Revealing the RNA-RNA interactome of the HIV-1 genome

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Project Summary/Abstract Retroviruses, like many RNA viruses, have high mutation rates, allowing rapid genome evolution to select for beneficial host factor interactions. Recently the importance of non-coding RNAs (ncRNAs) for host antiviral processes have been highlighted; however, many RNA viruses have also evolved to make use of host ncRNAs for their own benefit. Indeed, several microRNAs (miRNAs) have been identified that inhibit replication of mammalian RNA viruses while others increase replication. It is important to point out that repressed replication is likely to be advantageous to the virus in many instances. Furthermore, retroviruses are dependent on a host tRNA to prime reverse transcription of their genomic RNA (gRNA) into double-stranded proviral DNA. This fundamental tRNA-gRNA interaction precedes all enzyme-catalyzed processes during retroviral infection of a host cell. In addition, tRNA-derived fragments (tRFs) that result from endonucleolytic cleavage of tRNAs have recently been shown to inhibit endogenous retroviral replication by regulating reverse transcription. Due to the rapid response of HIV-1 to selective pressure, it is likely to have evolved mechanisms of responding to RNA- mediated host processes; however, comprehensive identification of the HIV-1 gRNA nucleic acid interactome is lacking. Here, we aim to test the overarching hypothesis that HIV-1 gRNA has evolved critical RNA-RNA interactions such as alternative conformations, long-range intra-molecular interactions and direct binding of host ncRNAs to optimize infectivity. The specific aims are to (1) identify HIV-1 gRNA intra-molecular base-pairing and inter-molecular host RNA interactions and (2) test the biological significance of HIV-1 RNA-RNA interactions.