Combination immunotherapy may help T cells fight HIV

An experimental HIV vaccine plus broadly neutralizing antibodies and an immune-stimulating drug helped control HIV for several months after patients stopped antiretroviral treatment, according to results from a small study published in the journal Nature on World AIDS Day.

“Is this a cure? No way. But this is a first step, sort of like those early, very complicated, partially effective combination antiretroviral regimens we were using back in the 1990s,” study co-author Dr. Steven Deeks of UCSF told the Bay Area Reporter. “With proof that we can actually at least partially make the immune system do what it really should do routinely, we now have a pathway to optimize the approach, just like we have done and continue to do with antiretroviral drugs.”

Antiretrovirals can keep HIV replication suppressed as long as treatment continues, but the virus inserts its genetic blueprints into the DNA of human cells, establishing a long-lasting reservoir that makes a true cure nearly impossible. Only 10 people with HIV are known to have been cured after stem cell transplants for cancer treatment. But experimental approaches may help delay or limit viral rebound after treatment interruption, known as a functional cure.

Deeks and colleagues, with support from amfAR: The Foundation for AIDS Research and the National Institutes of Health, designed a complex functional cure trial that aimed to induce long-term remission in people who stop antiretrovirals. Participants received a therapeutic vaccine, two broadly neutralizing antibodies (10-1074 and VRC07-523LS) and lefitolimod, an immune-modulating drug known as a TLR9 receptor agonist that may coax HIV out of hiding.

At the 2023 Conference on Retroviruses and Opportunistic Infections, study co-author Dr. Michael Peluso of UCSF reported that seven of the 10 participants experienced delayed rebound to lower-than-expected virus levels after antiretroviral treatment interruption. Six of them eventually saw their viral load rise after several months – compared with a typical rebound time of a few weeks – and one remained off treatment for more than 18 months.

According to Deeks, this person went back on antiretrovirals for personal reasons for a period but is now back off treatment four years later and maintaining viral control. The researchers are still following the participant and “trying to figure out exactly what happened,” Deeks said.

 
Tom Perrault, a former board member for the San Francisco AIDS Foundation who now splits his time between the Bay Area and New Orleans, was one of the participants who experienced delayed viral rebound. He started to get his hopes up after a few months of remission, but his viral load started to rise again about five months after stopping antiretrovirals.

“No one ever said this was going to work – in fact they told me it probably wasn’t going to work,” Perrault told the San Francisco Chronicle . “I have a chance to try to cure this thing. Of course I’m going to do it. They don’t cure this thing unless people do what I did. To have a chance at a cure, and to know that my participation could lead to it – that’s spectacular.”

In the December 1 Nature paper, the researchers reported that robust expansion of activated CD8 killer T cells early in the response to rebounding virus was associated with lower virus levels. Strong HIV-specific CD8 T-cell response is a hallmark of so-called elite controllers who naturally control the virus without treatment.

“It turns out the controllers had T cells that were able to expand dramatically once they ran into the virus,” co-author Dr. Rachel Rutishauser stated in a UCSF news release . “It’s like they were hanging out waiting for their target, kind of like a cat getting ready to pounce on a mouse.”

While delayed viral rebound is expected until the broadly neutralizing antibodies wear off or the virus becomes resistant to them, the slower rebound rate and the ability to sustain a low viral load for several months seen in this study suggest the immunotherapies had an additional effect, Rutishauser explained.

While these findings are promising, the study authors said more work is needed to figure out why some people were able to achieve at least partial viral control. What’s more, this trial required some 50 study visits over two years, and a more streamlined regimen would likely be necessary for wide practical use. Many experts fear, however, that federal budget cuts will curtail this kind of research.

“This study is not the endgame, but it is an important step in showing that we can make progress toward overcoming one of the biggest challenges in HIV research – helping a person’s immune system to control the virus without the need for life-long medication,” Peluso told the B.A.R. “The clinical results are exciting, but even more important is that we uncovered the biology that may explain them – that CD8 T cells became poised to respond earlier and more aggressively to HIV in those who went on to control the virus at low levels.”