Study Findings Could Explain Innate Resistance to HIV Infection

The ability of some people to remain HIV-negative despite repeated exposure to the virus may be tied to the presence of specific versions of two genes that interact to produce an immune response that prevents infection, according to a study by investigators at the Research Institute of McGill University Health Centre in Montreal (AIDS 2008;22:1487-91). The study's findings could eventually influence future HIV/AIDS treatments and the development of a vaccine to prevent HIV infection.

"I don't think it will change much right now in terms of treatment," said Salix Boulet, a Ph.D. student at McGill University and one of the study researchers. "But it might give clues to new types of therapy in terms of stimulating the innate immune system."

In the study, researchers followed 41 individuals who remained HIV-negative despite engaging repeatedly in high-risk behaviors, such as having unprotected sex or sharing needles. The researchers also followed 186 subjects who had primary HIV infection (i.e., in their first year of infection). They found that the 41 individuals who remained uninfected demonstrated coexpression of a certain combination of KIR3DL1 and HLA-B alleles that may serve to stimulate the body's natural killer, or NK, cells, helping to prevent HIV infection.

Specifically, the 3DL1*h/*y-HLA-B*57 combined genotype was more common among the exposed uninfected individuals (12.2 percent) than the individuals with primary infection.

The study, which was published in the July 16 issue of the journal AIDS, represents an "observation, not an 'all-or-nothing' phenomenon," said Boulet. "Some people who have these genes still get infected," said Boulet. "But they are much less likely to get infected if they have these genes."

Boulet said future research would focus on the different functions of NK cells and how they interact with specific genotypes.

"We are interested in seeing whether people with these genes have NK cells that are active or have a specific function of killing," said Boulet.

Meanwhile, another recently published study established that a variant of a gene found only in people of African ancestry increases the odds of becoming infected with HIV by 40 percent.

After people are infected, however, the same variant seems to slow progression of HIV disease, enabling individuals who carry the gene variant to live about two years longer than those who do not carry the variant, according to the study, which was published in the July 17 issue of Cell Host & Microbe.

"It's well known that individuals vary in their susceptibility to HIV and that, after infection occurs, the disease progresses at variable rates," said Sunil Ahuja, M.D., a professor at the University of Texas Health Science Center at San Antonio and a lead researcher on the study. "The mystery of variable infection and progression was originally thought to be mainly the result of viral characteristics, but in recent years, it has become evident that there is a strong host genetic component."

The study, which looked at 1,266 HIV-positive U.S. military personnel and 2,000 noninfected, otherwise healthy individuals, identifies one of the few genetic risk factors found only in people of African descent. The gene in question encodes a protein called Duffy antigen receptor for chemokines, or DARC, which primarily is found on the surface of red blood cells. In Africa, about 90 percent of people carry a DARC variant that leaves them lacking this red blood cell receptor.

Although this "DARC-negative" condition confers protection against infection by a particular malaria parasite, Plasmodium vivax, it leaves individuals with this variant more susceptible to HIV. Given the prevalence of this DARC variant in Africans, the researchers estimate that it could be responsible for about 11 percent of the HIV cases there.

P. vivax is not the parasite responsible for the millions of deaths from malaria that now occur on the African continent each year, leading the researchers to speculate that this particular DARC variant may be so prevalent today because, at one time, it conferred protection against another lethal strain of malaria.

"The big message of this paper is that something that protected people against malaria in the past is now leaving them more susceptible to HIV," said Robin Weiss, Ph.D., a professor of viral oncology at University College London and a co-author of the study report.