| Rare individuals report repeated unprotected sexual exposures to human immunodeficiency virus type 1 (HIV-1), yet remain seronegative and appear to resist infection with the virus. Mechanisms of protection for these exposed seronegative (ES) persons are largely undefined. Broadly, potential protective mechanisms include diminished target cell susceptibility to infection and elevated anti-viral immunity. While HIV-1-specific T cell-mediated immune responses in ES persons have been extensively investigated, relatively little is known regarding the role of diminished target cell susceptibility to HIV-1 in mediating persistent seronegativity. In this work, I investigated CD4 + T cell susceptibility to HIV-1 in 81 ES and 33 low-risk controls, revealing 6 individuals having markedly reduced capacity to produce HIV-1 in vitro. Importantly, HIV-1 coreceptor tropism and CCR5 expression by target cells cannot explain this defect, indicating that the low producer phenotype may result from events occurring post-entry. I also investigated whether polymorphisms in the host antiviral protein TRIM5alpha may contribute to HIV-1 protection among ES. This study revealed a TRIM5alpha haplotype which may promote HIV-1 acquisition rather than protection, indicating a more important role for human TRIM5alpha than has been postulated to date. |
