A common genetic mutation significantly delays the progression of HIV disease, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have found.
Philip M. Murphy, M.D., and David H. McDermott, M.D., of NIAID’s Laboratory of Host Defenses, led a research team that screened blood samples from HIV-infected individuals for mutations in the gene for CCR5, a key HIV co-receptor. The CCR5 gene encodes a protein on human immune cells that helps HIV enter and infect those cells. Recent studies have shown that individuals who produce mutant forms of CCR5 protein are more likely to resist HIV infection or have slower HIV disease progression than individuals who produce normal CCR5 protein.
This time, the researchers wanted to see if mutations in the promoter, a region of the CCR5 gene that regulates the quantity, rather than quality, of CCR5 protein, might also influence HIV disease progression. Their suspicions that such mutations would slow disease progression were confirmed. The scientists discovered that individuals with promoter mutations in both of the CCR5 genes they inherited developed AIDS almost four years later, on average, than HIV-infected individuals who lacked the mutation. Laboratory analyses showed that the mutant promoter was 45 percent less active, and thus less effective at promoting CCR5 protein production, than the normal promoter.
Approximately 20 percent of the HIV-infected individuals in the study possessed two copies of the mutant CCR5 promoter. Since the vast majority of these individuals were Caucasians, the researchers screened random blood samples from healthy donors to get an estimate of the promoter mutation’s prevalence among the general population. They found two copies of the mutation in 32 percent of African Americans, 28 percent of Asians, 18 percent of Caucasians and 10 percent of Hispanics in the sample.
"This is the first HIV disease-modifying genetic variant found in a regulatory region of the CCR5 gene," notes Dr. McDermott. "It is extremely common, has a broad racial distribution and exerts a strong protective effect against disease progression."
In addition to providing an important new piece to the puzzle of genetic protection against HIV disease, the finding could point to new opportunities in HIV treatment research.
"The information may have a therapeutic application if methods can be developed to block specific regulatory factors at this or other sites that affect CCR5 production."
A report of the study, titled "CCR5 promoter polymorphism affects HIV-1 disease progression," was published in the Sept. 12, 1998, issue of The Lancet .
Journal
The Lancet