Background:  In contrast to SIV, which induces immunodeficiency over a 1- to 3-year period, highly pathogenic SHIV causes an irreversible and systemic depletion of CD4⁺ T lymphocytes in rhesus monkeys within weeks of infection. Nonetheless, the seemingly more aggressive SHIV has proven to be easier to control by the same vaccine regimens that fail to contain SIV, suggesting that early events associated with in vivo infections by the 2 viruses may be dissimilar.

Methods:  Co-receptor usage by the highly pathogenic SHIV_DH12R and SIV_mac239 for entry into rhesus PBMC was evaluated using small molecule competitors specific for CCR5 and CXCR4. Flow cytometry was employed to characterize changes in CD4⁺ T-cell subsets during the first 4 to 6 weeks of SIV and SHIV infections. The effects of inoculum size or a potent RT inhibitor administered on day 5 or 14 post SHIV_DH12R inoculation were compared with published data for SIV infections.

Results:  Highly pathogenic SHIV_DH12R exclusively uses CXCR4 for infection of rhesus PBMC while SIV_mac239 utilizes CCR5 for entry into the same cells. During the period of peak SHIV_DH12R production, massive elimination of CXCR4⁺ naïve CD4⁺ T cells occurred. In SIV-infected monkeys experiencing loss of CD4⁺ T lymphocytes, CCR5⁺ memory CD4⁺ T cells were selectively depleted. In infected animals, SHIV_DH12R induced rapid and irreversible CD4⁺ T-cell loss in a dose-dependent manner whereas the slower evolving SIV-induced immunodeficiency is independent of inoculum size. A drug-induced suppression of SHIV replication during the first 2 weeks of infection that prevents a complete loss of CD4⁺ T cells, leads to very low to undetectable post-peak viremia and an asymptomatic clinical course for periods as long as 4 years; comparable therapy initiated after 48 hours of SIV inoculation invariably fails to prevent disease.

Conclusions:  The use of different chemokine co-receptors by pathogenic SHIV and SIV results in the targeted elimination of distinct CD4⁺ T-cell subsets during infection of rhesus monkeys. Coupled with clearly different clinical courses, sensitivities to a potent antiretroviral drug, and responses to changes in inoculum size, these results indicate that the mechanism(s) underlying the induction of immunodeficiency by SIV and SHIV are dissimilar.

Keywords: SHIV; natural history; co-receptor usage