The effects of toll-like receptor (TLR) agonist-induced immunity on Simian Immunodeficiency Virus (SIV) transmission and replication in rhesus macaques | Posted on:2010-01-22 | Degree:Ph.D | Type:Dissertation | University:University of California, Davis | Candidate:Wang, Yichuan | Full Text:PDF | GTID:1444390002977808 | Subject:Health Sciences | Abstract/Summary: | | 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. | Keywords/Search Tags: | SIV, TLR, Transmission, Animals | | Related items |
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