The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression

Abstract

Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding to both CD4 (ref. 1, 2) and to one of the chemokine receptors recently discovered to act as coreceptors3–11. Viruses that infect T-cell lines to form syncytia (syncytium-inducing, SI) are frequently found in late-stage HIV disease and utilize the chemokine receptor CXCR-4; macrophage-tropic viruses are non-syncytium-inducing (NSI), found throughout disease and utilize CCR-5 (ref. 3–11). We postulated that CCR-5 gene defects might reduce infection risk in seronegative subjects and prolong AIDS-free survival in seropositive subjects with NSI but not SI virus. Homozygous (Δccr5/Δccr5) and heterozygous (CCR5/Δccr5) CCR-5 deletions (ccr5)12,13 were found in 7 (2.7%) and 51 (19.5%), respectively, of 261 seronegative subjects from the San Francisco Men's Health Study. CCR-5/Δccr5 genotype was identified in 33 of 172 (19.2%) nonprogressors and 25 of 234 (10.7%) progressors from the seropositive arm of this cohort. The Δccr5 allele conferred a significant protective effect against HIV-1 infection (P = 0.001) and a survival advantage against disease progression (P = 0.02). Although both progressing and nonprogressing CCR5/Δccr5 subjects were identified, a distinct survival advantage was shown for those with NSI virus (P < 0.0001). Thus, the protective effect of Δccr5 against disease progression is lost when the infecting virus uses CXCR-4 as a coreceptor.

Cite this article

Michael, N., Chang, G., Loum, L. et al. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med 3, 338–340 (1997). https://doi.org/10.1038/nm0397-338

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