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

Sayuri Sakuragi,Jun-Ichi Sakuragi,Hironori Sato,Masaru Yokoyama,Tatsuo Shioda,Osamu Kotani

doi:10.3390/ijms22073435

Abstract

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.

Highlights

Eight mutants were constructed to pursue the determinant of packaging efficiency, and we found that the consecutive nucleotide substitution from GA to AC at positions 226 and 227 of the Human immunodeficiency virus type 1 (HIV-1) NL4-3 [10] was responsible for the subtype D phenotype (Figure 3D)
Recent reports indicate the prevalence of a wide variety of HIV-1 circulating recombinant forms (CRFs) all over the world [2,3]
We provide in vitro and in silico evidence suggesting a molecular mechanism by which HIV-1 controls the compatibility

Summary

Introduction

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. Such structural changes were minimal within the SL1 element involved in genome dimerization. Introduction with regard to jurisdictional claims in Retroviruses uptake homo-dimerized viral RNA genome into their own particle through an event that is called genome dimerization and packaging It is an essential and highly-distinguished step for retroviral replication, as the ultimate objective for the virus is the conservation and propagation of its genome.

Methods

Results

Conclusion