Role of RNA helicases in HIV-1 replication

Jeang, Kuan-Teh; Yedavalli, Venkat

Guarded optimism that small molecule helicase inhibitors can be developed against viruses arises from encouraging progress in non-retroviral systems. Unlike HIV-1, human herpesviruses physically encode helicases. The herpes simplex virus UL5 and UL9 genes are helicases in superfamily 1 and 2, respectively (77) . HSV UL5 together with UL8 and UL52 form a heterotrimeric helicase-primase complex responsible for unwinding duplex viral DNA at replication forks. Two recent studies provide proof-of-concept that the HSV helicase-primase can be targeted at low host cell toxicity by two new classes of drugs, amino-thiazolyphenylmolecules (78) and thiazole amide derivatives (79) . In addition, other studies suggest that the NS3 protein, a RNA helicase encoded by Hepatitis C virus and related West Nile virus and Japanese Encephalitis virus can be targeted to inhibit viral replication (80) (81) (82) . This conceptual break through in drug development is important because it indicates that target discrimination between different helicases by small molecule inhibitors is possible. Of relevance to HIV-1, a synthetic immunomodulator Murabutide was shown recently to suppress HIV-1 replication in macrophages and T cells. Murabutide was shown to inhibit the activity of RNA helicase RH116, blocking its positive transcriptional activity for HIV-1 gene expression (42) .