New Therapy May Offer "Functional Cure" For HIV

In a study published in Nature, researchers reported that they successfully put HIV into remission in simian trials—and human trials have already begun. The ‘functional cure’ wouldn’t entirely eliminate the virus or cure a person of HIV, however it could offer long periods during which a person living with HIV could forgo taking their daily antiretroviral medication.

“The objective of our study was to identify a functional cure for HIV – not to eradicate the virus, but to control it without the need for [antiretroviral therapy],” the study’s lead author, Dr. Dan Barouch said in a statement. Barouch, who teaches at Harvard Medical School, is also Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, which conducted the research. “Current antiretroviral drugs, although they’re lifesaving, do not cure HIV. They merely hold it in check. We are trying to develop strategies to achieve ART-free, long-term viral suppression.”

Indeed, one of the biggest barriers to any attempt at curing HIV is the fact that the virus can go dormant, developing large, unseen “reservoirs” (particularly in those who delay antiretroviral therapy), which can allow the disease to rebound if ART is ended or interrupted. In other words, even those with undetectable levels of HIV still have enough of the virus hiding that they must continue taking ART long term.

Scientists have known for several years that they first need to find a way to “wake” the virus that is sleeping in these reservoirs so that they can then attack it with antiretrovirals or other medications. Other studies have found that HIV can be reawakened by a drug that treats alcohol dependency an a cancer medication.

Those newly visible viral particles were then attacked by immune system responses that had been stimulated by an HIV vaccine (which is actually a combination of two previously developed vaccines — Ad26 and MVA) and an immune stimulant, TLR7.

In a two-year study, researchers followed a group of 36 rhesus monkeys infected with the simian version of HIV (SIV), who had been on antiretroviral drugs for six months, before being given the combo-vaccine, the immune booster TLR-7, or a combination of both. Then they monitored the impact on subjects’ viral loads and the time it took for HIV to rebound.

“We found the combination of Ad26/MVA vaccination and TLR7 agonist stimulation more effective than either component alone,” Col. Nelson Michael, director of MHRP, who helped design the preclinical study, said, according to VOA News. “This was especially striking in viral load set-point, which impacts the future course of the disease.”

Indeed, those treated with a combination vaccine and booster saw a decrease in viral load, and the virus was undetectable in 33 percent of these subjects when ART was stopped. Compared to the control group (who received no active treatment), researchers saw a “viral set point that was 100-fold lower and observed a 2.5-fold delay in viral rebound.”  The viral set point is the HIV viral load which stabilizes after a period of acute infection. In other words, the treatment dramatically reduced the viral load and also delayed the HIV from rebounding when antiretroviral therapy was stopped.

HIV vaccine development has been hampered because most vaccines work by initiating the response of immune cells, but HIV hijacks these T-cells, using them to replicate and killing them off in the process. To get around this issue, investigational HIV vaccines use other ‘vectors’ to deliver HIV antigens (instead of trying to get your immune system to develop these antigens itself). The two vaccines combined in the study use different vectors. MVA, Modified vaccinia virus Ankara is a modified smallpox viral vector, while Ad26 uses an adenovirus.

The resultant vaccine caused a robust immune response, both in the number of immune cells generated and breadth — the number of places on the virus the vaccine can target in the preclinical study. Cellular immune breadth was shown to correlate inversely with set-point viral loads and correlated directly with time to viral rebound. In other words, vaccines that can hit HIV in multiple ways may be more effective at eliminating the virus.

 "The really exciting thing is that when we combined the TLR-7 and the vaccine, then we saw, after we took the animals off of antiretroviral drugs, that the level of virus that they were replicating fell by a hundredfold. And in some of these animals it looks like we may be actually in a position where there's not much virus left circulating at all," said Michael.

While the monkeys in the study still have HIV, the disease is being controlled because the combination therapy has trained the immune system to control the virus.

Michael says this could give people living with HIV a “drug holiday” where people could go off antiretroviral drugs for up to years at a time, unless the virus rebounds. Obviously this would mean regular check-ups to verify the virus remains undetectable.

Janssen, in collaboration with MHRP, has already begun recruiting people for human studies to evaluate the safety and potential of this therapeutic vaccine for the treatment of those living with HIV who initiated ART during acute HIV infection. The Phase I/IIa study will also explore whether HIV remission achieved by the vaccine treatment will control the virus even when antiretroviral treatment is interrupted.

The study was also a demonstration of the importance of collaborative research. Researchers at BIDMC joined those at the United States Military HIV Research Program of the Walter Reed Army Institute of Research, in collaboration with Janssen Vaccines & Prevention B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Meanwhile, the Ad26 vaccine—one of two used in combination in the study—was developed in partnership between the National Institute of Allergy and Infectious Diseases, BIDMC, and Janssen; the MVA vaccine was developed by MHRP in collaboration with the Laboratory of Viral Diseases at NIAID; and the TLR7 agonist (immune booster) was developed by Gilead.