| Despite over a decade of intense effort, a vaccine preventing HIV infection has not emerged and HIV remains a worldwide pandemic. HIV is transmitted primarily through sexual contact at vaginal, rectal, and oral mucosal surfaces to infectious genital secretions. Mucosal surfaces may function as physical barriers that restrict viral access to the host, since HIV-1 sequences in recently infected recipients are relatively homogeneous, while those present in the blood of their donors are heterogeneous. In addition, mucosal surfaces may function as selective barriers, for the majority of HIV-1 isolates in most newly infected individuals are macrophage-tropic while those in their corresponding donors are dual-tropic. Therefore, as mucosal surfaces provide the first line of defense against HIV-infection, characterizing viral genotypes associated with mucosal transmission of HIV/SIV is essential in designing HIV prevention strategies. Accordingly, the primary goals of this dissertation were to develop SIV:macaque animal models for mucosal transmission of SIV/DeltaB670 and to determine if the genetic selection observed in HIV-infected humans occurs in SIV-infected macaques.; Thirty-seven macaques were inoculated either intravenously, intravaginally, orally, intracolonically, or intrarectally with varying SIV/DeltaB670 dilutions. The intestinally inoculated macaques progressed the most rapidly to disease, followed by the intravenously, orally, and vaginally inoculated groups in the order listed ({dollar}rho{dollar} = 0.033). Comparable to human studies, a decline in CD4+ T-lymphocytes in infected macaques was predictive of clinical disease progression. Further, the presence of p27 antigenemia, regardless of the route of inoculation, identified animals at risk of disease progression.; A comparative genetic analysis of SIV/DeltaB670 genotypes transmitted across vaginal, oral, colonic, and rectal mucosal surfaces in SIV-infected animals was performed on peripheral blood mononuclear cells collected early postinoculation. In the majority of infected animals, multiple genotypes were identified independent of the route of infection with genotypes identified most frequently in the inoculum. Thus, these data indicate no obvious selection for particular genotypes from within the SIV/DeltaB670 quasispecies at any of these mucosal surfaces. These data support the hypothesis that the mucosal barrier may play a minor role in HIV genotypic selection at mucosal surfaces and emphasize the need to evaluate the viral diversity present within the mucosal secretions of chronically infected individuals. |
