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Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging

Human immunodeficiency virus type 1 (HIV-1) uptakes homo-dimerized viral RNA genome into its own particle. A cis-acting viral RNA segment responsible for this event, termed packaging signal (psi), is located at the 5′-end of the viral genome. Although the psi segment exhibits nucleotide variation in...

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Autores principales: Sakuragi, Sayuri, Kotani, Osamu, Yokoyama, Masaru, Shioda, Tatsuo, Sato, Hironori, Sakuragi, Jun-ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036536/
https://www.ncbi.nlm.nih.gov/pubmed/33810482
http://dx.doi.org/10.3390/ijms22073435
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author Sakuragi, Sayuri
Kotani, Osamu
Yokoyama, Masaru
Shioda, Tatsuo
Sato, Hironori
Sakuragi, Jun-ichi
author_facet Sakuragi, Sayuri
Kotani, Osamu
Yokoyama, Masaru
Shioda, Tatsuo
Sato, Hironori
Sakuragi, Jun-ichi
author_sort Sakuragi, Sayuri
collection PubMed
description Human immunodeficiency virus type 1 (HIV-1) uptakes homo-dimerized viral RNA genome into its own particle. A cis-acting viral RNA segment responsible for this event, termed packaging signal (psi), is located at the 5′-end of the viral genome. Although the psi segment exhibits nucleotide variation in nature, its effects on the psi function largely remain unknown. Here we show that a psi sequence from an HIV-1 regional variant, subtype D, has a lower packaging ability compared with that from another regional variant, HIV-1 subtype B, despite maintaining similar genome dimerization activities. A series of molecular genetic investigations narrowed down the responsible element of the selective attenuation to the two sequential nucleotides at positions 226 and 227 in the psi segment. Molecular dynamics simulations predicted that the dinucleotide substitution alters structural dynamics, fold, and hydrogen-bond networks primarily of the psi-SL2 element that contains the binding interface of viral nucleocapsid protein for the genome packaging. In contrast, such structural changes were minimal within the SL1 element involved in genome dimerization. These results suggest that the psi 226/227 dinucleotide pair functions as a cis-acting regulator to control the psi structure to selectively tune the efficiency of packaging, but not dimerization of highly variable HIV-1 genomes.
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spelling pubmed-80365362021-04-12 Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging Sakuragi, Sayuri Kotani, Osamu Yokoyama, Masaru Shioda, Tatsuo Sato, Hironori Sakuragi, Jun-ichi Int J Mol Sci Article Human immunodeficiency virus type 1 (HIV-1) uptakes homo-dimerized viral RNA genome into its own particle. A cis-acting viral RNA segment responsible for this event, termed packaging signal (psi), is located at the 5′-end of the viral genome. Although the psi segment exhibits nucleotide variation in nature, its effects on the psi function largely remain unknown. Here we show that a psi sequence from an HIV-1 regional variant, subtype D, has a lower packaging ability compared with that from another regional variant, HIV-1 subtype B, despite maintaining similar genome dimerization activities. A series of molecular genetic investigations narrowed down the responsible element of the selective attenuation to the two sequential nucleotides at positions 226 and 227 in the psi segment. Molecular dynamics simulations predicted that the dinucleotide substitution alters structural dynamics, fold, and hydrogen-bond networks primarily of the psi-SL2 element that contains the binding interface of viral nucleocapsid protein for the genome packaging. In contrast, such structural changes were minimal within the SL1 element involved in genome dimerization. These results suggest that the psi 226/227 dinucleotide pair functions as a cis-acting regulator to control the psi structure to selectively tune the efficiency of packaging, but not dimerization of highly variable HIV-1 genomes. MDPI 2021-03-26 /pmc/articles/PMC8036536/ /pubmed/33810482 http://dx.doi.org/10.3390/ijms22073435 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Sakuragi, Sayuri
Kotani, Osamu
Yokoyama, Masaru
Shioda, Tatsuo
Sato, Hironori
Sakuragi, Jun-ichi
Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title_full Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title_fullStr Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title_full_unstemmed Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title_short Identification of a Novel Cis-Acting Regulator of HIV-1 Genome Packaging
title_sort identification of a novel cis-acting regulator of hiv-1 genome packaging
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036536/
https://www.ncbi.nlm.nih.gov/pubmed/33810482
http://dx.doi.org/10.3390/ijms22073435
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