Over 30 million people worldwide are infected with HIV, and although antiretroviral therapy (ART) has dramatically reduced mortality and advanced the quality of life of millions of HIV-infected people, only one adult is thought to have been cured to date. This man, Timothy Brown, previously known as “the Berlin patient,” received a bone marrow transplant from a donor who was naturally resistant to HIV infection due to a mutation in a key receptor HIV needs to enter a cell. While bone marrow transplantation is not feasible for the millions of others infected with HIV, scientists are testing several new treatment approaches that give hope that a cure for HIV may be within our grasp.
In Wednesday’s plenary session, “Tackling HIV Latency: Towards a Cure for HIV,” Sharon Lewin, MD, PhD, discussed the major barriers to curing HIV and new approaches to target and kill the virus that persists in HIV-infected subjects on ART.
Although combination ART is responsible for a major reduction in morbidity and mortality due to HIV, the virus cannot be eradicated by ART alone. This is because HIV is able to hide inside immune cells in an inactive state called latency, avoiding attempts at its destruction. Drugs can control actively replicating virus very efficiently, but they cannot touch virus in latently infected cells. A small number of long-lived, latently infected cells establish themselves shortly after infection and persist indefinitely, even following ART. Once ART is stopped, viral counts rebound rapidly in nearly all patients, making ART a life-long requirement and a major personal, medical, and economic burden. As a result, long-term control of the virus in the absence of ART—now called remission—is the Holy Grail of HIV therapy.
Lewin’s research has provided key insights into how latency is established in resting cells. This knowledge may help scientists discover a way to reverse the process—an essential goal, as a cure for HIV relies on the elimination of latently infected cells. One strategy being tested in clinical trials is to activate the latent virus in a person on ART. Activation of the virus will then either directly kill the cell, or alternatively, make the cell visible to immune-mediated clearance. This is frequently referred to as “shock and kill.”
Lewin’s lab has played a key role in identifying new agents and carrying out clinical trials of drugs that can “shock” latently infected cells. These agents include histone deacetylase inhibitors (HDACi), to reactivate latent HIV, forcing the virus to reveal its presence inside cells. HDACis induce and maintain viral latency through interaction with the HIV long terminal repeat promoter, similar to the control of other host genes. Increasing histone acetylation plays a crucial role in potentially reversing latency.
Lewin has pursued work in multiple clinical trials of HDACi in HIV-infected subjects on ART. While all trials to date have shown some capacity to activate latent virus, none have successfully eliminated latently infected cells. Furthermore, Lewin described HDACi as a “blunt instrument” that may cause long-lived adverse effects on gene expression and immune function, and she recognized the need for a safer intervention.
Lewin also highlighted data on HDACi and other newer, less toxic interventions that may have a potential role in the shock and kill approach. Strategies such as blocking immune checkpoint markers to reinvigorate infected cells or targeting a coreceptor of HIV to render cells resistant to infection are promising. Trials for these are in their infancy, but have shown potential. In spite of these advancements, one barrier to moving forward is a lack of good biomarkers that serve as indicators for stopping ART and predictors of cure or remission, Lewin said.
The recent launch of ambitious funding initiatives for an HIV cure from the National Institutes of Health, the American Foundation of AIDS Research, and other funding bodies—together with some innovative new partnerships between academia, pharma and community—have potential to significantly accelerate the basic scientific discoveries still needed to eliminate HIV persistence. Lewin stressed that “any cure must be cheap, scalable, and available to all.”