Substantial Resistance To HIV Infection Tied To Genetic Mutation

"We looked for this mutation in a large cohort of high-risk people who were HIV-negative. We found that bisexual and homosexual Caucasian men with one copy of the mutation had a 70% reduced risk of HIV infection compared with men who didn't carry the mutation at all," says Michael Marmor, Ph.D., Professor of Environmental Medicine and Medicine at New York University School of Medicine, the first author of the study. In previous studies it had been established that men with two mutant copies of the CCR5 gene had even stronger resistance to HIV infection

"Our finding suggests that strategies to prevent HIV infection by blocking receptors used by the virus need not block all of the receptors," says Dr. Marmor. "Reducing the number of receptor sites per cell may be adequate to provide an imperfect but important degree of protection."

There are thousands to tens of thousands of CCR5 receptors on the surface of a subset of immune cells called T-helper cells. In people with two copies of the delta-32 mutation there are no functional CCR5 receptors on these cells.

In order for HIV, the virus causing AIDS, to enter cells it usually must fuse with a receptor called CCR5 that sits on the surface of T-helper immune cells. The delta-32 mutation in the gene encoding the CCR5 protein results in a defective receptor site that blocks entry of the virus. People who carry two copies of the mutation, one from each parent, are resistant to HIV infection despite repeated exposures to the virus. People who carry one copy of the mutation, the study concludes, also may be substantially resistant.

Every gene has two alleles, or forms, one inherited from each parent. People who carry a gene with the same alleles are called homozygotes for a particular trait. People who carry a gene with two different alleles are called heterozygotes.

It has been known for several years that around one percent of Caucasians are genetically resistant to HIV because they are homozygous for the CCR5 mutation, meaning they have inherited two copies of the mutation, one from each parent. "These people, however, are not resistant to all strains of HIV," warns Dr. Marmor. "They should avoid behaviors that might expose them to relatively uncommon HIV strains that use receptors other than CCR5 to gain entry into cells."

Prior research had established that HIV-infected people who are heterozygous for the mutation progress to full-blown AIDS more slowly than people with no copies of the mutation. But it was unclear to what extent people with one copy of the mutation were protected against HIV infection.

The new study suggests that people with one copy of the mutation do have some protection against infection. It prospectively monitored a large cohort of bisexual and homosexual men to see how their CCR5 status correlated with the incidence of HIV infections.

The study, published in the current issue of the Journal of Acquired Immune Deficiency Syndromes, helps fill in the missing information about resistance to HIV infection among men at high risk of infection. The report also contained data on injection-drug users and women at sexual risk of HIV infection.

The study analyzed the prevalence of homozygotes and heterozygotes for the CCR5 mutation among 2,996 individuals, including 1,892 gay men, 474 male injection drug users, 283 female drug users, and 347 women at heterosexual risk of HIV infection. The men in the study were followed for 18 months. They had their blood tested for HIV every six months, and they responded to questionnaires that asked about their behaviors during the course of the study. The women were followed for 24 months, but too few were enrolled to yield statistically significant results.

Among the men, the study found that 40, or 1.3 percent, were homozygous, 387, or 12.9 percent, were heterozygous for the CCR5-delta-32 mutation, and 2,569 had no copies of the mutation. Men who were heterozygotes had a 70 percent reduced risk of HIV infection compared with men who did not carry the mutation. A total of 45 individuals during the course of the study became infected with HIV.

The data also revealed that 10.5 percent of white gay men in the study who were age 45 or older and who lived in San Francisco or New York City, and were HIV negative in 1995, were homozygous for the CCR5-delta-32 mutation. This observation, says Dr. Marmor, underscores the survival advantage provided by the homozygous mutation. Only one percent of Caucasians in the general population would be expected to be homozygous for the mutation.

The study cohort is culled from the larger HIVNET Vaccine Preparedness Study, which enrolled 4,892 people who were HIV negative, but had histories of behaviors that placed them at high risk of infection. Study sites were in Boston, Chicago, New York City, Philadelphia, Providence, San Francisco, and Seattle.

In addition to the lead investigator, Dr. Michael Marmor of the NYU School of Medicine, the study's co-authors include: Haynes W. Sheppard, Ph.D., of the California Department of Health Services, Berkeley; Deborah Donnell, Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle; Sam Bozeman, Ph.D., of ABT Associates, Cambridge, MA; Connie Celum, M.D., of University of Washington, Seattle; Susan Buchbinder, M.D., of the San Francisco Department of Health; Beryl Koblin, Ph.D., of the New York Blood Center, New York; and George R. Seage III, D.Sc., of the Harvard University School of Public Health, Boston.

The study was supported by the National Institute of Allergy and Infectious Diseases, a component of the National Institutes