The Regulation of HIV-1 mRNA Biogenesis

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The machinery regulating the transcription and processing of the human immunodeficiency virus type 1 (HIV-1) genome has been extensively studied for the past two decades, leading to the characterization of a complex set of interactions between viral and cellular factors. Our understanding of the basic molecular mechanisms regulating the expression of cellular genes has been greatly advanced by the lessons learned from this virus. Studies aimed at the understanding of transcription, capping, polyadenylation, splicing and export of the viral transcripts have helped in modeling the mechanisms regulating transcriptional and posttranscriptional events in the cell. Recent developments in the field have also shown that, similarly to cellular genes, transcription and processing of the viral mRNAs are functionally coupled and can potentially be regulated by small non-coding RNAs. HIV replication is a complex multistep process whereby, following the recognition of specific receptors and co-receptors on the host cell membrane, the virus enters the cell where the viral RNA genome is reverse transcribed and integrated into the cellular DNA. The integrated proviral genome is than transcribed by the host transcription machinery into a 9.2 kb primary transcript, which is alternatively spliced in mRNAs coding for the 9 viral genes. Tat and rev gene products are shuttled into the nucleus to aid the transcription process, the former, and export of unspliced transcripts, the later. Unspliced transcripts are packaged as viral genome into the nascent virions. Gag and env gene products code for the structural components of the new virions while the pol gene codes for key enzyme required for viral integration into the target host cell, which are than packaged within the virions. The products of the Vif, Vpr, Vpu and Nef genes are not essential for viral replication but are required for HIV pathogenesis and infectivity in-vivo. HIV-1 has developed a number of strategies to regulate the transcription and processing of its primary transcript. Interactions between viral RNA sequences, the host cell and viral proteins are necessary to express the nine gene products required for its replication. Alteration of the delicate balance between spliced and unspliced RNAs, or disruption of the viral RNA export pathway, can dramatically affect HIV-1 infectivity and pathogenesis (Amendt, et al., 1994, Jablonski & Caputi, 2009, Pollard & Malim, 1998, Purcell & Martin, 1993, Stoltzfus & Madsen, 2006, Wentz, et al., 1997). A better understanding of the mechanisms regulating the transcription and processing of the viral RNA may provide us with novel therapeutic targets.