Combined anti-retroviral therapy (cART) has been a crucial clinical tool in the battle against HIV for nearly two decades. But for some HIV-positive individuals, despite complete or near-complete suppression HIV replication by cART, both chronic inflammation and immune dysfunction persist, a condition that can slow T-cell recovery and accelerate the progression of HIV. 

New research from the UNC School of Medicine, published today in the Journal of Clinical Investigation, suggests that interfering with persistent type I interferon (IFN-I) signaling – a cellular protein pathway linked to chronic immune activation – can promote better immune recovery and viral suppression when used in combination with cART in animals.

Using humanized mouse models of HIV infection, researchers in the UNC lab of Lishan Su, PhD, professor of microbiology and immunology, developed an antibody to target human IFN receptors in the mice. By injecting HIV-infected mice with this antibody, Su’s lab reversed immune hyper-activation. Reducing this hyper-activation was found to reduce signs of T-cell exhaustion, reverse HIV-specific T-cell function and reduce HIV reservoir when combined cART. 

The findings represent an important step in controlling the virus, since HIV preferentially targets activated immune cells. By reducing the number of activated cells, the technique developed in Su’s lab limits the number of T-cells the virus can target to replicate itself.

“cART stops the growth of the virus but cannot achieve HIV-1 eradication,” said Liang Cheng, PhD, the first author of the paper and a research associate in Su’s lab. “The virus rebounds quickly when cART is discontinued because there are reservoirs of HIV-1 that persist during cART; therapy does not work against these reservoirs. The recovered adaptive immune response to HIV can help to eliminate the HIV-1 reservoirs and control the virus rebound after cART discontinuation.”

Chronic immune activation can remain a problem even for those patients whose viral replication has been successfully suppressed with cART.

These new findings suggest it is possible to deactivate the chronic immune response. This deactivation gives the adaptive immune system struggling against HIV a chance to recuperate. This is especially significant since chronic immune response is often the cause of T-cell depletion and dysfunction, and a driving force in the development of AIDS in HIV-positive patients.

According to Su, the findings suggest potential benefits in at least two clinical applications.

“First, this technique may be of help to those patients whose viral replication is suppressed but who are unable to fully recover immunologically,” said Su, also a member of the UNC Institute for Global Health and Infectious Diseases. “Second, it may help to control or reduce HIV-1 reservoirs in all cART-treated patients.  And this could potentially help cure HIV infection.” UNC has recently filed for a patent on the technique developed in Su’s lab that helped lead to these findings.