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People who inherit only one copy of a mutated gene that has an effect on HIV's ability to enter CD4 T-helper cells appear to be substantially less likely to become infected with the virus, according to a new report by researchers at New York University School of Medicine in New York City and collaborators at other institutions.

Such a protective effect, if proven, falls far short of completely safeguarding individuals who carry a single copy of the gene mutation from the risk of HIV infection. But, if the study's findings are validated, they suggest that drugs under development that are designed to mimic the mutation's effects need not work perfectly in order to offer a meaningful degree of protection.
Study participants were part of a larger research effort, the HIVNET Vaccine Preparedness Study, which enrolled 4892 HIV-negative high-risk individuals in seven US cities. The follow-up rate was 88% at 18 months.

The researchers interviewed participants about risk behaviors and tested them for HIV every 6 months for 18 months (for men) or 24 months (for women).

The final results did not include information about female participants because there were too few enrolled in the study for results to be statistically significant, noted Michael Marmor, MD, who led the work.

Some 1.3% of study participants had two copies of the gene with the mutation, and 12.9% had one. The investigators found (after adjusting for potential confounding associated with recent risk behaviors, including unprotected receptive anal sex) that during the 18-month follow-up period, men who carried one copy of the gene with the 32 mutation were 70% less likely to become infected compared with men who lacked the mutation.

Such a protective effect against infection "would be expected if individuals with this genotype have lower numbers of CCR5+ CD4+ T cells or reduced CCR5 expression," they said.

The study's findings also confirmed that men with two copies of the mutated gene appear to have substantial protection against infection compared with men with one or no copiesan effect most apparent among older MSMs living in cities with a high HIV prevalence. Although only 1% of the white population has a genetic makeup that includes two copies of the 32 gene mutation, nearly 11% of white gay men aged 45 or older who lived in San Francisco and New York City and were HIV negative when the study began in 1995 had two copies of the mutated gene, compared with 0.6% of men aged 18-29, 1.

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2% of men aged 30-34, and 4.7% of men aged 35-44.

"Strong natural selection pressures, probably unmatched in more recent times in the United States, were exerted on MSM populations, and it is not surprising that a substantial fraction of MSM who remained HIV-seronegative despite continued practice of anal intercourse should possess genetic resistance to infection with the most prevalent HIV strain," the researchers said.

However, even individuals with two copies of the mutated gene are not completely protected against HIV infection, because some strains of HIV use other coreceptors to infect cells. Tests revealed that the only person with this genetic makeup who became infected with HIV during the study had a strain of HIV that used CXCR4 receptors.

Gene Mutation Link With HIV Resistance

Joan Stephenson, PhD
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