Mutations in the kissing-loop hairpin of human immunodeficiency virus type 1 reduce viral infectivity as well as genomic RNA packaging and dimerization

Laughrea, Michael; Jetté, Louis; Mak, Johnson; Kleiman, Lawrence; Liang, Chen; Wainberg, Mark A.

doi:10.1128/jvi.71.5.3397-3406.1997

Cited by 145 publications

(106 citation statements)

References 66 publications

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“…1B, bold). There are two major motifs in HIV‐1; GUGCAC in subtypes A and C, and GCGCGC in subtypes B and D [14,15] (see also current alignments http://www.hiv.lanl.gov base 881–887). The loop is located between the primer binding site and the splice donor site at the end of the long terminal repeat (LTR) [16] and is involved in the dimerization of the HIV‐1 genome, packaging and proviral synthesis [17–21].…”

Section: Introductionmentioning

confidence: 99%

Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV‐1 genome dimerization and inhibit virus replication

et al. 2004

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We have evaluated antisense design and efficacy of locked nucleic acid (LNA) and DNA oligonucleotide (ON) mix-mers targeting the conserved HIV-1 dimerization initiation site (DIS). LNA is a high affinity nucleotide analog, nuclease resistant and elicits minimal toxicity. We show that inclusion of LNA bases in antisense ONs augments the interference of HIV-1 genome dimerization. We also demonstrate the concomitant RNase H activation by six consecutive DNA bases in an LNA/DNA mix-mer. We show ON uptake via receptor-mediated transfection of a human T-cell line in which the mix-mers subsequently inhibit replication of a clinical HIV-1 isolate. Thus, the technique of LNA/DNA mix-mer antisense ONs targeting the conserved HIV-1 DIS region may provide a strategy to prevent HIV-1 assembly in the clinic.

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Section: Introductionmentioning

confidence: 99%

Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV‐1 genome dimerization and inhibit virus replication

et al. 2004

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“…Because HTLV-1 ⌿ regions have not been fully characterized, it is possible that HTLV-1 ⌿, like BLV ⌿, is discontinuous (10,83) and includes elements that bind to NC in the U5 region. Retroviral packaging signals and dimerization sites usually overlap, and studies have suggested that gRNA dimerization and packaging are coupled (46,85,86). Here, we show that HTLV-1 NC specifically binds to both of the experimentally identified DISs in the HTLV-1 5Ј leader, indicating a potential role for NC in promoting gRNA dimerization.…”

Section: Rna-binding Specificity Of Htlv-1 Gag Domainsmentioning

confidence: 56%

Human T-cell leukemia virus type 1 Gag domains have distinct RNA-binding specificities with implications for RNA packaging and dimerization

Hatterschide

Syu

et al. 2018

Journal of Biological Chemistry

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Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus that has conclusively been shown to cause human diseases. In HIV-1, specific interactions between the nucleocapsid (NC) domain of the Gag protein and genomic RNA (gRNA) mediate gRNA dimerization and selective packaging; however, the mechanism for gRNA packaging in HTLV-1, a deltaretrovirus, is unclear. In other deltaretroviruses, the matrix (MA) and NC domains of Gag are both involved in gRNA packaging, but MA binds nucleic acids with higher affinity and has more robust chaperone activity, suggesting that this domain may play a primary role. Here, we show that the MA domain of HTLV-1, but not the NC domain, binds short hairpin RNAs derived from the putative gRNA packaging signal. RNA probing of the HTLV-1 5' leader and cross-linking studies revealed that the primer-binding site and a region within the putative packaging signal form stable hairpins that interact with MA. In addition to a previously identified palindromic dimerization initiation site (DIS), we identified a new DIS in HTLV-1 gRNA and found that both palindromic sequences bind specifically the NC domain. Surprisingly, a mutant partially defective in dimer formation exhibited a significant increase in RNA packaging into HTLV-1-like particles, suggesting that efficient RNA dimerization may not be strictly required for RNA packaging in HTLV-1. Moreover, the lifecycle of HTLV-1 and other deltaretroviruses may be characterized by NC and MA functions that are distinct from those of the corresponding HIV-1 proteins, but together provide the functions required for viral replication.

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“…This process involves specific interactions between Gag and the 5' end of the gRNA which contains the packaging signal (Psi) encompassing stem-loop 1 (SL1) to SL4 ( Figure 1A) (for reviews see (4)(5)(6)(7)). SL1 corresponds to the Dimerization Initiation Site (DIS), as it contains a short palindromic sequence in its apical loop that drives dimerization of the HIV-1 gRNA (8)(9)(10)(11)(12), and our group previously showed that the SL1 internal purine rich loop corresponds to a major Gag recognition signal (13)(14)(15). SL2 contains the major splice donor site, SL3 has been historically considered as the main packaging signal (16,17), and SL4 contains the translation initiation codon of Gag.…”

Section: Introductionmentioning

confidence: 99%

The two zinc fingers in the nucleocapsid domain of the HIV-1 Gag precursor are equivalent for the interaction with the genomic RNA in the cytoplasm, but not for the recruitment of the complexes at the plasma membrane

Bernacchi

Boutant

Bonzi

et al. 2020

Preprint

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The HIV-1 Gag precursor specifically selects the unspliced viral genomic RNA (gRNA) from the bulk of cellular and spliced viral RNAs via its nucleocapsid (NC) domain and drives gRNA encapsidation at the plasma membrane (PM). To further identify the determinants governing the intracellular trafficking of Gag-gRNA complexes and their accumulation at the PM, we compared, in living and fixed cells, the interactions between gRNA and wild-type (WT) Gag or Gag mutants carrying deletions in NC zinc fingers (ZFs), or a non-myristoylated version of Gag. Our data showed that the deletion of both ZFs simultaneously or the complete NC domain completely abolished intracytoplasmic Gag-gRNA interactions. Deletion of either ZF delayed the delivery of gRNA to the PM but did not prevent Gag-gRNA interactions in the cytoplasm,

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Mutations in the kissing-loop hairpin of human immunodeficiency virus type 1 reduce viral infectivity as well as genomic RNA packaging and dimerization

Cited by 145 publications

References 66 publications

Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV‐1 genome dimerization and inhibit virus replication

Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV‐1 genome dimerization and inhibit virus replication

Human T-cell leukemia virus type 1 Gag domains have distinct RNA-binding specificities with implications for RNA packaging and dimerization

The two zinc fingers in the nucleocapsid domain of the HIV-1 Gag precursor are equivalent for the interaction with the genomic RNA in the cytoplasm, but not for the recruitment of the complexes at the plasma membrane

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