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Elements in the 5′ Untranslated Region of Viral RNA Important for HIV Gag Recognition and Cross-Packaging

by Zetao Cheng, Olga A. Nikolaitchik, Alice Duchon, Jonathan M. O. Rawson, Vinay K. Pathak and Wei-Shau Hu

Viruses 2025, 17(4), 551; https://doi.org/10.3390/v17040551 - 10 Apr 2025

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Abstract

During retrovirus assembly, Gag packages unspliced viral RNA as the virion genome. Genome packaging is usually specific with occasional exceptions of cross-packaging RNA from distantly related retroviruses. For example, HIV-1 Gag can efficiently package HIV-2 RNA. To better understand how HIV-1 Gag selects packaging substrates, we defined elements in the HIV-2 5′ untranslated region (UTR) that are important for this process. Although sharing little homology, both HIV-1 and HIV-2 5′ UTRs have unpaired guanosines essential for packaging by their own Gag. Simultaneously substituting guanosines of nine sites in the HIV-2 5′ UTR caused severe defects in HIV-1 Gag-mediated packaging. Two of the nine sites are particularly important, mutating each one impaired HIV-1 Gag-mediated packaging, whereas the other sites required mutations in multiple sites to produce similar effects. Additionally, we identified one site that impacts HIV-1 Gag but is dispensable for HIV-2 Gag selective packaging. Furthermore, combining mutations has an additive effect on packaging defects for HIV-1 Gag, in contrast to the previously reported synergistic effects for HIV-2 Gag. Our study demonstrates that Gag proteins from two different retroviruses recognize and use mostly the same set of cis-acting elements to mediate RNA packaging and provide the mechanistic basis for genome cross-packaging. Full article

(This article belongs to the Section Human Virology and Viral Diseases)

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10 pages, 271 KiB

Open AccessCommentary

New Structure Sheds Light on Selective HIV-1 Genomic RNA Packaging

by Erik D. Olson, William A. Cantara and Karin Musier-Forsyth

Viruses 2015, 7(8), 4826-4835; https://doi.org/10.3390/v7082846 - 24 Aug 2015

Cited by 6 | Viewed by 11350

Abstract

Two copies of unspliced human immunodeficiency virus (HIV)-1 genomic RNA (gRNA) are preferentially selected for packaging by the group-specific antigen (Gag) polyprotein into progeny virions as a dimer during the late stages of the viral lifecycle. Elucidating the RNA features responsible for selective recognition of the full-length gRNA in the presence of an abundance of other cellular RNAs and spliced viral RNAs remains an area of intense research. The recent nuclear magnetic resonance (NMR) structure by Keane et al. [1] expands upon previous efforts to determine the conformation of the HIV-1 RNA packaging signal. The data support a secondary structure wherein sequences that constitute the major splice donor site are sequestered through base pairing, and a tertiary structure that adopts a tandem 3-way junction motif that exposes the dimerization initiation site and unpaired guanosines for specific recognition by Gag. While it remains to be established whether this structure is conserved in the context of larger RNA constructs or in the dimer, this study serves as the basis for characterizing large RNA structures using novel NMR techniques, and as a major advance toward understanding how the HIV-1 gRNA is selectively packaged. Full article

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