How antibodies and T cells could keep HIV in check—without ART

New research suggests that a combination of experimental immunotherapies could allow the body’s immune system to reprogram itself and control HIV without long-term use of antiretroviral therapy (ART). Combination immunotherapy techniques, including HIV vaccination and immune stimulation through broadly neutralizing antibodies (bNAbs), have shown promise in non-human primate research, but two newly published studies offer hope that these approaches could work in people, by working with parts of the immune response to control HIV. 

A combination against resting virus

In a small, proof-of-concept study conducted by the University of California–San Francisco (UCSF) and released on December 1, World AIDS Day, in Nature, researchers enrolled 10 participants, seven of which were able to keep HIV at low levels after going off ART for a significant length of time. 

All 10 had well-controlled HIV and started ART soon after they acquired the virus. For the study, all participants received a therapeutic vaccine to encourage their T cells to attack latent HIV (it’s resting in parts of the body—called the viral reservoirs—but not replicating). Then, they received an antibody combination including two bNAbs. They were also given the drug lefitolimod, which activates a protein called Toll-like receptor 9, which charges innate immune responses. (Innate immune responses are the body’s general, rapid-response defenses such as mucous membranes and chemical defenses like stomach acid or tears.) More long-acting bNAbs were given when ART was interrupted.

When ART is stopped, HIV typically rebounds in about two weeks and then increases rapidly. But in the UCSF study, only three of the 10 patients experienced the typical rapid rebound, while six maintained low levels of the virus for months. For one participant, HIV did not rebound for the length of the study.

Researchers found that those who controlled the virus were able to do so through T cells that expanded dramatically when confronting the virus. 

The most significant finding of the study was the identification of a biological response in the CD8+ T cells to the virus as it was re-emerging when ART was paused, according to Michael Peluso, MD, an assistant professor in UCSF’s Department of Medicine and the study’s first author. That finding gives researchers an important lead on what future interventions should be trying to achieve, he told POSITIVELY AWARE in an email. “We think that the combination of immunotherapies played a role in inducing that response, and this study gives us something to focus on in future studies which we can try to design to try to induce that response.”

Importantly, “elite controllers”—people with unique genetics that allow them to spontaneously control HIV without medication—were excluded from the study, researchers said. However, Peluso said they learned after the trial that several of the participants had certain genetic markers that have been associated with post-treatment control of HIV in some studies, but not in others. “We don’t think that alone explains the findings,” he told POSITIVELY AWARE. 

Peluso urged optimism and caution about the results of the combination immunotherapy used in the study.

“The results are not definitive, and the approach we used in this trial is not the endgame,” Peluso wrote. “Although we believe that we moved the needle in terms of helping some participants’ immune systems to have better control of HIV, this needs to be confirmed in larger studies with placebo arms, for example through networks like the ACTG [originally the AIDS Clinical Trials Group, now known as Advancing Clinical Therapeutics Globally].”

Peluso also said that the regimen administered to the participants was very complicated and not scalable. “The regimen included 34 weeks of immunotherapy interventions and very intensive monitoring, and the level of viral control achieved although impressive is still probably not good enough. No one would think that what we achieved here is better than ART. However, we have for so long framed inducing control of HIV without medications as an insurmountable challenge, and this trial provides hope that that challenge can be overcome.

“Regarding your final question,” he continued, “It is likely that all branches of the immune system play a role in achieving post-intervention control. We recently wrote a review on this. We think there were a variety of factors that played a role in our study—potentially some effect of the vaccine, followed by the bNAbs helping to prevent the typical explosive HIV rebound, and basically preventing the virus from outrunning the immune system, and the enhancement of HIV-specific CD8+ T cell responses due to the combination of interventions. Ultimately HIV-specific CD8+ T cells seemed poised and ready to go after HIV as it was emerging, and that CD8+ T cell response was the strongest correlate of control.”

An immune cell that keeps HIV in check

One other study, also published on December 1 in Nature, offers additional hope for an ART-free future with the finding that some people control HIV without ART after receiving bNAb infusions. The study, conducted by Mass General Brigham and the Ragon Institute, concluded that some people with HIV who are given bNAbs can safely stop taking ART and still maintain control of the virus for years, while others taking bNAbs do not achieve remission. It offers an insight into how the body’s natural defenses could be boosted to achieve long-term HIV remission, researchers say. 

The team analyzed blood samples from 12 people with well-controlled HIV in four different clinical trials who received bNAbs before stopping ART. They compared samples from two groups: seven participants who could keep the virus at very low levels for up to seven years of bNAb treatment with samples of five participants who experienced viral rebound. The team found that in the group who didn’t experience viral rebound, CD8+ T cells, which they call “post-intervention controllers,” effectively multiplied and killed HIV continually. Treatment with bNAbs was helpful in enhancing the ability of existing CD8+ T cells to fight infection, but the team concluded that having robust HIV-targeting CD8+ T cells—cells that mimic a stem-cell state—before treatment with bNAbs was key, although the bNAbs appear to have enhanced existing immune responses. 

“These individuals are distinguished by the quality of their pre-existing cellular immune responses against HIV, specifically the ability of their CD8+ T cells to proliferate and kill infected cells,” said the study’s senior author, David Collins, PhD, an investigator at the Ragon Institute of Mass General Brigham, MIT and Harvard, in an email.

Collins acknowledged that the study was small and will need to be followed up in larger trials, with placebos, to identify ways to reduce the HIV reservoir and determine optimal timing and dosing with bNAbs. But he said that its results clearly show the importance of enhancing the immune system to achieve durable post-treatment control of HIV. “Building on these findings, it will be important to develop approaches to elicit these protective immune features in a larger proportion of people living with HIV to achieve a functional cure that is both scalable and effective.”

Adding it up

Both authors emphasized that the results are preliminary and they don’t clarify how bNAbs and other therapies might charge the immune system to fight HIV. But the studies add to a growing body of research that gives hope for an alternative to lifelong ART. 

In a commentary, also published in Nature, Jonathan Li, MD, an associate professor at the Harvard Medical School, said that both studies point to the importance of regenerative, adaptive anti-HIV CD8+ T cell response for bNAbs to be effective and that they suggest a delicate balance of viral proteins—or antigens—“sufficient to stimulate CD8+ T cell immunity but not overwhelm it, could be central to achieving post-ART HIV control.”

Both studies underscore three key principles, Li wrote. “First, the quality of anti-HIV CD8+ T cells matters, especially the presence of stem-cell-like antiviral CD8+ T cells that are capable of sustained proliferation and cytotoxic responses. Second, bNAbs and T cells might act in synergy, given that effective anti-HIV antibodies can delay or reduce the immediate post-ART viral rebound (or do both) and create an immune environment that is conducive to enhancing effective cellular responses. Third, therapeutic combination approaches that incorporate several branches of the immune response are likely to hold the greatest promise. Coordinated use of T cell-inducing vaccines, bNAbs and other immunomodulators might reproduce the rare immune features in people who achieve post-ART HIV control.”

What’s in a word?

For more than three decades ART has transformed HIV from a virus that usually led to death into a chronic and manageable condition. Still, taking daily pills for life (or getting regular injections in the case of long-acting ART) can be a burden. And while ART suppresses viral replication, it doesn’t completely reduce chronic inflammation, a condition that can lead to health problems like cardiovascular disease and neurocognitive disorders. That’s why the HIV research community continues to search for alternatives. 

There is a robust and active debate about what management of HIV without ART should be called—terms such as “long-term remission” or “functional cure.” Peluso said that the most accurate term is “post-intervention control,” to indicate that it was achieved after a set of interventions that go beyond standard ART. Both studies indicate that there is likely no silver bullet for this control, but rather a complex strategy to enhance the body’s immune system.