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

Nature Medicine volume 3, pages 338–340 (1997)Cite this article

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.

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Authors and Affiliations

  1. Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, Maryland, 20850, USA

    Nelson L. Michael, John R. Mascola & Deborah L. Birx

  2. Henry M. Jackson Foundation, Rockville, Maryland, 20850, USA

    George Chang

  3. School of Public Health, University of California, Berkeley, California, 94720, USA

    Leslie G. Loum

  4. Department of Infectious Diseases, Naval Medical Research Institute, Bethesda, Maryland, 20889, USA

    John R. Mascola

  5. California Department of Health Services, Berkeley, California, 94704, USA

    Dale Dondero & Haynes W. Sheppard

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  1. Nelson L. Michael
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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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