Human Cells Can "Silence" HIV Genes

For the first time, scientists have shown that humans use an immune defense process common in plants and invertebrates to battle a virus. The new finding that human cells can silence an essential part of HIVs genetic make-up could have important implications for the treatment of people infected with the virus. Led by Kuan-Teh Jeang, MD, PhD, of the National Institute of Allergy and Infectious Diseases (NIAID), part the National Institutes of Health, the researchers published their findings in this weeks issue of the journal Immunity.

"This research suggests that a novel approach to HIV therapy targeting a stable component of HIV might be feasible," says NIAID Director Anthony S. Fauci, MD.

The phenomenon, called RNA silencing, was detected first in plants and later in insects. Although plants and insects lack the sophisticated immune defenses of higher organisms, they nevertheless successfully battle viruses by detecting, and then silencing, viral genetic material. Silencing leads to the destruction of viral RNA. Viruses, however, are not permanently defeated because they have evolved ways to suppress the silencing action.

Until now, scientists have not had clear evidence that RNA silencing plays a role in the defensive repertoire of mammals and other vertebrates. Jeang and his colleagues set out to determine if RNA silencing (also called RNA interference or RNAi) contributes to human cells defense against HIV.

They asked three questions. First, does HIV have genetic sequences that an HIV-infected cell can detect and transform into the necessary precursors of RNAi, called short interfering RNA (siRNA)? Second, do human cells use siRNAs to disable HIV? Third, if human cells try to battle HIV using RNAi, does HIV have a way to evade the defensive maneuver? The answer to all three questions, the scientists determined, is yes.

The most unexpected finding, according to Jeang, was the way HIV uses one of its proteins, called Tat, to suppress the silencing efforts of the cell. HIV is well known for evading drugs by quickly mutating its genes. However, the virus could not evade the newly discovered sequence-specific siRNA attack by mutation. Instead, HIV required a virally encoded protein to blunt the assault. Jeang believes that Tat may be shielding a rare HIV Achilles heel, a genetic sequence that, for functional reasons, the virus cannot change in order to escape siRNA attack. This novel siRNA sequence discovered by the team may lead to the development of new RNAi-based drugs to which HIV would not be able to develop resistance by simple mutation.

The first author of the paper is Yamina Bennasser, PhD, of NIAID. Other authors are Shu-Yun Le, PhD, of the National Cancer Institute and Monsef Benkirane, PhD, of the Institut de Genetique Humaine in Montpellier, France.

Reference: Y Bennasser et al. Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity 22:1-13 (2005).