MUCOSAL INFECTION OF MACAQUES WITH AN ACUTELY LETHAL SIV

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DESCRIPTION (based on applicant's abstract): The major route of transmission of HIV-1 is across mucosal surfaces between sexual partners or infected mothers and their fetuses or neonates. However, essentially nothing is known about the cells that facilitate passage of virus or virus-infected cells across mucosa or that are initially infected after passage of virus to primary sites of replication. To devise effective treatments and vaccines, it is important to understand the pathogenesis of HIV following mucosal transmission and to determine whether there are differences between mucosal and parenteral infection, in primary and secondary sites of virus replication, and in initial immune responses to the virus. Such insight into infectious diseases can be gained most efficiently through the use of animal models. Infection of pig- tailed macaques (Macaca nemestrina) with a virulent simian immunodeficiency virus, designated SIVsmmPBj14, provides several advantages over other SIV models. Two important advantages are: first, rapid onset of disease, which reproduces the multisystemic acute HIV-1 infection in humans and results in death in less than 2 weeks; and second, the virus preferentially replicates in gut-associated lymphoid tissue. Based on preliminary experiments indicating that the disease course following mucosal infection is altered relative to that observed after intravenous infection with SIVsmmPBj14, the following hypothesis will be tested: mucosal infection of pig-tailed macaques with SIVsmmPBj14 results in less severe disease sequelae than does intravenous infection because viral replication occurs in mucosal lymphocytes and macrophages. As a result, virus dissemination is inhibited more effectively by cytotoxic cells in mucosal tissues compared with similar effector cells induced in peripheral lymphoid organs after parenteral exposure. Macaques will be infected with SIVsmmPBj14 by atraumatic exposure of genital or rectal mucosal surfaces. At regular intervals during the first few hours and days after inoculation, animals will be euthanized and the kinetics of viral replication and dissemination, and tissue sites and cell types that support viral replication, will be determined using immunohistochemistry, in situ hybridization, and PCR-based assays. In addition, leukocytes that infiltrate areas of active SIV replication will be characterized phenotypically and functionally by assessing cell surface antigens, cytolytic activity, and use of specific T-cell receptor Vb and Vd gene segments. Finally, biologic and molecular properties of viruses isolated from peripheral and mucosal tissues and fluids will be determined. These studies should provide important insights into the earliest events that occur following mucosal infection by a primate lentivirus.