Impaired Viral Entry Cannot Explain Reduced CD4 + T Cell Susceptibility to HIV Type 1 in Certain Highly Exposed Individuals

Abstract

Rare individuals report repeated unprotected HIV-1 sexual exposures, yet remain seronegative for years. We investigated the possibility that reduced in vitro CD4⁺ T cell susceptibility to HIV-1 infection protects such highly exposed seronegative (ES) individuals. Susceptibility to three R5-tropic HIV-1 isolates, regardless of inoculating dose, was remarkably similar between 81 ES and 33 low-risk controls. In 94% (99/105) of donors, we observed a 1.36 log-unit range in HIV-1_JR-CSF production, with similar results for HIV-1₁₁₉₂. The median frequency of intracellular Gag⁺ T cells after single-round infection was similar in ES (5.2%) and controls (7.2%), p = 0.456. However, in repeated testing, CD4⁺ T cells from two controls (6.1%) and four ES (4.9%) exhibited a 10- to 2500-fold reduction in HIV-1 production and required 5- to 12-fold greater HIV-1₁₁₉₂ and HIV-1_JR-CSF inocula to establish infection (TCID₅₀). Reduced viral entry cannot explain the low producer phenotype; no differences in CCR5 receptor density or β-chemokine production were observed. In conclusion, we have identified a remarkably narrow range of HIV-1 susceptibility in seronegative donors regardless of risk activity, which can be applied as a benchmark to assess vaccine-induced antiviral effector activities. However, CD4⁺ T cells from a subset of individuals demonstrated reduced HIV-1 susceptibility unexplained by impaired entry, lending support to the possibility that cellular restriction of HIV-1 may account for continued seronegativity in some of those having repeated sexual exposure. Identifying the host-virus interactions responsible for diminished in vitro susceptibility may contribute to the development of novel therapeutic strategies.