Protective enzyme may advance HIV disease progression

Indoleamine 2,3-dioxygenase 1 — an enzyme produced by the body to fight harm related to chronic inflammation — may facilitate disease progression in patients with HIV by inducing T-cell function loss and subsequent immunosuppression, recent study data indicated.

Researchers from University of California, San Francisco, analyzed patients in various stages of HIV infection who were enrolled in the Study of the Consequences of Protease Inhibitors Era (SCOPE) or UCSF options cohort. Their objective was to assess the effect that indoleamine 2,3-dioxygenase 1 (IDO1) activity has on T helper 17 cells and T regulatory cells in patients with HIV. T helper 17 aids in maintaining the integrity of the rectosigmoid mucosa, and T regulatory prevents inflammation but may also disable immune responses to HIV.

“We confirmed that IDO1 activity is associated with HIV disease progression. But we went further and also looked at the T helper 17 and T regulatory balance and found that the change in the ratio leading to decreasing T helper 17 cells is also associated with HIV disease progression,” said study researcher, David Favre, PhD, of the National Immune Monitoring Laboratory, Montreal, in a press release

Results showed that production of IDO1 disrupted the balance of these T cells, according to the researchers, by triggering a growth in T regulatory and a decline in T helper 17 proportions in patients with HIV. This disparity provides increased opportunity for bacteria to enter the gut through the damaged mucosa, causing new inflammatory reactions to develop, while T regulatory cells prevent immune responses to HIV in other areas of the body.

“In most instances, reducing inflammation following immune system activation is beneficial. But, in HIV disease, this can establish a reinforcing cycle that is strongly linked to disease progression, and that may help HIV persist in patients,” said study researcher Jeff Mold, PhD, of 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 T helper 17 and T regulatory cells, further weakening of the mucosal defenses and even more inflammation.”

Trials examining the efficacy of IDO1 inhibitors for cancer immunotherapy are currently taking place, and the researchers said their data may contribute to developing these inhibitors for HIV treatment and prevention.

“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,” said Steven Deeks, MD, professor of medicine at the UCSF division of HIV/AIDS at San Francisco General Hospital.

Study researcher Joseph M. McCune, MD, PhD, chief of the UCSF division of experimental medicine, said he and Deeks will conduct a study on whether disruption of IDO1 will lead to a decrease in immune activation and therefore reduce viral persistence.

Favre D. Sci Transl Med. 2010;doi: 10.1126/scitranslmed.3000632.