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Resistance to HIV-1: it’s in the genes (6/30/98)

Scientists have suspected for several decades that an individual’s genetic makeup may influence the body’s response to various infectious diseases and have known that a percentage of those who are at high risk for acquiring HIV-1 resist the infection. They have also known that some persons infected with HIV-1 live for many years with no immune damage.

Does this mean that a person’s genetic makeup will prevent invasion by the HIV virus? Or can a particular set of genes delay the progression of the disease to AIDS, and death, in those already infected?

Several prominent research groups around the country have been working feverishly to answer these questions. A group of scientists at The University of Texas Health Science Center at San Antonio, under the direction of a husband-wife team, Sunil Ahuja, MD, assistant professor in the departments of medicine and microbiology, and Seema Ahuja, MD, assistant professor in the department of medicine, in collaboration with Lt. Col. M. J. Dolan of Wilford Hall Medical Center, San Antonio, have announced their discovery of gene mutations associated with altered rates of HIV-1 disease progression.

The researchers examined mutations in genes for immune molecules called chemokines and chemokine receptors in 1090 individuals infected with HIV-1. In this large group of patients, these researchers found a mutation in a chemokine receptor gene that is associated with a delay in HIV-1 disease progression in African-Americans, and possibly also Hispanics and Native Americans, but not in Caucasians. In addition, another mutation associated with an acceleration in the course of the disease is described. Their recent findings are reported in the July issue of Nature Medicine.

HIV invades certain immune cells by taking advantage of molecules on the surface of those cells and one group of molecules used by HIV to enter the cell is called chemokine receptors. "Think of these molecules as keys that HIV uses to enter the cell," Dr. Ahuja, an infectious diseases expert, says. "The recent discovery that HIV uses co-receptors (chemokine receptors) to enter the cell is a major breakthrough in HIV research. The first co-receptor that HIV latches onto to enter the cell is called CC chemokine receptor 5 (CCR5).

"The HIV virus uses different co-receptors during different phases of the disease," the researcher continues. "Like a young man who chooses a partner at a dance but quickly loses interest and selects another partner, the HIV virus initially ‘dates’ CCR5 but very quickly begins to mutate and loses its affinity for this co-receptor. It then attaches itself to other co-receptors, such as CC chemokine receptor 2 (CCR2), to enter other immune cells of the body, such as T cells."

Some chemokines have anti-HIV-1 properties, according to Dr. Sunil Ahuja. "Since chemokines play an important role in HIV-1 disease and since receptors are important gateways for the entry of HIV into the body, it was natural that investigators suspected that mutations in these genes might influence the rate at which HIV-1 disease may progress in different persons."

Individuals who have a genetic mutation that completely prevents an expression of CCR5 resist acquiring HIV. "This mutation is very much like a gene condom," explains Dr. Ahuja. "However, I should stress that this doesn’t mean that one shouldn’t use precautions, since some individuals who have this defect can still get infected. What is interesting, though, is this mutation is found in mostly Caucasians and not in minority groups, such as Hispanics and African-Americans." Almost one percent of healthy Caucasians in the United States have the mutation in both copies of CCR5 without any obvious immune defects.

Dr. Ahuja also described a mutation in a different gene for a chemokine called SDF that actually accelerates the progression of HIV toward AIDS. Individuals who have this particular mutation on average die about three years more quickly than those who lack the mutation. In addition, the researchers have identified a new mutation in the CCR5 genes that is associated with a delay in disease progression; this mutation is situated in a region of the gene that controls the amount of CCR5 produced by the cell.

Lt. Col. Dolan of Wilford Hall Medical Center pointed out that the mutation that is associated with a delay in disease progression in infected African-Americans is in another chemokine receptor called CCR2. Interestingly, this mutation in the gene for CCR2 is found more frequently in African-Americans, Hispanics and other minority groups than in Caucasians.

"This study shows the power of modern genetic tools applied to a large and carefully defined group of patients," states Robert A. Clark, MD, professor at the Health Science Center and chairman, department of medicine. "The results give new insight into both the evolution of the chemokine receptor system genes and the critical role of this system in HIV progression in patients."

Lead authors of the research paper published in Nature Medicine, Srinivas Mummidi, DVM, PhD; Seema Ahuja, MD; and Enrique Gonzalez, MD, point out that this is the first HIV genetic mutation found that delays the disease progression in African-Americans. This is important since African-Americans account for 57 percent of all new AIDS cases in the United States even though they make up only 13 percent of the population. The Joint United Nations Program on HIV/AIDS (UNAIDS) and the World Health Organization have reported that HIV infects nearly 25 percent of all adults in Botswana and Zimbabwe, a new world high, and at least 10 percent of the population in other African countries. In some isolated areas, the rate is as high as 70 percent.

Asked whether he would advocate genetic testing in patients at high-risk for acquiring HIV or those already infected, Dr. Ahuja replied, "Definitely not! These are association studies, not cause-and-effect studies. We still are not certain how these mutations exert their protective effects. Nor do we know for sure why the same mutation that is present in African- Americans and Caucasians is only beneficial in the former group."

The Ahuja-Dolan team members are actively seeking answers to these questions with the assistance of Health Science Center faculty Victor Tryon, PhD, department of microbiology, Peter O’Connell, PhD, and Fiona E. Craig, PhD, both from the department of pathology.

"These studies highlight the importance of our genetic makeup in resisting infectious diseases in general," Dr. Ahuja concludes, "and our ongoing studies might lead to the development of novel anti-HIV drugs."

Funding for these studies was from the Kleberg Foundation, the Department of Veterans Affairs and other local grants.

Contact: Jan Elkins, (210) 567-2570