This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction. SIVsm, the virus that naturally infects sooty mangabeys (SMs), is accepted as being highly pathogenic for rhesus macaques (Rh). Accidental or experimental transmission of SIVsm to Rh and subsequent virus adaptation resulted in highly pathogenic reference strains of SIVmac and SIVsmm. However, these strains were generated under the unnatural conditions of serial passage. Therefore, the pathogenesis of the parental strains needs to be addressed. The recent description by our group of highly divergent SIVsm lineages co-circulating in the TNPRC SM colony provided the opportunity to test our hypothesis that SIVsm is not intrinsically highly pathogenic in Rh. Methods. Ten Rh of Indian origin were infected with primary isolates of SIVsm belonging to 5 different lineages (2 Rh per group). Plasma viral loads (VLs), humoral immune responses and immunophenotypic markers were measured during acute and chronic SIVsm infection for up to 540 days. Results and discussion. The dynamics of primary SIVsm viral replication in Rh showed significant differences from SIVmac pathogenesis in Rh. After high levels of replication during primary infection, generating peaks of VL of 108-109 copies/ml, VL was rapidly controlled by the macaque host during the chronic phase of infection. VLs after the set point showed a decreasing trend, reaching values of 104 copies/ml in 8 out of 10 Rh and 103 copies/ml in 4. VL was undetectable in the remaining 2 Rh during later time points. These values were closer to those observed in chronically infected HIV-1 patients. During acute infection when Rh had high VLs, significant depletion of intestinal effector cells occurred, but the magnitude of this depletion was lower than that observed during Rh infection with SIVmac. Unlike SIVmac infections, there was a tendency to restore the pool of intestinal target cells (CD4+CCR5+) in animals at later time points. VLs in lineage 1-infected Rh were slightly higher compared to the newly discovered lineages. Lineage 1 contains the reference strains SIVsmB670, SIVsmPBj and SIVsm660. Our study shows that the virulence of primary SIVsm isolates in Rh is significantly lower than previously accepted. The long-term goal of this study is to understand the evolution of viral virulence in this novel SIVsm-Rh system. This animal model of SIV infection will more closely reproduce HIV pathogenesis in humans and may be more useful than current models for the evaluation of vaccines and the immune correlates of protection. This pilot project funded by TNPRC, generated preliminary results which were used to apply for a COBRE project and then an RO1. Both these grants were awarded.
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