A new study suggests that HIV throws off the balance of two types of inflammation-reducing cells, thus allowing the virus to persist in the body and cause ongoing damage to the immune system. This finding—published May 19 in the journal Science Translational Medicine and announced by researchers at the University of California in San Francisco (UCSF)—could lead to a new generation of effective HIV medications that operate in a completely different manner from current antiretroviral (ARV) drugs.

Researchers have known for more than a decade that some primates infected with HIV's cousin, simian immunodeficiency virus (SIV), don't ever get sick from the infection, while other primates do get sick and die from an AIDS-like syndrome. Paradoxically, the primates that remain healthy appear to be protected due to a weak response to the virus. This finding, along with a growing body of research, has led many scientists to suspect that the immune damage and illness in HIV disease is largely due to an overactive immune response to the virus—a process called inflammation.

To pinpoint the cause of the inflammation in HIV disease, David Favre, PhD, from the National Immune Monitoring Laboratory in Montreal, and his colleagues from UCSF and the National Institute of Allergy and Infectious Diseases, focused on the body's production of an enzyme called indoleamine 2,3-dioxygenase 1 (IDO1). This enzyme plays an important role in helping the body shut down inflammation after it has successfully dealt with an infection. While the ability to mount an inflammatory response is key to controlling many infections, chronic inflammation is harmful to the body in a number of ways. Arthritis and colitis are just two diseases caused by chronic inflammation.

Favre and his team found that IDO1 suppresses out-of-control inflammation by balancing production of two types of T-cells: TH17 cells, which keep the barrier of mucosal cells in the gut intact, and Tregs, which help keep inflammation under control from a number of infectious organisms, including HIV.

In HIV disease, the mucosal barrier in the gut breaks down early, allowing bacteria to spill out into the blood. This causes inflammation, which increases HIV reproduction, which in turn keeps the mucosal barrier from healing—a feedback loop that researchers believe contributes to disease progression and a host of other problems, such as cardiovascular disease and certain cancers. Favre and his colleagues found that HIV disrupts IDO1's ability to effectively balance TH17 and Treg cells, which might be at the heart of this feedback loop.

“In most instances, reducing inflammation following immune system activation to fight infection is beneficial. But, in HIV disease, this can establish a reinforcing cycle that is strongly linked to disease progression and that may help HIV to persist in patients,” said study lead coauthor Jeff Mold, PhD, from the UCSF Division of Experimental Medicine.  “Mucosal defenses are breached, microbes cross over, and inflammation results. This leads to increasing IDO1 activity, continued changes in the balance of TH17 and Treg cells, further weakening of the mucosal defenses and even more inflammation.”

While Favre, Mold and others will continue to confirm IDO1's roll in disease progression, other researchers—including Michael Murray, MD, from Harvard Medical School in Boston, and Steve Deeks, MD, from UCSF—will focus on whether suppressing IDO1 might slow HIV disease progression. Murray authored a review of intriguing work on IDO1 inhibiting drugs in cancer in the same issue of Science Translational Medicine.

“Most of an infected person's own immune responses that are known to affect HIV disease outcomes cannot be manipulated or altered clinically and, hence, have not really had much of an impact for patients. This work, however, is very different, as it has uncovered several possible pathways that might be addressed clinically with developing or available therapeutics,” Deeks said.

Should IDO1 inhibitors prove effective at reducing inflammation and controlling HIV replication, they could become one of the most promising new avenues of HIV treatment since modern ARVs were introduced in 2000.