Gene mutation speeds up progression to AIDS

Up to 13% of population has susceptible genotype

Researchers at the National Cancer Institute (NCI) in Frederick, MD, have concluded that some people progress to AIDS more rapidly if they possess a recessive genetic variation that makes their cells more receptive to HIV infection.1

The researchers studied the CCR5 gene. This gene’s promoter region determines how often and when the gene manufactures cell surface receptors, which are the points at which a new virus enters a cell to make copies of itself.

Researchers discovered that HIV-infected people whose CCR5 gene contains the promoter allele CCR5P1 progress to AIDS two years faster than those who don’t. This variation is not in the coding region of the gene, but in the regulatory region, which determines how much of the receptor protein is produced on the cell’s surface. The gene is recessive, meaning it works only when both of a person’s parents carried it.

"This is not the first gene that was discovered to have genetic sensitivity to HIV; it’s the fourth," says Stephen O’Brien, PhD, a geneticist and head of the Laboratory of Genomic Diversity at NCI. O’Brien led the team of NCI researchers.

"The first discovery was a mutation in the center of CCR5 that caused it to be completely resistant to HIV infection," O’Brien says, adding that these types of mutation discoveries have provocative implications for HIV therapy.

Tracking a moving target

AIDS progression is a competition between a rapidly replicating virus and the body’s T-cells that are fighting the infection, O’Brien explains. So far, the war on AIDS has focused on arming the body’s immune system with powerful chemical weapons that help it fight the virus. But that strategy has not worked well because the virus is a moving target that mutates at a rate of once per replication, with one billion replication mutations each day, O’Brien says.

Researchers also are studying defense strategies that would prevent the virus from beginning its replication process.

"If we can interfere with the cellular protein made by the host that’s required for infection and replication, then you don’t have a moving target, you have a fixed target," O’Brien suggests.

"If you knock out CCR5, you shut out HIV from replicating because CCR5 is the doorway by which HIV enters a new cell," he adds.

The NCI study and other receptor research may have important implications for vaccine research, says Kenneth Mayer, MD, chief of the infectious disease division of Memorial Hospital in Pawtucket, RI, and professor of medicine at Brown University in Providence, RI.

"The research lets us assess what’s needed for HIV entry," Mayer says. "The better we understand what causes resistance to HIV, the better we can try to replicate the ways in which the cells in the body are either more resistant or susceptible to HIV."

Drugs could block viral entry

This knowledge could result in a vaccine that gives protective immunity to HIV, or it could lead to the development of drugs that would block HIV access to certain receptors, Mayer adds.

Scientists have tried for more than a decade to develop drugs that block HIV access to certain receptors, Mayer says. "Part of the reason they haven’t succeeded is because they haven’t understood the mechanisms of viral entry that these genetic studies are helping us to understand."

The NCI study’s researchers compared the genes of more than 2,600 people infected with HIV with the genes of 474 healthy people. The study includes a genetic association analysis of five cohorts of people with AIDS. It showed that infected individuals whose CCR5 regulatory region contained the promoter allele CCR5P1 progressed to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection.

The researchers estimate that 10% to 17% of patients who develop AIDS within three and a half years of HIV-1 infection also have the CCR5P1 genotype. The study shows that 12.7% of Caucasians and 6.7% of African-Americans carry a CCR5P1 genotype. This genotype’s influence on accelerating AIDS is strongest in the initial four to six years after infection. This is because CCR5 is the primary manufacturer of HIV-1 receptors in the early years of infection.

The study authors described an individual’s acceleration to AIDS by using AIDS endpoints that reflect advancing morbidity. These were defined by the Atlanta-based Centers for Disease Control and Prevention as individuals with CD4 counts of fewer than 200 cells/milliliter or individuals that died from the disease.

Reference

1. Martin M, Dean M, Smith M, et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 1998; 282:1,907-1,911.