Using Naturally-Occurring Antibodies to Treat HIV
A recent report published in Nature describes promising findings of a study testing the safety, tolerability and antiviral efficacy of a broadly neutralizing antibody (nBAb) called 3BNC117. This is the first study to show, in human participants, that a broadly neutralizing antibody significantly reduces viral loads and decreases viral rebound in people living with HIV—giving hope for its eventual use in treatment and cure strategies.
Broadly neutralizing antibodies (bNAbs) are produced by the immune system of some people living with HIV. What’s special about bNAbs is that they are able to prevent HIV from entering host CD4 cells—and they’re able to do this with many different strains of HIV. The bNAb 3BNC117 is able to neutralize 195 (out of 237 total) strains of HIV. It was isolated from an elite controller—a person whose body spontaneously controls HIV infection without antiretroviral therapy.
The fact that the bNAb can neutralize so many strains of HIV is very important, according to lead researcher Johannes Scheid, MD, PhD, because one of the big problems with HIV is that it’s so diversified.
In an open-label phase I study, 12 HIV-negative and 17 HIV-positive individuals received an intravenous dose of 3BNC117. Doses varied in concentration: Each participant received either a 1, 3, 10, or 30 mg/kg-1 dose. Fifteen of the HIV-positive people in the study were not taking antiretroviral therapy (ART); two were taking ART but had detectable viral loads. Viral loads were measured during the study for up to 56 days post-dose.
Viral load decreases were dose-dependent, with people receiving the highest 10 or 30 mg/kg doses kg-1 getting the most benefit. Ten out of the 11 individuals receiving these doses had their viral loads drop by up to 2.5 log10. The authors explain that the one individual who did not benefit from the infusion was infected with a strain of HIV that was completely resistant to 3BNC117.
Scheid and his team expected an antiviral effect in this study because previous tests of bNAb in animals were successful. Even so, they were “pleasantly surprised and very happy” about the effectiveness of 3BNC117.
“The fact that we saw this significant drop—with one agent—is certainly significant,” explained Scheid. He believes that, down the road, as more bNAbs are tested, combination bNAb therapy treatments will work better than single-agent ones. “In a way, it’s similar to ART drugs,” he says, since each type of bNAb binds to HIV in a slightly different way—increasing the likelihood that every strain of HIV a person is infected with can be recognized and blocked. But testing combinations of bNAbs is something that probably won’t happen for another year or so, he says, since individual bNAb testing must be completed first.
Participants reached the lowest viral load levels about seven days after getting the infusion, with viral load decreases still significantly lower 28 days post-dose. Even after 56 days, half of the individuals who received the highest dose still did not have their viral loads rebound to the same pre-treatment level.
Scheid says they still don’t know for sure why viral levels did not completely rebound after 3BNC117 therapy. “It’s a possibility that with this—by giving the antibody—we are changing, permanently, the immune response to the virus. We can speculate that [the antibody] is not just a blocking agent, but that’s just speculation at this point.”
Broadly neutralizing antibodies prevent HIV from invading host cells by latching onto a protein—called “Env”—on the surface of the virus particle. This protein is responsible for helping the virus fuse, enter and infect target host cells (usually CD4 cells). When bNAbs bind to this surface protein, the virus is blocked and unable to enter CD4 target cells. The work of bNAbs doesn’t stop there. It’s thought that once the antibodies bind to HIV, they “tag” the virus particle for the immune system—essentially, marking the virus cell for destruction by natural killer or other cells.
The treatment was well tolerated by both HIV-negative and HIV-positive participants; there weren’t any serious adverse heath events reported during the study. One exciting characteristic of bNAb therapies, says Scheid, is that they’re naturally-occurring proteins that may be less toxic to patients than current ART drugs. “It’s something that the human body makes. That’s exciting. Because with HIV therapy, you’re always thinking about the long-run.”
Although researchers still aren’t clear about how 3BNC117 may be used in future therapies, it’s implications for treatment and cure are evident. The long half-life of 3BNC117—how long it takes to break down in the body to half of its original concentration—is exciting from a treatment perspective, while its apparent ability to activate the immune system holds hope as a cure strategy.
“These antibodies are not just stopping the virus the way ART drugs do. They really engage the immune system. There’s excitement at the moment about latency reactivation of HIV in the context of thinking about ways to cure HIV. Because the problem—what stands in the way of curing people with HIV—is that there is this large reservoir of virus where it sits and ‘wakes up’ when you stop therapy. In that context, antibodies are very exciting because they could potentially tag whatever displays the virus the moment the virus wakes up.”
Caskey, M. and others. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. June, 2015.