UNC researchers discover new way to control HIV
January 24, 2017
Over the past 20 years antiretroviral therapy (ART) has dramatically cut the number of AIDS deaths, but in 2014, HIV was still the eighth leading cause of death among Americans aged 25-34 and ninth among those between 35 and 44.
Part of the problem is that not everyone receives these treatments, but a more fundamental issue is that there are important symptoms of HIV that ART does not necessarily stop. The most notable of those is chronic immune activation, a method by which HIV creates more immune cells that it can replicate in and kills off those that could be considered a threat.
Now researchers from the UNC School of Medicine have discovered that blocking a chemical pathway in the immune system could both tamp down chronic immune activation and help kill off the last remnants of the HIV virus hiding in the human body.
HIV grows and replicates in the cells of the immune system, including macrophages and, most often, T-cells, which are white blood cells grown in the thymus gland that train themselves to attack specific invaders. T-cells activate when they find an invader they need to fight, and HIV can only replicate itself inside these activated T-cells.
Normally, a majority of the body’s T-cells remain inactive as they wait around for something to fight. HIV, however, has surface proteins that can force nearby T-cells to activate. The issue there is that T-cells are programmed to undergo apoptosis—a programmed cell death that works like a self-destruct button—not long after they activate, lest there be too many killer immune cells floating around in the bloodstream.
Over the past 15 years, research has shown that even though the HIV virus itself kills the T-cells inside which it replicates, apoptosis of nearby uninfected cells is more prominent in the decline of T-cells that marks the transition from HIV to AIDS.
Antiretroviral drug cocktails drastically decrease the virus’s ability to replicate, but they do not completely wipe out the virus, says Liang Cheng, a research associate at UNC School of Medicine. Cheng is also lead author of the paper describing this research, published in the Journal of Clinical Investigation. As long as there is some virus around, its surface proteins can cause chronic immune activation, which not only harms the immune cells but also the tissues that these immune cells affect. Even when the virus is beaten down and well controlled with ART drugs, patients can still exhibit immune dysfunction.
Cheng and Lishan Su, a professor of microbiology and immunology at UNC School of Medicine and senior author of the study, investigated the signaling pathways that help activate immune cells to see if switching them off could control this immune response.
They found that blocking a specific type of interferon, a category of protein involved in controlling how the immune system acts, fully reversed the immune hyperactivity. The researchers targeted type I interferon, which specifically controls how the immune system goes about attacking viruses. Using humanized mice, they were able to create an antibody that would block the receptors where type I interferon binds. The mice given this antibody showed none of the immune dysfunction that was seen in normal HIV-infected mice.
Further, Su and Cheng found that limiting immune hyperactivity helped to decrease the size of the tiny virus colonies left over after ART. Even when the virus is well-controlled with ART, reservoirs of HIV live on in a dormant state, ready to multiply when a patient stops taking ART drugs. When the researchers gave the mice the interferon antibody, they found that the reservoirs shrunk and after stopping ART, it took HIV longer to rebound than in mice that did not receive the antibody.
Su and Cheng hypothesize a few explanations for the decrease in reservoir size in their paper. With the immune system left to function normally, it is possible that the deactivated T-cells could have time to recognize infected cells as a threat and kill them. Another possibility is that the infected cells could undergo their own apoptosis if they recognize HIV as a threat. That, combined with fewer activated T-cells in the area to help the HIV multiply, could decrease the population over time.
Whatever the cause, anything that diminishes the HIV reservoirs represents a concrete step on the path to curing HIV. That benefit, combined with halting one of the more dangerous symptoms of HIV infection could make interferon antibodies a powerful weapon in the fight against HIV and AIDS.
Daniel Lane covers science, medicine, engineering and the environment in North Carolina.