Today, people living with HIV typically must take antiretroviral therapy (ART)—a daily regimen usually of three or more antiretroviral drugs—to stay healthy and prevent transmission of the virus to others.
An HIV cure in the classic sense would require the elimination of the reservoir of all virus-carrying cells. These cells, which contain HIV DNA, have entered a resting state such that they do not produce any parts of the virus unless they become activated. HIV reservoir cells can survive in this resting state for years, even for life, while remaining invisible to the immune system and antiretroviral drugs.
An alternative to a classic cure is sustained ART-free remission. This objective would not involve eradicating the HIV reservoir, but rather would allow a person living with HIV to keep latent virus suppressed without daily medication.
Boosting the Immune System to Achieve HIV Remission
Most approaches to achieving sustained ART-free remission involve altering the immune system to induce long-term control of HIV. Researchers attempt to manipulate the immune system with interventions that target HIV and HIV-infected cells or that change the behavior of immune cells to better address the infection.
One promising intervention for achieving ART-free remission is broadly neutralizing antibodies, or bNAbs. These potent proteins can block nearly all HIV strains from infecting human cells in the laboratory and facilitate the killing of cells that have already been infected. While bNAbs develop naturally in some people with HIV, they usually do so either in amounts too small to provide a significant benefit or too late after infection to control the rapidly replicating and mutating virus. Studies are now underway in animals and people who have been taking ART to determine whether periodic infusions or injections of bNAbs can keep HIV suppressed after ART is halted. Scientists are developing bNAbs with improved attributes, including greater potency and longer duration in the body, and are testing treatment with combinations of two or three bNAbs in a manner akin to combination ART. Read about the encouraging 2018 results of a small clinical trial testing infusions of a bNAb duo for ART-free remission and about the creation and preliminary testing of a three-in-one bNAb.
Scientists also are testing whether bNAbs against the virus can produce ART-free remission by inducing long-lasting, immune-mediated control of the virus without further intervention. A study led by scientists at NIAID and Rockefeller University showed that giving infusions of two different bNAbs to monkeys infected with the simian form of HIV enabled the immune systems of some of the animals to control the virus long after the antibodies were gone.
Another approach to ART-free remission involves antibodies that bind to parts of the immune system. One such strategy targeted a host immune cellular receptor called alpha-4 beta-7. A study giving short-term ART and infusions of an anti-alpha-4 beta-7 antibody to monkeys infected with a simian form of HIV reportedly led to prolonged control of the virus in some animals and replenishment of immune cells after all treatment stopped. An NIH study that tried to replicate this outcome did not achieve consistent results, however.
NIAID scientists conducted a small, early-phase clinical trial in which people living with HIV that was well controlled with ART received infusions of vedolizumab, an anti-alpha-4-beta-7 antibody that is FDA-approved for ulcerative colitis and Crohn’s disease. These volunteers received both ART and vedolizumab at the beginning of the study, paused ART while continuing to receive the antibody, and finally stopped all treatment. The regimen was safe and well tolerated but did not generate lasting control of the virus.
In a different strategy toward ART-free remission, scientists primed killer T-cells with fragments of HIV proteins. The researchers 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 suggested that a therapeutic vaccine that similarly boosts the T-cell response to HIV might be successful in achieving long-term control of the virus. NIAID scientists tested one such experimental therapeutic vaccine and found it to be safe but not effective. Other investigators have explored creating therapeutic vaccines that induce the immune system to produce bNAbs to achieve ART-free remission, but this research is still at a very early stage.
Using Very Early ART to Achieve HIV Remission
Because ART is so effective at bringing down HIV levels in the blood, some researchers have 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. As of 2018, three cases of sustained ART-free remission in children after early, limited ART have been reported.
The first of these cases involved a child from Mississippi born in 2010. The “Mississippi Baby” became infected with HIV from her mother at birth but began aggressive ART 30 hours later. She continued taking ART for the first 18 months of her life before stopping the medication. Although she was not seen in a clinic until 5 months after her last dose of ART, doctors found that—remarkably—she did not have a detectable viral load when she resumed receiving medical care.
The child continued to appear to be in sustained ART-free remission for two years when, in 2014, researchers announced that the child had detectable levels of HIV. While this was an unfortunate development, the case study illuminated key research questions and showed that periods of HIV quiescence in the absence of ART may be possible. Much work has been done to try to understand where the virus was “hiding” in this child and what led to its eventual rebound. In related research, NIAID is co-funding a clinical trial to explore whether giving ART soon after birth to infants who became infected with HIV in the womb leads to remission of the virus, enabling the children eventually to stop treatment for an extended time.
Since the Mississippi Baby’s case came to light, two additional cases of sustained ART-free remission in a child after early, limited ART have been reported. In 2015, researchers reported that a French child who was born with HIV in 1996, started anti-HIV therapy at age 3 months, and stopped treatment sometime between ages 5.5 and 7 years continued to control the virus without drugs more than 11 years later. Then in 2017, scientists reported that a nine-year-old South African child who was diagnosed with HIV infection at one month of age and received ART during infancy had suppressed the virus without ART drugs for 8.5 years. Learn more about the South African child.
Taken together, these three unusual cases have strengthened the hope that by treating HIV-infected children for a brief period beginning in infancy, physicians may be able to spare them the burden of life-long ART and the health consequences of long-term immune activation typically associated with HIV disease.
Developing Long-Acting ART to Aid HIV Remission Strategies
Along with testing the impact of very early ART, researchers are trying to optimize ART by developing long-acting therapeutics that can suppress HIV for extended periods. Long-acting therapeutics could offer convenience, cost savings, and ease of use to the millions of people worldwide who must otherwise take multiple drugs daily to maintain a low viral load.
Early and long-acting ART may be critical to achieving complete viral suppression and reducing the size of the HIV reservoir. These factors, in turn, could improve the success of strategies for sustained ART-free remission and HIV eradication.
Long-acting antiretroviral medication is also being tested for preventive use. View an infographic on long-acting HIV prevention research supported by NIAID.