One copy of mutation may help resistance: Study
One copy of mutation may help resistance: Study
Study finds 70% reduced risk of HIV infection
It’s well-known that the homozygous type of two copies of the 32 base pair deletion in the CCR5 chemokine receptor provides resistance to HIV-1 infection. But there have been fewer data pertaining to what happens when a person has only one copy of the CCR5 delta 32 genotype. A recent study shows that even heterozygous CCR5 D 32 genotype, found primarily in European Caucasians, provides significant protection from infection during exposure to HIV-1. The finding suggests that a clinical strategy to block CCR5 receptor sites does not need to block all receptor sites to achieve substantial protection from HIV infection.1
"Once infected, it’s well-known that people with heterozygous CCR5 D 32 progress more slowly to AIDS and have better survivability," says Michael Marmor, PhD, professor of medicine and environmental medicine at the New York University School of Medicine in New York City. "There’s also data to show that incidence of neonatal transmission is less likely in cases of CCR5 D 32 heterozygocity," Marmor adds. "But in adults, it was not clear whether the heterozygous state is associated with any resistance to HIV infection."
Problems of interpretation
One of the problems with earlier data was that data were based primarily on cross-sectional findings, which studied the prevalence of homozygocity of mutation, heterozygocity, and homozygocity wild-type in people with infection vs. those without infection, Marmor says. "You can fall prey then to various biases and various difficulties in interpretation," he explains.
The research done by Marmor and colleagues was designed to study HIV-negative individuals who were at high risk for infection. The large-cohort study included 2,996 subjects from eight cities in the United States, and 1,892 of the participants were men who have sex with men (MSM). There also were 474 injection drug users (IDUs), 347 women at heterosexual risk, and 283 female IDUs.1 Of this group, 40 people (1.3%) were homozygous CCR5 32/D 32, and 387 (12.9%) were heterozygous CCR5 32. Most of these people were Caucasian.
The study showed that among high-risk HIV-seronegative MSM, both homozygous and heterozygous CCR5 delta 32 receptor site mutations were associated with protection against HIV infection. "The beauty of this study is that it is multi-institutional, it’s very large, and it meets rigorous standards with an excellent retention rate," Marmor says. Initially, 4,892 people were enrolled, and consent was obtained from 2,996 people who were studied for 18 to 24 months, Marmor says.
A new strategy
"I think the general finding suggests that manipulations or blocking of CCR5 receptor sites might provide another strategy to slow the progression of disease," he says. "If the virus can’t find the right receptor sites, it has a harder time finding a way to infect a new cell."
One of the study’s findings was that there was a substantial prevalence of delta 32 homozygous genotype in Caucasian MSM from U.S. epicenters of the epidemic, including New York and San Francisco, Marmor says. "We found that 10.5% of a small group of older gay men from those two sites were CCR5 delta 32 homozygous," Marmor says. "That’s a fascinating survival of the fittest, a Darwinian selection." These men were older than 45 years of age at the time of enrollment, which suggests they were living in those cities at the onset of the epidemic and during the period of the most rapid spread of HIV infection. "So here’s a mutation we’d expect to find in 1% of gay men, and we found it in 10% of that age or older," Marmor says. "These are survivors of a very strong pressure, strong selection pressures, and the question is whether in the remaining 89.5% there are other mechanisms of resistance that we can identify."
This suggests that future research should focus on recruiting older uninfected MSM in New York City and San Francisco, where the epidemic first occurred. Many of these men likely were exposed to HIV-1 but remained uninfected because of their CCR5 D 32 mutation.1
While 95% of the HIV strains circulating in the United States use the CCR5 receptor, there is a minority of strains that use a coreceptor called the CXCR4, so it is possible for individuals who are homozygous for the CCR5 D 32 mutation to become infected with a type of HIV, Marmor notes. "We did see one infection in an individual who was CCR5 delta 32 homozygous," Marmor says. But that person was infected with a syncytia-inducing phenotypic virus that used CDCR4 receptors.
Reference
1. Marmor M, Sheppard HW, Donnell D, et al. Homozygous and heterozygous CCR5 32 genotypes are associated with resistance to HIV infection. J AIDS 2001; 27:472-481.
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