Gene Mutations May Slow Progression of HIV

FREDERICK, Md—Mutations in two genes that produce chemokine receptors—CCR5 and CCR2—account for about 30% of long-term survivors of HIV infection, that is, patients whose disease has not progressed to AIDS within 10 to 20 years of infection, said Stephen J. O’ Brien, PhD, of the NCI’s Laboratory of Genomic Diversity.

Previous work had identified a deletion mutation in CCR5, a cell surface co-receptor with CD4 for HIV infection, that mediates HIV infection and progression. Genotype analysis of more than 4,000 individuals enrolled in several AIDS cohorts showed that high-risk individuals who lack both normal copies of the CCR5 gene are significantly less likely to become infected with HIV despite repeated exposure.

Those with one missing copy of the CCR5 gene and one normal gene can become infected, but, on average, progression to AIDS is delayed for two to four years. However, these findings accounted for only a small proportion of observed long-term survivors.

Laboratory studies had suggested that CCR2 is used by some strains of HIV infection, and the NCI scientists subsequently found a substitution mutation of CCR2 (known as CCR2-64I). In the current study, the researchers looked for this CCR2 mutation in 3,003 HIV-infected individuals from five cohorts. The altered CCR2 gene was found to be common in all ethnic groups, whereas the CCR5 mutation is found only in Caucasians (Science 277:959-965, 1997).

There were no significant differ-ences in frequency of CCR2-64I between exposed unin-fected and HIV-infected individuals in any of the cohorts, Dr. O’Brien said.

In a group of 58 uninfected individuals at extremely high risk because they had received HIV-contaminated clotting factor or had had frequent unprotected sex with high-risk partners, no differ-ences in CCR2 genotype frequencies were noted. Thus, unlike the CCR5 mutation, the CCR2 mutation does not appear to protect against HIV infection.

In a subgroup of 891 HIV-infected patients whose approximate time of seroconversion was known because they were enrolled before seroconversion, those with one or both copies of the CCR2 mutation had a consistent two- to three-year delay in median time to progression, compared with those who had two normal copies of the gene.

“The demonstration that having mutant alleles at these genes [CCR5 and CCR2] is protective against progressing to AIDS has important implications for therapy, because chemokine receptors are required cellular ports for HIV-1 cell entry and spread,” Dr. O’Brien concluded.

His co-workers in the study included Drs. Michael W. Smith and Mary Carrington of Science Applications International Corp. and the NCI, Frederick, Md, and Dr. Michael Dean of the NCI’s Laboratory of Genomic Diversity.