Research indicates that about 1% of patients with HIV are able to keep the infection under control without the need for antiretroviral therapy (ART). Dubbed “controllers,” these patients have been thought to hold clues on how to develop a vaccine against HIV because of their unique immune responses. “The body’s defenses in these patients allow them to fight the virus more effectively than others with the infection but don’t prevent them from being infected,” says Richard T. D’Aquila, MD. “Understanding the underlying processes could help researchers determine which immune responses should be boosted in non-controllers so that their stronger defenses could hold the line against HIV without ART in the same way these processes happen in controllers.”
Controllers have plasma viral loads that are consistently less than 5,000 copies/mL as well as stable, high CD4 cell counts for many years without ART, according to Dr. D’Aquila, senior author of a study of controllers published in PLoS ONE. For their study, the research team investigated a newly discovered immune defense called the APOBEC3 system. APOBEC3 proteins work within immune system cells to block replication of HIV. In most patients with HIV, a gene produced by HIV works to remove APOBEC3 from cells so that HIV can replicate. “We hypothesized that controllers may have a stronger APOBEC3 defense than most patients with HIV,” Dr. D’Aquila notes.
Upon studying the cells of controllers, the investigators found that controllers do indeed have larger supplies of APOBEC3, long after acquiring HIV, in specific white blood cells. It is within these cells (resting memory T cells) where HIV lies inactive until ART is stopped in most patients. However, in controllers, the extra supply of APOBEC3 causes any replication made from the resting memory T cells to inherit APOBEC3, making the virus ineffective. “We believe that the controllers’ first line of defense weakens the ability of HIV to eliminate all APOBEC3, and that it is eliminated in non-controllers,” says Dr. D’Aquila.
If Dr. D’Aquila’s team is able to show in ongoing research that APOBEC3 levels are depleted in the first few months of infection in non-controllers, they hope to then determine if starting ART within a window of 4 to 6 months helps preserve this defense and better control HIV in a larger number of patients in the absence of ART. “We’re also working to identify molecules that might become drug candidates that could boost APOBEC3 levels or block the ability of HIV to deplete APOBEC3,” he adds. “These medications could make more people better able to control HIV and hopefully allow them to stop ART after a few years instead of remaining on ART every day for the rest of their lives.”
De Pasquale MP, Kourteva Y, Allos T, D’Aquila RT. Lower HIV provirus levels are associated with more APOBEC3G protein in blood resting memory CD4+ T lymphocytes of controllers in vivo. PLoS ONE. 2013; 8:e76002. Available at www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0076002&representation=PDF.
Kourteva Y, De Pasquale M, Allos T, et al. APOBEC3G expression and hypermutation are inversely associated with human immunodeficiency virus type 1 (HIV-1) burden in vivo. Virology. 2012:430:1-9.
Graf E, Mexas A, Yu J, et al. Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART. PLoS Pathog. 2011;7:e1001300.
Saez-Cirion A, Hamimi C, Bergamaschi A, et al. Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers. Blood. 2011;118: 955-964.