In contrast to HIV-1 infection of humans and SIV infection of rhesus macaques (RMs), which are almostinvariably associated with AIDS, natural lentiviral infections of African primates, such as SIVsmm infection ofsooty mangabeys (SM), are typically non-pathogenic. The mechanisms underlying this non-pathogenicphenotype remain largely unknown; however, we have previously shown that a key feature of nonpathogenicSIV infection is the absence of chronic, generalized immune activation in the context of lowcellular immune responses to the virus. As the HIV-associated immune activation (IA) is thought to be a keyfactor in the pathogenesis of AIDS, we proposed that the lack of IA protects SIV-infected SMs from diseaseprogression. In further studies, we observed that SM-derived plasmacytoid dendritic cells (pDCs) producesignificantly lower levels of type 1 interferon (IFNs) in response to toll-like receptor (TLR)-7 or -9 stimulationthan human or RM-derived pDCs. These findings led us to hypothesize that a blunted type 1 IFN responsesto TLR-7/9 stimulation mediated by SIV or its products protects SIV-infected SMs from developing thegeneralized immune activation associated with pathogenic HIV/SIV infections.
The aim of this project is to directly test this hypothesis by treating naturally SIV-infected SMs with IFN-a andTLR-7/-9 stimulation, as well as treating SIV-infected RMs with anti-IFN-a antibody and TLR-7/-9 inhibitors.These interventions will allow us to determine whether and to what extent differences in the level of pDCsresponsiveness to TLR-7/-9 stimulation and/or IFN-a production between RMs and SMs are responsible forthe striking differences in the level of immune activation observed in these two species after SIV infection.The results of these studies will improve our understanding of the mechanisms underlying the lack ofdisease in SIV-infected SMs and determine whether targeting TLR-7/9 activation and/or IFN-a production arepromising targets for therapeutic interventions aimed at reducing the HIV-associated chronic immuneactivation.
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