amfAR, The Foundation for AIDS Research

Defective—But Still Dangerous

New research shows that defective HIV proviruses can undermine immune response

It has long been known that a large proportion of HIV proviruses—HIV DNA that has been integrated into a target cell’s genome—is defective. But new evidence suggests that while it may be defective—that is, incapable of producing infectious HIV particles—it is far from harmless.

Brad Jones PhotographDr. Brad JonesDefective proviruses distract the immune system from eliminating cells harboring infectious virus, according to a team of researchers from George Washington and Johns Hopkins universities. That means the immune system expends resources killing cells that will never produce infectious virus.

This can shield infectious HIV from attack by drugs or the body’s natural defenses and exhaust the immune system. Furthermore, since most HIV tests measure both infectious and defective provirus, it can complicate efforts to accurately assess a patient’s viral load and confound the ability to monitor how well a “shock-and-kill” cure approach is working.

Writing in the April 12 issue of Cell Host and Microbe, amfAR grantee Dr. Brad Jones of George Washington and colleagues reported that despite mutations, a subset of defective proviruses—called "hypermutated"—produced all of the typical markers of HIV infection, such as RNA and proteins.

They also observed that cytotoxic T cells (CTLs) recognized the "hypermutated" provirus as dangerous HIV. CTLs specialize in identifying and killing virus-infected cells. Thus, CTLs’ ability to pinpoint and target the real threat appeared greatly impaired, according to lead study investigator Dr. Ya-Chi Ho of Johns Hopkins.

Ho said more information on the mutant viruses is needed to discover ways to eliminate them and, ultimately, find a cure for HIV.