Fresh Hope of a Functional Cure for HIV

At least that’s the hope of Yuntao Wu, Ph.D., professor in the Center for Infectious Disease Research at George Mason University, buoyed by findings of a proof-of-concept study in rhesus macaques that was published recently in Gene Therapy (DOI: 10.1038/s41434-024-00467-9). The approach, which he nicknamed Rev-targeting HIV immunotherapy (RHIT, pronounced “right”), succeeded in reducing viral rebound upon ART termination. In one of the animals, plasma and central nervous system viremia remained at an undetectable level most of the time for over two years.  

The HIV virus hides out in reservoir cells, making it difficult for the immune system to detect and eliminate completely, Wu explains. Patients therefore need ART for the rest of their life to inhibit HIV release from reservoir cells. Rev is a viral protein that is needed for HIV replication and only exists in HIV reservoir cells, and administration of the Rev-dependent HIV-like particle into these compartments can make them targetable. 

The novel therapeutic agent is an HIV Rev-dependent type of lentiviral vector, a type of retrovirus that can be used to deliver genetic material into the HIV-producing reservoir cells, he continues. Once inside reservoirs, the vector uses Rev as the trigger to express therapeutic genes to kill or inactivate reservoirs. Wu developed the vector more than two decades ago during his postdoctoral training at the National Institutes of Health.  

Currently, less than 0.5% of infected individuals naturally achieve sustained, drug-free control of HIV replication through their immune system (so-called “elite” controllers or neutralizers), says Wu. For all others, the immune system must rely on daily ART to control the virus. 

ART was unquestionably a breakthrough for HIV treatment and prevention, improving the quality of life and increasing longevity for patients. But it is not a cure, so research since ART hit the market in 1987 has shifted to sustained viral remission and eradication, Wu says. 

More ‘Self-Controllers’

ART works by blocking viral proteins and can reduce HIV levels to an undetectable level within a few months, but it does not reduce viral reservoirs. Experimental approaches to eliminating viral reservoirs include those that either “shock and kill” or “block and lock,” as opposed to the “rehab and redeem” tactic being taken by Wu’s team—what he likens to “turning a bad guy into a good one.” 

The focus is on selectively targeting the reservoirs, he says. The HIV-like particle, equipped with a Rev sensor that can detect the presence of Rev, triggers the production of a therapeutic protein in reservoir cells. “We use it to modulate the cells to release defective viruses which can stimulate anti-HIV immunity,” says Wu. 

In the monkey given three injections of the particle, higher titers of the neutralizing antibodies coincided with the period when HIV was undetectable. This suggests that the Rev-targeting HIV immunotherapy could put more people on parity with the tiny fraction of HIV patients who naturally self-control the virus, says Wu. With a new therapy to stimulate the immune control, he adds, the goal is to get half or more of HIV patients currently on antiretroviral therapy to be “just like the self-controllers.” 

First-in-human trials are still about three years away and heavily funding-dependent, Wu says. The Rev-dependent vector will initially be an add-on therapeutic to the standard ART regimen, but later efficacy studies would attempt to help a significant proportion of participants get off drug treatment.  

Wu says he expects that in people the novel therapeutic will require multiple doses, personalized to an individual’s immune system response, to enable patients to stop taking ART. One reason it could be hard to get much above the 50% mark anytime soon is the large proportion of patients who have been infected for many years, which tends to weaken the immune system. Repair of that damage is a longer-term objective of the research team. 

But after more than 30 years, “there is hope” of a life-altering breakthrough with HIV, Wu stresses. “In the coming 10 years, we might have a long-term solution closer to a functional cure”—and HIV might no longer be the “scary” diagnosis that it remains to this day.