Once the human immunodeficiency virus (HIV) enters a cell, there is no going back. The virus inserts its genetic material into the genome of the host cell, and the viral genes become a permanent part of the cell until it dies. As a result, the cell either makes copies of the virus that infect other cells, or it doesn’t express the viral genes — making it a latently infected cell. In the latter scenario, the infected cell becomes part of the latent HIV reservoir and remains invisible to the immune system. Yet, it can reactivate at any point and spread the virus again.

David Margolis, an infectious disease researcher at the University of North Carolina at Chapel Hill, has spent much of his career studying the latent HIV reservoir and how to get rid of it for good. The latent reservoir is the reason that HIV remains incurable to this day, despite highly effective antiretroviral therapy (ART) that suppresses the virus by preventing it from replicating. “[The latent HIV reservoir] persists for years and decays very slowly, such that you would need to be on treatment for more than 70 years for the virus to be eradicated,” he said.

Decades ago, scientists started investigating the use of latency-reversing agents, or drugs that “awaken” the latently infected cells. Their goal was to make these cells visible to the immune system again so that it could kill them all off and the individual would be cured. Yet, clinical trials have shown that while these drugs do activate latent cells, they have failed to lead to a reduction in the viral reservoir on their own (1).

Now, researchers are pursuing a promising new strategy: the combination of a latency-reversal agent with a broadly neutralizing antibody (bNAb) to help boost the immune system’s response. “It is a well-known thing from cancer research that antibodies against cancer epitopes, they can induce the person's own immune system to be better at fighting off the cancer. So, the same idea, we're trying to apply for HIV,” said Jesper Gunst, a physician scientist at Aarhus University whose team was one of the first to try out this novel approach. In 2022, he and his colleagues demonstrated that it led to a vaccine-like effect in some newly diagnosed people with HIV who were able to attain sustained suppression of the virus without ART (2).

Based on this work, teams across the world are studying a similar strategy with clinical trials testing whether the use of bNAbs can offer long-term control over HIV. Other researchers are also using bNAbs for other exciting directions — like preventing someone from acquiring HIV or preventing transmission from mother to baby.

“I hope to see bNAbs becoming a part both of prevention, treatment, and cure,” said Gunst, adding that new studies testing long-acting ART might be better suited to prevent new infections. However, when it comes to curing HIV, he said, “I think the bNAbs are superior compared to the antiretrovirals.”

Controlling HIV with a boost from bNAbs

To help the immune system kill off infected cells, bNAbs use their Y-shape to bind one of their ends to the envelope of HIV particles and neutralize them so that they can no longer infect cells. BNAbs then use their other end to flag the infected cells, which calls the immune system to destroy them. Gunst said that when he and his team began their Phase 1b/2a clinical trial testing the use of the bNAb 3BNC117 with romidepsin, a latency-reversal agent, it was a novel idea to try to intervene soon after someone was newly diagnosed and started on ART (2). “At that time, when a person is viremic, the reservoir is more labile or more prone to intervention because it hasn't stabilized,” said Gunst. In giving the bNAb to participants around day 7 and day 21 after starting ART, they showed that the participants who received the bNAb with or without romidepsin had a faster decay of their viral reservoir compared to participants that received ART alone. The results were enhanced in people whose HIV envelope sequences were sensitive to the antibody.

When they paused ART in 20 participants for 12 weeks — a common intervention in HIV trials to test the long-lasting effects of a drug — they found that those who were sensitive to the antibody were more likely to show some control over their HIV without any treatments at all. “That's not what we normally see. It is extremely rare to have some sort of control of the virus,” said Gunst.

In fact, one of the participants achieved complete control over his HIV after the bNAb therapy without ever needing to go back on ART. In another Phase 2a trial where participants paused their ART for 25 weeks, Gunst’s team showed that the amount of virus in the person’s body built up slower in the bNAb groups, and again, several participants achieved complete control (3).

“You could say that these bNAbs are not a magical recipe for control of the virus, but nevertheless, in these two trials, we have three individuals completely controlling the virus despite undetectable level of bNAbs,” said Gunst. His team is now actively studying what factors lead some participants to have such a robust vaccinal effect, whereby infusion of a bNAb trains the immune system to fight off the viral particles and infected cells like a vaccine.

Gunst is also part of the international RIO trial that is testing whether one dose of two bNAbs, 3BNC117–LS and 10‑1074‑LS, can control the viral load in participants without the use of ART. At the Conference on Retroviruses and Opportunistic Infections in March, their team announced that after 20 weeks without ART, the participants who received bNAbs were 91 percent less likely to show viral rebound compared to placebo over 20 weeks, and six participants retained complete control beyond 48 weeks after the last bNAb dose.

However, Gunst said that moving forward, this approach will need to take into consideration the problem of viral resistance. “If you just give one bNAb without anything else, the virus will mutate and develop resistance towards that bNAb,” he said.

Preventative bNAbs for breastmilk

Other researchers are using bNAbs to prevent a person from ever obtaining HIV in the first place. Gabriella Scarlatti, a virologist and trained pediatrician at the San Raffaele Scientific Institute, is part of a Phase 1 trial called PedMAb doing just that — by protecting babies from the breastmilk of mothers with HIV. Her team, along with researchers in France, Norway, and South Africa, is partnering with the South African Medical Research Council to run the trial in Chatsworth, South Africa.

“In babies, you know more or less when they get infected because the big bulk of the infections occurs [after] pregnancy during breastfeeding,” said Scarlatti, adding that while most mothers receive ART during pregnancy, it’s often more difficult for them to stick to taking them after pregnancy due to the demands of a newborn baby. “In the last 10 years, the cases of mother-to-child transmission — vertical transmission — has really decreased a lot. There are still around 120,000 babies infected [each year],” she said.

It may seem like preventing transmission could be as easy as preventing breastfeeding, but Scarlatti emphasized that’s not the case due to both health and economic factors. “Breastmilk comes with a lot of nutrients, not only to feed the baby from a point of view that it will grow … [it] contains immune cells that help the baby [and] contains a lot of antibodies that help the baby to combat diseases, especially in the very first few months,” she said. In addition, she pointed out that breastmilk is free while baby formula is not — plus, it also requires adding clean, boiled water that may not be easily accessible.

The results are so good for the time being that we can't stop it just now. We would be losing the opportunity to give kids an easy way to remain HIV-free. 
- Gabriella Scarlatti, San Raffaele Scientific Institute

The PedMAb team tested two bNAbs — VRC07-523LS and CAP256V2LS — that they injected subcutaneously into the thighs of infants soon after they were born and again at three months. They originally hoped to wait to give the second dose when the babies were six months old based on adult data, but they found that they needed to up the dosage likely because the babies had doubled their weight. They showed that both bNAbs were safe with only minor skin reactions (4,5). While the Phase 1 trial did not test for efficacy, Scarlatti said, “All of [the babies] were followed for at least six months, and none were HIV-infected during this period.”

Scarlatti and the rest of the team were excited to move on to Phase 2, but unfortunately, they are not able to at this time. Although they are funded by a European grant, the bNAbs they were testing come from NIH, and they are no longer able to use them after the Trump administration’s recent restrictions on NIH HIV projects in South Africa. Instead, the PedMAb team is now planning to start from scratch with a new Phase 1 trial that will test new bNAbs that are not produced by the NIH. But, because their new antibody hasn’t been tested in adults yet either, they will have to back up even further and start with a Phase 1 trial in adults. To spin the situation into a positive one, Scarlatti said that they will begin testing intramuscular injections now in addition to subcutaneous ones. “If we want, in the future, to go out in the field and use the monoclonals everywhere, we know that the subcutaneous injection is a little bit more difficult,” said Scarlatti.

But to make matters worse, their grant is set to expire at the end of 2025. They likely will not have time to get back into the pediatric trials by that time and will be forced to seek out new funding.

Yet, Scarlatti and her collaborators are unwavering in their pursuit to continue. “We are positive we'll do it,” she said. “The results are so good for the time being that we can't stop it just now. We would be losing the opportunity to give kids an easy way to remain HIV-free.”

References

1. Debrabander, Q. et al. The efficacy and tolerability of latency-reversing agents in reactivating the HIV-1 reservoir in clinical studies: a systematic review. J Virus Erad 9, 100342 (2023).
2. Gunst, J.D. et al. Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial. Nat Med 28, 2424–2435 (2022).
3. Gunst, J.D. et al. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med 29, 2547–2558 (2023).
4. Goga, A. et al. OA-498 PedMAb1 clinical trial: safety assessment of CAP256V2LS to prevent breastmilk HIV transmission in HIV-1 exposed uninfected neonates. BMJ Glob Health 8, (2023).
5. Goga, A. et al. Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants: study protocol for a phase I trial. BMC Infect Dis 24, 712 (2024).