A major obstacle to curing people of HIV infection is the way the virus hides in a reservoir primarily of dormant immune cells called resting memory CD4+ T cells. One potential approach to curing HIV infection is to awaken these latent CD4+ T cells so they start making HIV proteins. This would alert the immune system that the cells are infected, and, in theory, generate an immune response that kills them. It has been unclear, however, whether typical immune mechanisms for killing virally infected cells would eliminate HIV-infected CD4+ T cells awakened from the HIV reservoir.
To answer this question, NIH grantee Robert F. Siliciano, M.D., Ph.D., of the Howard Hughes Medical Institute and the Johns Hopkins University School of Medicine, and colleagues extracted immune cells and reservoir-based HIV from 25 infected people to study in the laboratory and in mice. Ten of these people had started combination anti-HIV therapy early (within 3 months of infection) and 15 had started late (3 months or more after infection). In the early-treatment group, scientists found that most of the HIV-infected CD4+ T cells in the viral reservoirs were sensitive to detection by killer T cells, the immune cells that seek and destroy infected cells. By contrast, nearly all of the HIV that infected CD4+ T cells in the reservoirs of the late-treatment group had developed mutations that enabled the infected CD4+ T cells to escape detection by the killer T cells that typically dominate the immune response to HIV infection.
Despite this, the scientists discovered that most HIV-infected people in the late-treatment group also had other killer T cells that recognized parts of HIV that had not mutated, but these cells were ineffective at destroying their targets. To boost the killing capacity of these cells, the researchers stimulated them with a mixture of HIV protein fragments before exposing them to unmutated parts of the virus. The boosted cells effectively killed the HIV-infected cells in both the laboratory and mice altered to have human immune systems. This suggests that a therapeutic vaccine that similarly boosts the T-cell response to HIV could be part of a strategy for curing chronic HIV infection.
K Deng et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature DOI: 10.1038/nature14053 (2015).
Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH, is available for comment.