Abstract
Infectious retrovirus particles contain two copies of unspliced viral RNA that serve as the viral genome. Unspliced retroviral RNA is transcribed in the nucleus by the host RNA polymerase II and has three potential fates: (1) it can be spliced into subgenomic messenger RNAs (mRNAs) for the translation of viral proteins; or it can remain unspliced to serve as either (2) the mRNA for the translation of Gag and Gag–Pol; or (3) the genomic RNA (gRNA) that is packaged into virions. The Gag structural protein recognizes and binds the unspliced viral RNA to select it as a genome, which is selected in preference to spliced viral RNAs and cellular RNAs. In this review, we summarize the current state of understanding about how retroviral packaging is orchestrated within the cell and explore potential new mechanisms based on recent discoveries in the field. We discuss the cis-acting elements in the unspliced viral RNA and the properties of the Gag protein that are required for their interaction. In addition, we discuss the role of host factors in influencing the fate of the newly transcribed viral RNA, current models for how retroviruses distinguish unspliced viral mRNA from viral genomic RNA, and the possible subcellular sites of genomic RNA dimerization and selection by Gag. Although this review centers primarily on the wealth of data available for the alpharetrovirus Rous sarcoma virus, in which a discrete RNA packaging sequence has been identified, we have also summarized the cis- and trans-acting factors as well as the mechanisms governing gRNA packaging of other retroviruses for comparison.
Highlights
Retroviruses are positive-sense, single-stranded RNA viruses that are ubiquitous in nature, causing cancers and immunodeficiency syndromes in a variety of organisms, including humans.Retroviruses encode enzymes that reverse transcribe their viral RNA genomes into a double-stranded cDNA that integrates into the host-cell chromosome, resulting in the formation of a provirus
How do retroviruses distinguish unspliced messenger RNAs (mRNAs) from genomic RNA (gRNA)? It is likely that retroviruses take advantage of host proteins and noncoding RNAs that interact with newly synthesized viral RNA (vRNA) in the nucleus to direct unspliced vRNA toward the splicing, mRNA export, or encapsidation pathway
It is feasible that different retroviral Gag proteins have adapted to their specialized intracellular environments and use different strategies to identify, select, and bind gRNA
Summary
Retroviruses are positive-sense, single-stranded RNA viruses that are ubiquitous in nature, causing cancers and immunodeficiency syndromes in a variety of organisms, including humans. The vRNA can remain unspliced, and this full-length RNA serves two roles: (i) as mRNA for the translation of the retroviral proteins Gag and Gag–Pol; or (ii) as the gRNA. The mechanisms by which Gag identifies and selects the unspliced vRNA as its genome is unclear, and several major questions pertaining to gRNA packaging remain unanswered. Because unspliced retroviral RNA is 50 capped and 30 polyadenylated, it is indistinguishable from cellular mRNAs, which are hundreds to thousands of times more abundant within the cell [4], lowering the probability that Gag interaction with the vRNA occurs by chance. It was thought that the Gag protein interacted with the unspliced vRNA in the cytoplasm or at the plasma membrane [5] It was not clear how the gRNA was transported to the site of Gag interaction. Rous sarcoma virus (RSV) have brought us closer to solving a few of these mysteries
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