HIV Splicing as a Target
Anti-retroviral drugs developed over the last two decades are all broadly based on the same mechanism: the binding and blocking of essential viral proteins. While remarkably effective, this strategy has been challenged by the appearance of drug resistant variants within a naturally heterogeneous viral population. To overcome this obstacle, Jamal Tazi and his team1
have taken a completely different approach, “based on the targeting of a cellular factor used by the virus,” as he explains.
Tazi and his team’s discovery stems from their expertise in RNA splicing, the process that removes regions of RNA to make them “translatable” into proteins. “We became interested in HIV because the virus uses the same splicing machinery as the cell,” he explains. In particular, cellular splicing enhancer proteins are required for HIV infection to strike a balance between the RNAs that are spliced to encode essential viral proteins, and those left unspliced to provide the full-length RNA genome of new viruses. It is this specific aspect of HIV infection that Tazi’s group aimed to exploit when they screened indole derivatives for their capacity to hinder the activity of cellular splicing enhancers.2
One compound, IDC16, was shown to disrupt HIV RNA splicing and its effect diminishes HIV particle production. Treatment of cultured infected T-cells with IDC16 blocks the replication of lab-adapted strains, as well as that of viruses that have developed multi-drug resistance. The risk that the splicing enhancer protein targeted by IDC16 could develop resistance is low because cellular genes very rarely mutate. As for the virus, “the adaptation to splicing inhibitors will be extremely difficult if not impossible,” states Dr. Tazi. “If the virus mutates the sequences that interact with splicing factors, it will no longer be able to replicate.”
“We are in the identification phase,” continues Tazi, “about 5 to 10 years away from clinical trials.” So far, we have identified the doses that inhibit splicing of HIV RNA in vitro, without affecting the subset of cellular mRNAs tested. The current goal is to identify IDC16 derivatives that are more stable and have low toxicity in humans. “We know that other viruses that use RNA splicing are blocked by IDC16,” Tazi adds, suggesting that indole derivatives could greatly advance general viral treatment.
1. Institut de Génétique Moléculaire (CNRS, Université de Montpellier I).
2. N. Bakkour et al., “Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance,” Plos Pathogens. 3(10): 1530-39. 2007.