Early Events Following Oral Transmission of Simian Immunodeficiency Virus: From Viral Entry to Host Immune Response




Milush, Jeffrey Martin

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Approximately 40 million people worldwide are infected with HIV, the causative agent of AIDS. The primary mode of HIV transmission (75% of all transmissions) between individuals occurs across mucosal tissues (vaginal, rectal, oral). The goal of this thesis was to assess the virologic and immunologic events following oral inoculation of macaques with Simian Immunodeficiency Virus (SIV) and correlate these findings with disease progression. To assess the virologic events involving viral entry and spread, macaques were orally inoculated with SIV and necropsied at early times post-infection (days 1 - 14). These studies were the first to identify the preferential entry sites for the virus as the oral and esophageal mucosa, as well as the tonsils. Furthermore, SIV rapidly disseminated to peripheral lymph nodes resulting in systemic infection by 2 to 4 days post-infection. The rapidity with which SIV spreads throughout the lymphatics indicates a major obstacle for a vaccine recall immune response to eliminate infected cells prior to dissemination. Analyses of immunologic events through the assessment of mucosal innate immune gene expression, as well as the initiation of the adaptive immune response, were undertaken in a second group of SIV orally inoculated macaques. Two hypotheses were proposed: 1) An innate mucosal immune response at the site of entry (oral mucosa) would result in the induction of a timely SIV-specific adaptive immune response; and 2) Maintaining a healthy mucosal barrier during chronic infection would prevent the onset of opportunistic infections. My data support hypothesis one, as during early times post-infection (2 - 21 days), gingival mucosal innate response gene expression correlated with the ability toinduce timely SIV antibodies and reduce plasma viral loads. In addition, my data assessing events during chronic infection (day 70) indicated an association between elevated expression of mucosal innate response genes, particularly chemokines, with an absence of opportunistic infections, thus supporting hypothesis two. From these studies assessing viral and immune correlates of SIV transmission, I conclude that vaccines capable of inducing high titer neutralizing antibodies at the mucosa, as well as increased mucosal innate immune responses, will be most efficacious in preventing mucosal HIV transmissions.

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