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Using a Simian Immunodeficiency Virus (SIV) rhesus macaque model to study the biology of HIV-1 mucosal transmission, we demonstrated that although Toll-like receptor (TLR) agonists could induce type-1 interferon responses, it was not sufficient to prevent sexual transmission of SIV. In the animals treated with the TLR7 agonist, imiquimod, and the TLR9 agonist, CpG, we detected IFN-alpha and other anti-viral effecter molecules in vaginal-cervical secretions. However, both TLR agonists also induced proinflammatory cytokines expressions in the genital mucosa. In imiquimod treated animals, we showed a massive mononuclear cell infiltration consisting of activated CD4+ T cells, DC, and beta-chemokine-secreting cells. All the TLR agonist-treated monkeys became infected after intravaginal SIV challenge. Importantly, the set-point vRNA level in TLR ligand treated animals was significantly higher than that in control animals. We also studied the effectiveness of CpG when used as an adjuvant in combination with a therapeutic vaccine in SIV infected animals receiving antiretroviral therapy (ART). We found that compared to saline-treated control animals, the animals treated only with the therapeutic vaccine, AT2-inactivated SIV239, showed significantly lower plasma vRNA levels after ART stopped. However the CpG adjuvant treatment attenuated the protective effect of AT-2 inactivated SIV as a therapeutic AIDS vaccine, even though AT2-inactivated SIV239+CpG vaccinated animals showed augmented SIV specific IgG antibody responses as compared to all the other 3 groups. Animals treated with CpG alone showed significantly higher level of viral replication associated with increased SIV specific T cell activations. Our findings dramatically highlight the value of SIV/rhesus macaque models in studying HIV pathogenesis and evaluating the safety and efficacy of new immunological strategies to interfere with HIV infection.
Understanding the host response immediately following mucosal HIV-1 infection will be pivotal in determining whether the immune response induced by a vaccine will successfully sense and control viral replication. In order for effective vaccine strategies and modalities to be developed, these earliest immunological events must be fully assessed in a non-biased manner. Nonhuman primates (NHP), specifically Rhesus macaques (RM), serve as a model to investigate the immunological landscape immediately post-challenge and to define the spatiotemporal path of simian immunodeficiency virus (SIV). SIV infection of RM serves as a model of human HIV infection as it recapitulates many of the virological, immunological, and pathological features of HIV infection vii in the human host. In this thesis I will test the hypothesis whether transcriptional analysis will allow a sensitive measure of the early innate immune responses that accompany detection of the SIV virus in the periphery. I have determined that an early inflammatory profile arises early in tissues proximal to the challenge site that precedes widespread immune activation and the systemic antiviral interferon response. This study defines in detail the spatiotemporal relationship between virus and host immune response and may be a valuable resource in guiding future vaccine design strategies.