The human immunodeficiency virus (HIV) is no longer a death sentence, yet a cure remains elusive. While current therapies can successfully manage active infection, the virus can survive in tissue reservoirs—including macrophage cells, which play an important role in the immune system.
David Russell, the William Kaplan Professor of Infection Biology in the College of Veterinary Medicine, and his research team in the Department of Microbiology and Immunology have pinpointed a novel angle of attack that could eradicate these viral reservoir cells – while leaving healthy cells untouched.
In their study, published March 27 in Proceedings of the National Academy of Sciences, Russell’s team, led by first author and postdoctoral fellow Saikat Boliar, describe how a genetic regulator called SAF helps HIV-infected macrophages avoid cell death. After blocking SAF in HIV-infected cells, the researchers found that these reservoir cells then self-destructed.
While macrophages—immune cells that consume foreign entities in the body—are helpful in fighting off certain microbes, they provide the perfect foxhole for HIV. Some researchers believe these infected macrophages are the reservoirs for persistent HIV infection.
Researchers wanted to investigate what cellular mechanisms were at play that helped keep infected macrophages alive so they turned their attention to long noncoding RNAs (lncRNAs) – genetic coding elements that turn genes up or down, but do not translate directly into proteins themselves.
The team screened a panel of 90 well-characterized lncRNAs in three distinct populations of human macrophages: healthy cells, HIV-infected cells and “bystander” cells—those that had been exposed to HIV but not infected.
The investigators found that SAF was more prevalent in the HIV-infected macrophages. Previous studies found SAF prevented self-destruction in cells. Russell and his team suspected SAF was protecting HIV-infected macrophages from dying.
To prove this theory, the team blocked SAF’s action using another noncoding RNA called small interfering RNA (siRNA), which effectively degrades targeted RNAs such as SAF. The researchers silenced SAF in the healthy, infected and bystander macrophage populations; the HIV-infected cells suddenly self-destructed, while the healthy and bystander cells remained unscathed.
This discovery taps into a novel angle in curing HIV: selectively destroying persistently infected cells. The Russell team is eager to exploit it for potential therapies. This work was supported by the NIH.