The infection of cells by HIV type 1 (HIV-1) can be restricted by host factors through a variety of mechanisms. Identification and characterization of restriction factors against HIV-1 help to explain why effective viral infection can be established in certain cell types but not in others, and suggest new approaches to the control of HIV-1 replication. Zinc-finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses, including Ebola virus and some alphaviruses.

In a study carried out by Professor Guangxia Gao’s group at the Institute of Biophysics, Chinese Academy of Sciences, ZAP was found to inhibit HIV-1 infection by promoting the degradation of specific viral mRNAs. Gao’s group discovered that overexpression of ZAP rendered cells resistant to HIV-1 infection in a ZAP expression level-dependent manner, whereas depletion of endogenous ZAP enhanced HIV-1 infection. Both human and rat ZAP inhibited the propagation of replication-competent HIV-1. ZAP specifically targeted the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. They provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3’end. In addition, ZAP recruits cellular decapping complex through its cofactor RNA helicase p72 to initiate degradation of the target viral mRNA from the 59 end. Depletion of each of these mRNA degradation enzymes reduced ZAP’s activity. Their results indicate that ZAP inhibits HIV-1 by recruiting both the 5’and 3’mRNA degradation machinery to specifically promote the degradation of multiply spliced HIV-1 mRNAs.

This work was conducted in collaboration with researchers from the Ohio State University, USA and the Kunming Institute of Zoology, Chinese Academy of Sciences. It was supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Chinese Academy of Sciences. The results of this work were published online before print in PNAS on August 29, 2011 as a research article which titled “Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation”.