Differential infection patterns of CD4⁺ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections

Nonhuman primate natural hosts for simian immunodeficiency viruses (SIV) develop a nonresolving chronic infection but do not develop AIDS. Mechanisms to explain the nonprogressive nature of SIV infection in natural hosts that underlie maintained high levels of plasma viremia without apparent loss of target cells remain unclear. Here we used comprehensive approaches (ie, FACS sorting, quantitative RT-PCR, immunohistochemistry, and in situ hybridization) to study viral infection within subsets of peripheral blood and lymphoid tissue (LT) CD4⁺ T cells in cohorts of chronically SIV-infected rhesus macaques (RMs), HIV-infected humans, and SIVsmm-infected sooty mangabeys (SMs). We find: (1) infection frequencies among CD4⁺ T cells in chronically SIV-infected RMs are significantly higher than those in SIVsmm-infected SMs; (2) infected cells are found in distinct anatomic LT niches and different CD4 ⁺ T-cell subsets in SIV-infected RMs and SMs, with infection patterns of RMs reflecting HIV infection in humans; (3) T_FH cells are infected at higher frequencies in RMs and humans than in SMs; and (4) LT viral burden, including follicular dendritic cell deposition of virus, is increased in RMs and humans compared with SMs. These data provide insights into how natural hosts are able to maintain high levels of plasma viremia while avoiding development of immunodeficiency.