Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication

Venaud, S.; Yahi, Nouara; Fehrentz, J.L.; Guettari, N.; Nisato, Dino; Hirsch, Ivan; Chermann, Jean‐Claude

doi:10.1016/s0923-2516(06)80119-6

Cited by 20 publications

(11 citation statements)

References 23 publications

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“…We have proposed previously that one possible target of the PR in the early phase is the mature nucleocapsid (NC) protein, based on PR-mediated NC processing in the core particles of Equine infectious anemia virus, a lentivirus similar to Human immunodeficiency virus 1 (HIV-1) (Roberts & Oroszlan, 1989, 1990Roberts et al, 1991a, b), and on the presence of a corresponding cleavage site in the NC protein of HIV-1 (Tözsér et al, 1993, 2004. Our proposal is supported further by the finding that specific inhibitors of HIV-1 PR are able to block primary infection (Baboonian et al, 1991;Venaud et al, 1992;Nagy et al, 1994;Panther et al, 1999;Goto et al, 2001), although others have not observed this effect (Jacobsen et al, 1992;Kaplan et al, 1996;Uchida et al, 1997).…”

supporting

confidence: 59%

Replication-dependent fitness recovery of Human immunodeficiency virus 1 harbouring mutations of Asn17 of the nucleocapsid protein

Tőzsér

Shulenin

Young

et al. 2006

Journal of General Virology

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The genetic stability of attenuated Human immunodeficiency virus 1 (HIV-1) variants harbouring mutations (Gly or Lys) of Asn17, the protease-cleavage site of the proximal zinc finger of the nucleocapsid protein, was studied. All possible codons for the Gly mutants were tested as starting sequences. Long-term replication assays revealed that the mutants were unstable; mutations of Gly17 to Arg, Ala, Ser and Cys, as well as a Lys17Asn reversion, were observed. Replication kinetic assays in H9 cells revealed that the replication of Ala, Ser and Arg mutants was improved substantially compared with the Gly variant; the infectivity of Ala17 and Ser17 viruses was equal to, and that of Arg17 was almost equal to, the infectivity of the wild-type virus. Kinetic analysis of the cleavage of oligopeptides representing the corresponding nucleocapsid-cleavage sites revealed that all mutations improved cleavability, in good agreement with the previously proposed role of nucleocapsid cleavage in HIV-1 replication.

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supporting

confidence: 59%

Replication-dependent fitness recovery of Human immunodeficiency virus 1 harbouring mutations of Asn17 of the nucleocapsid protein

Tőzsér

Shulenin

Young

et al. 2006

Journal of General Virology

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“…Thus, two sepa- (26). In past instances when infected cells treated with HIV-1 protease inhibitors have exhibited a 40-kDa band, the band may have been discounted as reflecting incomplete inhibition of protease activity by the drug (89,92). The fact that p40…”

Section: Discussionmentioning

confidence: 99%

The Human Immunodeficiency Virus Type 1gagGene Encodes an Internal Ribosome Entry Site

Buck

Shen²,

Egan³

et al. 2001

J Virol

149

161

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Several retroviruses have recently been shown to promote translation of their gag gene products by internal ribosome entry. In this report, we show that mRNAs containing the human immunodeficiency virus type 1 (HIV-1) gag open reading frame (ORF) exhibit internal ribosome entry site (IRES) activity that can promote translational initiation of Pr55 gag . Remarkably, this IRES activity is driven by sequences within the gag ORF itself and is not dependent on the native gag 5-untranslated region (UTR). This cap-independent mechanism for Pr55 gag translation may help explain the high levels of translation of this protein in the face of major RNA structural barriers to scanning ribosomes found in the gag 5 UTR. The gag IRES activity described here also drives translation of a novel 40-kDa Gag isoform through translational initiation at an internal AUG codon found near the amino terminus of the Pr55 gag capsid domain. Our findings suggest that this low-abundance Gag isoform may be important for wild-type replication of HIV-1 in cultured cells. The activities of the HIV-1 gag IRES may be an important feature of the HIV-1 life cycle and could serve as a novel target for antiretroviral therapeutic strategies.Like other complex retroviruses, human immunodeficiency virus type 1 (HIV-1) employs a variety of mechanisms to express numerous proteins from a single-genomic-length RNA transcript. One such mechanism is the regulated splicing of the primary transcript into more than 30 distinct mRNA species (65,(74)(75)(76). Other mechanisms for the production of different polypeptides from mature viral mRNA species rely on translational events that are atypical of normal host protein translation.The initiation of translation of most eukaryotic mRNAs is thought to occur by a process involving ribosome scanning. In this model, the 40S ribosomal subunit binds to the 5Ј end of a capped mRNA (80, 81), commences scanning toward the 3Ј end, and initiates translation upon encountering an AUG codon in suitable context (often referred to as a "Kozak" context) (47,49,50). The 60S ribosomal subunit is then recruited, and translation of a single polypeptide begins.Translation of some HIV-1 mRNAs can depart from this basic model in several ways. Translation of the pol open reading frame (ORF) requires a Ϫ1 frameshift at a "slippery" sequence within the gag ORF. This frameshift allows roughly 5 to 10% of translating ribosomes to bypass the normal gag stop codon, enabling translation of a Gag-Pol precursor protein (reviewed in reference 32). Other HIV-1 gene products, including Env and Nef, have been shown to be translated by "leaky" scanning of ribosomes past the vpu and rev AUGs, respectively (74,75,77).Another alternative mechanism for translational initiation is driven by RNA structural elements referred to as internal ribosome entry sites (or segments) (IRESs). IRESs are thought to promote initiation of translation by directly binding ribosomes, with participation of other host cell factors, in a manner independent of the mRNA cap or of scann...

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“…The protease inhibitors ( P I ) w o r k a g a i n s t H I V i n t h e l a t e s t a g e o f viral replication to prevent infectious virus production from infected cells. They block the protease enzyme, which is necessary for the production of mature virions 32 . Seven compounds of the PI class have been approved by the US Food and Drug Administration (FDA): saquinavir (SQV), indinavir (IDV), ritonavir (RTV), nelfinavir (NFV), amprenavir (AMP), lopinavirritonavir (LPV), and atazanavir (ATV).…”

Section: Protease Inhibitorsmentioning

confidence: 99%

The Changing Trends of HIV Subtypes and Its Implication on Mother-to-Child Transmission

Kiptoo¹

2011

Recent Translational Research in HIV/AIDS

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Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication

Cited by 20 publications

References 23 publications

Replication-dependent fitness recovery of Human immunodeficiency virus 1 harbouring mutations of Asn17 of the nucleocapsid protein

Replication-dependent fitness recovery of Human immunodeficiency virus 1 harbouring mutations of Asn17 of the nucleocapsid protein

The Human Immunodeficiency Virus Type 1gagGene Encodes an Internal Ribosome Entry Site

The Changing Trends of HIV Subtypes and Its Implication on Mother-to-Child Transmission

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