TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T-cells with no measurable effect on susceptibility to SIV infection

Studies using transformed human cell lines suggest that most SIV strains use CCR5 as co-receptor. Our analysis of primary rhesus macaque CD4+ T-cell clones revealed marked differences in susceptibility to SIVmac239 infection. We investigated whether different levels of CCR5 expression account for clonal differences in SIVmac239 susceptibility. Macaque CD4+ T-cells showed significant CCR5 downregulation 1-2 days following CD3 mAb stimulation, which gradually recovered at resting state, 7-10 days after activation. Exposure of clones to SIVmac239 during their CCR5low or CCR5high expression states revealed differences in SIV susceptibility independent of surface CCR5 levels. Furthermore, a CCR5 antagonist similarly reduced SIVmac239 infection of clones during their CCR5low or CCR5high expression states. Our data suggest a model where i) very low levels of CCR5 are sufficient for efficient SIV infection, ii) CCR5 levels above this threshold do not enhance infection, and iii) low level infection can occur in the absence of CCR5.