Is This the Key to a Cure?

Aunique group of poz folks called post-treatment controllers are able to maintain viral suppression even during periods of treatment interruption. Although they aren’t actively taking antiretroviral medications, they remain undetectable. New research suggests how these rarities may hold the key to a functional cure.

Post-treatment controllers should not be confused with elite controllers, people who test positive for HIV but don’t become ill or show other signs of being poz, despite never going on antiretroviral treatment. Post-treatment controllers are the handful of HIV-positive people who begin antiretroviral therapy then go off HIV medications and are still able to maintain viral suppression.

Usually such treatment interruptions lead to HIV rebounding within three to four weeks, but a very small minority of people have kept the virus suppressed for 24 weeks or longer after interruption. Naturally, researchers want to understand who these people are and how they are able to maintain viral suppression without medication. Two new studies have provided keys to both.

“Post-treatment controllers represent a natural model of sustained remission,” Jonathan Li, M.D., of Brigham and Women’s Hospital’s Infectious Disease Clinic and lead author on both studies told Science Daily. “Understanding these individuals can lead to new insights for HIV therapies.”

Reviewing the data collected from 14 clinical studies involving treatment interruption, the researchers found that 67 people out of 700 participants had managed to maintain viral loads of 400/ml or lower for at least 24 weeks after their antiretroviral treatment was interrupted.

Further results, published in The Journal of Infectious Disease, showed that those who were treated soon after diagnosis were significantly more likely to become post-treatment controllers than those who started treatment later. Other long-term benefits of early intervention (rather than withholding treatment until someone gets sick) have been recognized for years, and since 2015, the World Health Organization has recommended early treatment for everyone diagnosed with HIV.

A second study on post-treatment controllers, published in The Journal of Clinical Investigation, specifically compared HIV reservoirs in post-treatment controllers and post-treatment non-controllers (those who don’t maintain viral suppression after treatment interruption). HIV is known to “hide” in such reservoirs, where it isn’t susceptible to antiretrovirals nor seen in blood tests, but from which it can later rebound, if treatment is interrupted.

In the second study, Li’s team examined HIV DNA sequences in the cells of both groups. Before treatment interruption, researchers noted that post-treatment controllers had significantly smaller reservoirs (despite having roughly the same amount of active/inactive viral DNA overall).

Previously, research noted that low levels of total HIV DNA had been associated with short-term delays in viral rebound. Two Boston patients who underwent stem cell transplants retained viral suppression afterwards for 12 and 32 weeks respectively. But the new study suggests “factors in addition to reservoir size must play an important role in determining time to rebound. Such factors could include differences in viral replication rate and/or robust anti-HIV immune responses.”

Another intriguing discovery was that reservoirs of even defective viral DNA could play a part in whether someone is able to maintain viral suppression off of antiretroviral medications. Individuals with delayed viral rebound had smaller percentages of defective viral DNA than those whose HIV rebounded quickly. Researchers admitted, “The reason behind this counterintuitive result is unclear.” (One would think more defective DNA would make HIV more robost, not less.) Possible explanations include that more defective viral DNA may be a sign of bigger HIV reservoirs.

Researchers also found “an association between higher levels of [natural killer] cell activation and HIV-specific T cell activity with lower levels of total and defective proviral genomes.” Natural killer cells play a critical role in viral immunity and viral control. They found more natural killer cells when there was less defective HIV DNA.

“This suggests that a more robust HIV-specific immune response can identify and effectively eliminate HIV-infected cells, even those harboring defective proviruses,” the researchers wrote. “These findings support the concept that defective HIV genomes can lead to viral RNA transcription and antigen production, which leads to interactions of cells harboring defective HIV genomes with both the innate and adaptive immune system.”

The Journal of Clinical Investigation report concluded, “Until recently, the defective proviral reservoir appears to have been underappreciated, but these results support the concept that defective proviruses are far from [dormant] and are likely playing key roles in immune activation, shaping anti-HIV immune responses, and may be a marker of the timing of plasma viral emergence after ART discontinuation.”

Those with lower levels of defective viral DNA may have more chance of retaining viral suppression despite interruptions in treatment.

“Each year, there are millions of new HIV [diagnoses],” Li said to Science Daily. “The results of these studies may help inform the design of strategies and trials aimed at achieving HIV remission, which we hope will bend the curve of this epidemic.”

Post-treatment controllers may be considered functionally cured while their viral loads remain suppressed during their periods of treatment interruption, however the majority will experience a viral rebound eventually.

According to the Journal of Infectious Diseases report, 55 percent of the post-treatment controllers maintained HIV control for two years, and approximately 20 percent maintained viral suppression for five years or more. Even controlling HIV for two years without antiretroviral medication would be a huge boon for those living with HIV. Without a doubt, a longer functional cure is everyone’s end goal.