Abstract
Like other retroviruses, human immunodeficiency virus type 1 (HIV-1) selectively packages genomic RNA (gRNA) during virus assembly. However, in the absence of the gRNA, cellular messenger RNAs (mRNAs) are packaged. While the gRNA is selected because of its cis-acting packaging signal, the mechanism of this selection is not understood. The affinity of Gag (the viral structural protein) for cellular RNAs at physiological ionic strength is not much higher than that for the gRNA. However, binding to the gRNA is more salt-resistant, implying that it has a higher non-electrostatic component. We have previously studied the spacer 1 (SP1) region of Gag and showed that it can undergo a concentration-dependent conformational transition. We proposed that this transition represents the first step in assembly, i.e., the conversion of Gag to an assembly-ready state. To explain selective packaging of gRNA, we suggest here that binding of Gag to gRNA, with its high non-electrostatic component, triggers this conversion more readily than binding to other RNAs; thus we predict that a Gag–gRNA complex will nucleate particle assembly more efficiently than other Gag–RNA complexes. New data shows that among cellular mRNAs, those with long 3′-untranslated regions (UTR) are selectively packaged. It seems plausible that the 3′-UTR, a stretch of RNA not occupied by ribosomes, offers a favorable binding site for Gag.
Highlights
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), is a retrovirus
~20–30 nucleotides can support assembly under these conditions [9]. This means that, at least in vitro, HIV-1 virus-like particles (VLPs) assembly does not depend on the length of the packaged RNA: proper Gag–Gag interactions can occur even when the RNA is extremely small compared to the length of the genomic RNA (gRNA) (~9.7 kb)
One of these messenger RNAs (mRNAs) species is ankyrin repeat and SOCS box containing 1 (ASB-1) mRNA [35]. We noted that this mRNA has an unusually long 30 -untranslated regions (UTR), and wondered whether this might contribute to the relatively efficient encapsidation of this mRNA. We have explored this question by re-analyzing our earlier microarray data [35] on the mRNA species packaged in HIV-1 and murine leukemia virus (MLV) particles in the absence of Ψ-containing RNA
Summary
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), is a retrovirus. The MA domain is involved in the interaction of Gag with membranes, but can bind to RNA; the CA domain mediates most of the protein-protein interactions between Gag molecules; NC, which is positively charged and contains two small zinc fingers, plays a major role in interactions of Gag with nucleic acids; and p6 contributes to the release of the assembled particle from the host cell by interacting with the cellular endosomal sorting complexes required for transport (ESCRT) machinery. There is still no molecular mechanism that explains how the gRNA is preferentially packaged in the presence of a large excess of cellular and spliced viral RNAs. While it is clear that the zinc fingers within NC are essential for specific packaging of the gRNA [3,5], it is not known whether other domains of Gag are involved. It seems possible that selective packaging of the gRNA in HIV-1 depends on the strength of Gag–Gag, as well as on Gag–RNA interactions
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