Protein Changes in Immune System Determine Ability to Control HIV Without Drugs

People who are controlling HIV are able to prime their own immune system, to get it to target the virus very effectively.

A small number of people with HIV have the ability to control the infection without therapy. They dont develop clinical disease, are less likely to transmit HIV to others and the number of key infection fighting cells in their immune system remains stable.

Why this small minority of so-called HIV "controllers" about one in 300 people infected with HIV are able to keep the virus in check with their immune system has been unclear to scientists for almost two decades.

But new results from a multinational study involving more than 300 investigators at over 200 institutions around the world may have found the genetic basis for the answer.

"People who are controlling HIV are able to prime their own immune system, to get it to target the virus very effectively. And thats what this paper demonstrates nicely," says Joseph J. Eron, MD, study co-author and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill. Eron also directs the clinical core for the UNC Center for Aids Research.

The study was led by investigators from the Ragon Institute of Massachusetts General Hospital, MIT and Harvard and from the Broad Institute of MIT and Harvard. It found differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.

A report of the research appears online in the journal Science on Nov. 4.

The cellular immune system relies largely on HLA-B to recognize and destroy infected cells. "In other words, the immune systems success in controlling HIV is based on how well it can take parts of the virus and carry them to the membrane of the infected cell where they can be displayed and marked for destruction by killer T cells," Eron explained.

Thus, according to co-senior author Dr. Bruce Walker, director of the Ragon Institute, "Of three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS."

The research involved a multi-ethnic genome-wide association study (GWAS) of some 1,000 controllers and 2,600 individuals whose HIV infection had progressed. Blood samples were tested for variants throughout the genome, which identified about 300 sites that were statistically associated with immune control of HIV.

All of the sites, or single nucleotide polymorphisms (SNPs), were found only within regions of chromosome 6 that code for HLA proteins. And direct testing of those SNPs linked five amino acids within the HLA-B protein to differences in viral control.

"To do studies like this, it really does take a village," Eron says, pointing out that the work required the participation of the hundreds of HIV controllers, among them UNC patients, and many having traveled to Boston for testing.

"The needle in the haystack are the controllers especially those whose levels of HIV are below the limit of detection. We know theyre infected because they have a positive antibody response and occasionally theyll have a little bit of virus in their blood plasma."

The UNC clinical scientist added that these individuals generally are enthusiastic about making a contribution to knowledge. "Many see it as their responsibility to give blood to help figure out how others with HIV can arrive at their state."

The new findings could form the basis for additional studies that might eventually lead to a vaccine against HIV.

The research was supported in part by grants from the Bill and Melinda Gates Foundation and the National Institutes of Health.