Effective ART allows HIV to remain suppressed in blood and tissues without replicating to high levels. However, this effective treatment does not result in curing the disease because HIV can avoid these drugs and the immune system’s natural response by remaining latent in a small number of long lived immune cells. This small amount of HIV that persists in people taking ART is called the HIV reservoir.
While individuals with ART-suppressed HIV have a negligible risk of transmitting the virus and are less likely to experience most symptoms and complications, the level of HIV in their blood—known as viral load—will rebound to harmful levels if they stop ART because of the viral reservoir. Many people on ART with undetectable viral loads live full, healthy lives and do not risk transmitting the virus to others, but maintaining this status requires regular treatment. A cure that brings on treatment-free remission would allow a person with HIV to maintain an undetectable viral load without regular treatment. A person with treatment-free remission would be functionally cured of HIV; he or she would still be infected with a very low level of virus, but would be able to live his or her life with negligible risk of spreading HIV and without the need to take medication daily. Though many challenges still exist, both treatment and cure research are working toward this goal.
Optimizing HIV Therapy
Because ART is so effective at bringing down HIV levels in the blood, some researchers theorized that introducing medication as quickly as possible after infection may prevent HIV from building up a formidable reservoir and render therapy no longer necessary. Experts initially believed this was the case in a child from Mississippi born in 2010. The child became infected with HIV from her mother at birth but began aggressive ART 30 hours later. She continued on ART for the first 18 months of her life before stopping the medication. She was not seen in a clinic until 5 months after her last dose of ART, but remarkably, doctors found that she did not have a detectable viral load. She continued to appear to have treatment-free remission for two years when, in 2014, researchers announced that the child did have detectable levels of HIV. While this was an unfortunate development, this case study illuminated key research questions and showed that periods of quiescence of HIV in the absence of therapy may be possible. A great deal of work is now being done to try to understand where the virus was “hiding” in this child and what led to the eventual rebound of her viral load.
In addition to selecting the right timing for HIV therapies, researchers are also trying to optimize ART by developing long-acting therapeutics that will be able to suppress viral load for long periods of time. Long-acting therapeutics could offer convenience, cost savings, and ease of use to the millions of people worldwide who must take multiple medications daily or multiple times a day to maintain a low viral load. While these advancements in treatment do not replace the need for treatment-free remission, early and long-acting ART may act as critical components of achieving complete viral suppression and reducing the size of the persistent viral reservoir to improve the success of viral remission and viral eradication cure strategies.
Long-acting anti-HIV medication is also being tested for preventative use. View our infographic on long-acting antiretroviral therapy for prevention.
Boosting the Immune System
Most approaches to achieve treatment-free remission involve altering the immune system to induce long-term control of HIV. Researchers attempt to manipulate the immune system with antibodies and therapeutic vaccines that target HIV and HIV-infected cells and with therapies that change the behavior of immune cells to better address the infection.
Broadly neutralizing antibodies, or bNAbs, are potent proteins that block a high percentage of global HIV strains from infecting human cells and facilitate the killing of cells that have already been infected. While they can develop naturally in some people with HIV over time, they usually do so in amounts too small to provide a significant benefit, or they develop too late to control the virus as it mutates over time. Researchers are now exploring how several types of naturally occurring bNAbs in appropriate amounts may be able to control HIV and lead to treatment-free remission. Powerful bNAbs, several of which have already been tested in clinical trials may one day induce treatment-free remission. Alternatively, a therapeutic vaccine that induces the immune system to produce bNAbs may one day lead to long-term control of the virus. Watch a video on current efforts to create and test a therapeutic vaccine for HIV at the NIH Clinical Center.
Researchers are also exploring how immune cells can be manipulated to control HIV in the long term. Chronic viral infections like HIV lead to T-cell exhaustion, in which immune cells called T-cells do not adequately perform their normal functions of identifying and killing virus-infected cells. Scientists have developed antibodies known as anti-PD1 or anti-PD-L1 that have been shown to combat T-cell exhaustion in the lab and in clinical trials for cancer by blocking a cell receptor-ligand interaction that causes cells to atrophy and die. Researchers are now asking whether these drugs may be able to help control levels of HIV in the blood. Learn more about a recent clinical trial of anti-PD-L1 therapy for HIV.
Using another strategy, in 2015, scientists primed killer T-cells with fragments of HIV proteins. The scientists found that these boosted cells effectively killed HIV-infected cells in petri dishes and in mice genetically-modified to have human immune systems. The study suggests that a therapeutic vaccine that similarly boosts the T-cell response to HIV could be successful in achieving treatment-free remission.
Most recently, NIAID researchers achieved viral suppression in a small preclinical trial of monkeys infected with SIV, the nonhuman primate form of HIV, using an experimental treatment that involved an antibody against a cellular receptor called a4b7 integrin. Researchers gave the monkeys 90 days of ART and either no additional treatment or, four weeks after starting ART, a 23-week course of the antibody, which resembles vedolizumab, a drug approved by the U.S. Food and Drug Administration to treat ulcerative colitis and Crohn’s disease in humans. Of the 11 monkeys who received the antibody, eight of them achieved full viral suppression, while the untreated monkeys all experienced viral rebound. Because scientists do not yet understand why this antibody had such a striking effect, NIAID will continue to study the underlying mechanism of this experimental treatment regimen. Read more about the preliminary success of an antibody against a4b7 integrin to suppress viral load in monkeys with SIV. Learn more about a small clinical trial to test vedolizumab in people living with HIV.