Simian immunodeficiency viruses (SIVs) naturally infect many species of African nonhuman primates, typically causing a chronic non-pathogenic infection. Baboons do not harbor SIVs, despite having overlapping habitats with natural SIV hosts. Previous work has demonstrated baboons are resistant to chronic SIV infection in vivo. The mechanisms underlying resistance remain unknown but their elucidation could provide new targets for HIV intervention. We sought to identify stages of SIV restriction in baboons using the pathogenic SIV-rhesus macaque model for comparison.
SIV replicated in baboon PBMC but had delayed kinetics compared to rhesus PBMC; however, SIV replication in isolated CD4 cells was similar between species. Viral loads were reduced in baboon CD4 cells when co-cultured with CD8 T and NK cells, highlighting their role in the suppressive activity seen in baboon PBMC. Rhesus and baboon CD4 cells had similar levels of SIV binding, reverse transcription, integration, and egress. Interestingly, baboon PBMC produced higher levels of MIP-1α, MIP-1β, and RANTES than rhesus PBMC; levels were highest in baboon CD4 cultures containing CD8 T cells. MIP-1α, MIP-1β, and RANTES are known to suppress HIV/SIV infection through competitive binding for CCR5, the principal HIV/SIV entry co-receptor. Indeed, inhibition of CCR5-binding chemokines in baboon PBMC increased viral loads.
We generated baboon-adapted SIVs (SIVbn) by serial passage in PBMC or isolated CD4 cells and analyzed changes to the genome by deep sequencing. Non-synonymous mutations across the genome appeared early in PBMC passages; a significant portion of changes were in Env. By contrast, changes to CD4-passaged SIVbn were gradual and few became fixed by the final passage. These findings mirror those from our in vitro infections and suggest SIV faces stronger selective pressure in baboon PBMC than in isolated CD4 cells. Thus, we propose that one mechanism of baboon SIV resistance is mediated by elevated expression of CCR5-binding chemokines.