Modeling of host immune responses to HIV and SIV using functional genomics reveals a disruption of innate immunity

HIV infection induces a vast program of host gene expression that may contribute to the immunopathologies observed in AIDS, however the genes involved in this response are poorly characterized. High density microarrays were used to analyze gene expression induced in cynomolgus macaques acutely infected with SHIV89.6P, a model recombinant virus consisting of SIV core and HIV-1 env and accessory genes. I observed that acute infection induces robust expression of type I interferon stimulated genes (ISGs). Further, a decrease in the post-infection mRNA levels of TLR4, CD14 and several interleukin 1 receptor family members was also observed. Peak levels of viremia co-incided with ISG expression, suggesting that expression of type I interferon antiviral pathway in naive hosts fails to control viral replication.; These findings were extended by examining the mRNA expression of interferon alpha, beta, gamma and 17 ISGs in cynomolgus macaques immunized with attenuated lentiviral vaccines against SHIV89.6P challenge. I demonstrate that vaccine efficacy is associated with elevated peripheral blood mRNA levels of interferon alpha and beta prior to challenge. I also examined the expression of toll-like receptors (TLRs) in vaccinated animals and demonstrated that, although TLR mRNA levels were similar between naive and vaccinated animals prior to challenge, macaques that were vaccinated, but unprotected, demonstrated a decrease in the TLR expression after SHIV89.6P challenge. TLRs, therefore, may represent a novel pathway targeted during viral infection to circumvent host immunity.; Lastly, the ability of HIV-infected persons to respond to TLR ligands ex vivo was examined. I tested a panel of agonists for their ability to induce secretion of pro-inflammatory cytokines in peripheral blood. I demonstrate that patients undergoing long term asymptomatic HIV-1 infection have significantly higher responses to TLR3 and TLR4 agonists than uninfected controls. In contrast, patients developing rapid HIV disease had lower responses to TLR3 and TLR4 ligands than controls. The difference in TLR4 activity was not due to altered levels of receptors on peripheral blood macrophages. In summary, this thesis describes several innate immune genes dysregulated during SIV or HIV-1 infection, and may aid in the development of strategies for novel vaccines against HIV transmission or therapies for HIV associated disease.; Keywords. SIV, HIV, SHIV89.6P, macaque, vaccines, toll-like receptors, interferon.