A main obstacle to an HIV cure is that viral DNA integrates into the chromosomes of memory T cells (blue), which evade destruction unless they produce new virus (red).Jonathan Karn, F. Kizito et al., PNAS, 121(18):e2202003121 (2024)
New antibody studies boost hope for HIV cure
Pioneering trials discover potential strategy to keep virus in check after stopping treatment
By Jon Cohen
SAN FRANCISCO—“It’s been very rough the last few weeks,” epidemiologist Wafaa El-Sadr said here on 9 March during the opening ceremony of the largest annual HIV/AIDS conference in the United States. El-Sadr had a major grant from the U.S. Agency for International Development, which President Donald Trump’s administration terminated, and Columbia University, where she works, saw $400 million in other federal grants and contracts cut over its alleged failure to address antisemitism on campus. Now, she said, “I feel I’m with friends and family.”
Shock, grief, and anger about the U.S. cuts in funding for public health and biomedicine dominated many of the conversations as 3700 HIV/AIDS researchers, health care workers, and advocates gathered last week for the Conference on Retroviruses and Opportunistic Infections. Meeting chair Diane Havlir, an HIV/AIDS researcher at the University of California, San Francisco (UCSF), denounced the “abrupt withdrawal” of funding for HIV treatment and prevention services as “cataclysmic and cruel.”
“The recklessness we’re seeing is like dropping an egg on the floor: You can’t just pick it up and put it back the way it was,” said HIV/AIDS advocate Rebecca Denison. Denison, who has lived with HIV for 35 years, told scientists at the meeting: “Your work saved my life.”
But the conference also brought some hopeful news. Promising data suggest a drug could ward off HIV infection for a full year after a single injection, a potential breakthrough in so-called pre-exposure prophylaxis (PrEP). Researchers also reported that unusual antibodies could help people control HIV without antiretroviral drugs—a possible step toward a cure. “We’ve made major progress,” said Steven Deeks, an HIV cure researcher at UCSF.
The PrEP data come on the heels of two large efficacy trials that showed a single shot of the drug lenacapavir offered solid protection against HIV infection for 6 months. That was a major improvement over current once-daily prevention pills, and an achievement Science named its 2024
Breakthrough of the Year. At the meeting, scientists from Gilead Sciences, the maker of lenacapavir, presented data from a trial in which 40 participants received a 5-gram dose of lenacapavir, more than five times higher than the earlier formulation. After 1 year, drug levels in participants’ plasma exceeded those seen with the lower dose at 6 months, suggesting the drug would remain protective. “As a clinical pharmacologist, it gives me great pleasure to see a small molecule last this long,” Gilead’s Renu Singh said.
UC San Diego virologist Douglas Richman agrees the data, described in an 11 March paper in The Lancet, are “very impressive.” A downside of the high dose, given as an injection into a gluteal muscle rather than a subcutaneous shot in the belly: pain at the injection site. Icing the area before the shot helps, and Singh says the dose will likely be reduced. Gilead plans to launch efficacy trials this year.
PrEP alone can’t reverse worrisome trends in HIV epidemiology, researchers say. An estimated 1.3 million people were infected last year, far more than the 370,000 that the Joint United Nations Programme on HIV/AIDS 5 years ago set as its goal for this year. The Middle East, North Africa, Eastern Europe, Central Asia, and Latin America have seen expanding epidemics. Epidemiologist Chris Beyrer, who heads the Duke University Global Health Institute, said the latest projections show that without a vaccine—still nowhere in sight—or a cure, HIV prevalence will continue to grow even if PrEP use is scaled up.
Still, long-acting PrEP could make a major difference—and that promise is in jeopardy. On 6 February, the U.S. Department of State said the President’s Emergency Plan for AIDS Relief—which has provided PrEP for 91% of the 8 million people who have used it so far—will now only support the drugs for pregnant or breastfeeding people, a small fraction of those at high risk of HIV. “We are shocked that the amazing investment that was done by the U.S. government has been suddenly cut,” said Beatriz Grinsztejn, head of the International AIDS Society.
Research, however, continues to fuel hope, even against the central obstacle to curing HIV: the “reservoir” of immune cells in infected people that harbor viral DNA, integrated into their chromosomes. Even when antiretroviral drugs successfully suppress the virus, this latent HIV can roar back when people stop taking their medication.
For the past 20 years, cure researchers have tested drugs called latency reversal agents that try to shock the reservoir cells into producing virus, which should lead to their self-destruction or an immune attack. The hope was that the remaining, smaller reservoirs should be easier for the immune system to keep in check. But that strategy hasn’t worked: Most everyone who paused their antiretroviral drugs after taking latency reversal agents saw their HIV skyrocket within a few weeks.
Now, Deeks’s group and a half dozen others have recruited people who have fully suppressed HIV with antiretroviral drugs and given them rare antibodies that, in test tube studies, “neutralized” a wide range of HIV variants. (Many antibodies simply bind to the virus, and those that neutralize it typically only work against a limited number of viral mutants.) Without any interventions, only 4% of people who stop their drugs still controlled their infections 84 days later, a recent meta-analysis showed. But in a handful of trials done so far, the virus was undetectable for at least 84 days in 10% to 20% of those who received these broadly neutralizing antibodies (bNAbs) and then stopped treatment. “It’s not perfect, but at least it’s a signal that’s worthwhile building on,” said clinician and epidemiologist Ole Schmeltz Søgaard, who studies HIV cures at Aarhus University.
Thumbi Ndung’u of the Africa Health Research Institute reported on the first cure study in Africa, which used two bNAbs in 20 women. In four of them, the virus remains undetectable 55 weeks after they stopped taking drugs, and one has been off medication for 2.5 years. “It’s now a question of trying to figure out why is there that small signal,” Ndung’u said.
Another study, in the United Kingdom and Denmark, randomly assigned 68 people to receive either two bNAbs or a placebo. Twenty weeks after stopping all treatment, 75% of those in the bNAb group had not rebounded, versus 8.8% in the placebo group. Most treated people received a second dose of bNAbs at 20 weeks, and seven of those went on to maintain complete control for at least another year, an “extremely unusual” result, said immunologist Sarah Fidler of Imperial College London, who presented the findings. Determining “why it works in some people and not others is absolutely key,” she said, noting there are many players in the primitive “innate” and the more sophisticated “adaptive” immune systems.
One possibility is that when bNAbs bind to HIV as it rebounds, the resulting complex leads to an extra potent attack on the virus called “the vaccinal effect,” which boosts T cells that target infected cells for destruction. Søgaard described evidence for a vaccinal effect in a study participant who received a latency reversal agent and bNAbs and has controlled HIV without treatment for more than 7 years.
Some people produce high levels of antibodies on their own that have similar neutralizing powers. Mauro Garcia, a Ph.D. student at Johns Hopkins University, described how people who had higher levels of these “autologous” neutralizing antibodies (aNAbs) against HIV had a highly significant delay in viral rebound after they stopped taking drugs. Assessing these aNAb levels in people on treatment, Garcia said, provides a “strong predictor” of who will be able to keep the virus in check on their own.
“It’s not just one mechanism that’s maintaining control” against HIV after treatment is stopped, Søgaard said. He thinks the immune system remains the best route to a cure. “I’m focused on enhancing immunity,” he said, “and I think that’s the way to go for now.”
Source:https://www.science.org/