Polymorphisms in HIV-1 Gag Are Associated With Plasma Viral Load

In chronic untreated HIV infection, the total number of HLA-associated polymorphisms in the viral gene encoding the Gag protein is inversely associated with plasma viral load, according to a report in the July 11th issue of AIDS.

"Study results are consistent with a growing body of evidence suggesting that certain HIV proteins may be better vaccine candidates than others," Dr. Zabrina L. Brumme from Partners AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts told Reuters Health. "Specifically, the HIV Gag region, which encodes numerous structural components of the virion, may represent an appropriate vaccine target."

Dr. Brumme and colleagues undertook a population-based identification of HLA-associated polymorphisms in Gag and investigated their relationship with plasma viral load in chronically HIV-infected, treatment-nave patients harboring predominantly subtype B infections.

The authors identified 111 unique HLA-associated polymorphisms, of which 50 (45%) represented escape polymorphisms (amino acids enriched in the presence of a specific HLA allele) and 61 (55%) represented reversion polymorphisms (enriched in the absence of a specific HLA allele).

There was a modest inverse correlation between the total number of HLA-associated polymorphic sites in Gag within each individual and the plasma viral load, the investigators say, "supporting the hypothesis that a broad ability to target Gag contributes to HIV immune control."

The proportion of escaped sites correlated positively with plasma viral load, the researchers note, and there was a trend toward an inverse correlation between the proportion of escaped Gag codons and lower CD4 cell counts.

"Elucidating the contribution of HIV immune escape mutations to the clinical course of HIV disease (including plasma viral load) has proved to be an extremely complex and challenging task," Dr. Brumme commented.

"That being said," she continued, "we are continuing to investigate this phenomenon in independent populations of HIV-infected individuals, including individuals whose dates of infection are known, and who are followed over time. In this way, we can observe a direct temporal association between selection of the specific mutation, and the subsequent changes in plasma viral load."

"If evidence continues to accumulate in support of this hypothesis, future candidate vaccines against HIV that are designed to stimulate cellular immune responses to the virus may focus more on specific HIV proteins such as Gag," Dr. Brumme said.

"We really have much more to learn about how the human immune response tries to fight HIV and how the virus adapts to this challenge," Dr. Brumme added. "Studies such as ours contribute to understanding this fundamentally important issue and will help direct HIV vaccine design efforts."

AIDS 2008;22:1277-1286