4, 12 Similar kinetics of the immune responses to SIV have been reported in another natural host, the African green monkey. 6-11 In SIV-infected SMs, the low immune activation that is observed during the chronic phase of infection is established as the result of the relatively rapid resolution of a strong innate and adaptive immune response to the virus that occurs during the acute phase of infection and lasts approximately 4-6 weeks after the initial inoculation. The low immune activation observed in chronically SIV-infected SMs represents a key phenotypic difference from pathogenic HIV/SIV infection of humans and macaques, in which chronic immune activation is a major marker and predictor of disease progression, both in the natural history and in the setting of antiretroviral treatment. The results of the present study indicate that administration of type I IFNs in SIV-infected SMs induces a significant anti-viral effect that is not associated with a detectable increase in chronic immune activation. Flow cytometric analysis of lymphocytes in the blood, lymph nodes, and rectal biopsies did not reveal a significant decline of CD4 + T cells, a robust increase in lymphocyte activation, or change in the level of SIV-specific CD8 + T cells. Interestingly, we observed an approximately 1-log decrease in viral load that persisted through day 35 of treatment. Gene-expression profiling revealed a strong up-regulation of IFN-stimulated genes in the blood of treated animals, confirming the reagent's bioactivity. To assess the effects of IFN-I signaling in this setting, in the present study, we administered recombinant rhesus macaque IFNα2-IgFc (rmIFNα2) to 8 naturally SIV-infected SMs weekly for 16 weeks.
We hypothesized that low levels of IFN-I signaling may help to prevent chronic immune activation and disease progression in SIV-infected SMs. A key feature differentiating nonpathogenic SIV infection of sooty mangabeys (SMs) from pathogenic HIV/SIV infections is the rapid resolution of type I IFN (IFN-I) responses and IFN-stimulated gene expression during the acute-to-chronic phase transition and the establishment of an immune quiescent state that persists throughout the chronic infection.
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