“Elite controllers” provide clues for an HIV cure strategy

Progress has been made in the treatment and prevention of HIV, but obstacles remain. Every day, 3,500 people are newly infected with HIV. Globally, nearly one-quarter of all people living with HIV (PLWH) do not have access to lifesaving antiretroviral therapy (ART), which suppresses replication of the virus. A cure for HIV is needed to end AIDS once and for all.

HIV is controlled by suppressive ART, but some intact virus hides out in the body and reactivates if ART is removed. Any cure strategy would likely need to control or eradicate any virus that rebounds once treatment is stopped.

A small number of people living with HIV (PLWH), however, seem to already have a natural ability to control HIV without ART. About 0.5% of all PLWH are “elite controllers,” individuals who can maintain undetectable levels of infectious HIV in the absence anti-HIV medications.

Understanding elite controllers

Several of these individuals have been followed for decades in research centers worldwide in order to understand the mechanisms in the body that produce this control and other factors that may be in play.

Many unique features have been revealed.

Regarding sex, females are represented up to four-fold more than males. In terms of immunology and genetics, the antiviral immune activity of elite controllers has been mostly linked to HIV-1-specific T cell responses, as evidenced by a strong enrichment for certain protective human leukocyte antigen (HLA) tissue types that regulate killer T cell activity. And in terms of patterns by which HIV inserts itself into host T cells, elite controllers have viruses buried into “gene deserts,” regions of chromosomes from which active HIV is difficult to induce.

Looking at different reservoir sites

Most of these findings were based on circulating blood cells. What about lymph nodes from such individuals, sites which harbor the vast majority of latent HIV?

A research team, including amfAR grantee Dr. Xu G. Yu of the Ragon Institute of MGH, MIT and Harvard, and Brigham and Women’s Hospital, studied two female elite controllers over the course of decades, with paired blood and inguinal (groin) lymph nodes collected and stored. One was diagnosed with HIV in 1992 at age 31 and the other was diagnosed in 2011 at age 44. Neither had ever used ART, and both had the protective HLA gene signature B*57, which has been associated with a more effective immune control of HIV.

A 7-10-fold lower frequency of intact latent proviruses was found in the lymph nodes vs. blood, with many of those viruses integrated in chromosomal areas containing inactive genes. Over 9-10 years of follow-up, a 3-18-fold decrease in the HIV reservoir was seen. These observations were consistent with the hypothesis that viral reservoirs in elite controllers are under strong, likely immune-mediated, control in both blood and lymph node.

The researchers believe that their study “may inform the development of functional cure strategies aiming to induce drug-free control of HIV in larger numbers of people living with HIV.”

By Jeffrey Laurence, MD