using the macaque model, our laboratory has focused its work on oral transmission of HlV/SIV, a route that is important for mother-to-child (vertical) transmission through breast feeding and for transmission during oral sex when virus is present in semen. However, it still remains unclear what the most important events are which permit the actual transmission itself. Here we expand upon our previous findings by assessing the impact of immune activation on the transmission of SIV administered into the oral cavity of macaques. We hypothesize that higher levels of immune activation will increase the potential for SIV to elicit a productive infection. These studies will utilize a low dose regimen of viral Inoculations to mimic the viral levels that are present in breast milk and semen. We will assess transmission of SIV while the mucosa is experiencing a state of immune activation, gingivitis. Gingivitis is a common inflammation of the oral mucosa in humans and therefore may be impacting oral transmission in humans exposed to HIV containing semen (through receptive oral intercourse). These studies assessing the impact of the immune response on oral transmission are likely be applicable to other sites of mucosal transmission, and will be important for determining the immune mechanisms that impact the success of SIV/HIV mucosal transmission. Our long term goal is to utilize these findings to aid in the design of SIV/HlV vaccines that are able to elicit sterilizing immunity by preventing the infection of the first target cell when mucosal sites are exposed to HIV/SIV.
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