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Potent Inhibition of HIV-1 Replication by a Tat Mutant

Herein we describe a mutant of the two-exon HIV-1 Tat protein, termed Nullbasic, that potently inhibits multiple steps of the HIV-1 replication cycle. Nullbasic was created by replacing the entire arginine-rich basic domain of wild type Tat with glycine/alanine residues. Like similarly mutated one-e...

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Autores principales: Meredith, Luke W., Sivakumaran, Haran, Major, Lee, Suhrbier, Andreas, Harrich, David
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768900/
https://www.ncbi.nlm.nih.gov/pubmed/19901984
http://dx.doi.org/10.1371/journal.pone.0007769
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author Meredith, Luke W.
Sivakumaran, Haran
Major, Lee
Suhrbier, Andreas
Harrich, David
author_facet Meredith, Luke W.
Sivakumaran, Haran
Major, Lee
Suhrbier, Andreas
Harrich, David
author_sort Meredith, Luke W.
collection PubMed
description Herein we describe a mutant of the two-exon HIV-1 Tat protein, termed Nullbasic, that potently inhibits multiple steps of the HIV-1 replication cycle. Nullbasic was created by replacing the entire arginine-rich basic domain of wild type Tat with glycine/alanine residues. Like similarly mutated one-exon Tat mutants, Nullbasic exhibited transdominant negative effects on Tat-dependent transactivation. However, unlike previously reported mutants, we discovered that Nullbasic also strongly suppressed the expression of unspliced and singly-spliced viral mRNA, an activity likely caused by redistribution and thus functional inhibition of HIV-1 Rev. Furthermore, HIV-1 virion particles produced by cells expressing Nullbasic had severely reduced infectivity, a defect attributable to a reduced ability of the virions to undergo reverse transcription. Combination of these inhibitory effects on transactivation, Rev-dependent mRNA transport and reverse transcription meant that permissive cells constitutively expressing Nullbasic were highly resistant to a spreading infection by HIV-1. Nullbasic and its activities thus provide potential insights into the development of potent antiviral therapeutics that target multiple stages of HIV-1 infection.
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spelling pubmed-27689002009-11-10 Potent Inhibition of HIV-1 Replication by a Tat Mutant Meredith, Luke W. Sivakumaran, Haran Major, Lee Suhrbier, Andreas Harrich, David PLoS One Research Article Herein we describe a mutant of the two-exon HIV-1 Tat protein, termed Nullbasic, that potently inhibits multiple steps of the HIV-1 replication cycle. Nullbasic was created by replacing the entire arginine-rich basic domain of wild type Tat with glycine/alanine residues. Like similarly mutated one-exon Tat mutants, Nullbasic exhibited transdominant negative effects on Tat-dependent transactivation. However, unlike previously reported mutants, we discovered that Nullbasic also strongly suppressed the expression of unspliced and singly-spliced viral mRNA, an activity likely caused by redistribution and thus functional inhibition of HIV-1 Rev. Furthermore, HIV-1 virion particles produced by cells expressing Nullbasic had severely reduced infectivity, a defect attributable to a reduced ability of the virions to undergo reverse transcription. Combination of these inhibitory effects on transactivation, Rev-dependent mRNA transport and reverse transcription meant that permissive cells constitutively expressing Nullbasic were highly resistant to a spreading infection by HIV-1. Nullbasic and its activities thus provide potential insights into the development of potent antiviral therapeutics that target multiple stages of HIV-1 infection. Public Library of Science 2009-11-10 /pmc/articles/PMC2768900/ /pubmed/19901984 http://dx.doi.org/10.1371/journal.pone.0007769 Text en Meredith et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Meredith, Luke W.
Sivakumaran, Haran
Major, Lee
Suhrbier, Andreas
Harrich, David
Potent Inhibition of HIV-1 Replication by a Tat Mutant
title Potent Inhibition of HIV-1 Replication by a Tat Mutant
title_full Potent Inhibition of HIV-1 Replication by a Tat Mutant
title_fullStr Potent Inhibition of HIV-1 Replication by a Tat Mutant
title_full_unstemmed Potent Inhibition of HIV-1 Replication by a Tat Mutant
title_short Potent Inhibition of HIV-1 Replication by a Tat Mutant
title_sort potent inhibition of hiv-1 replication by a tat mutant
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768900/
https://www.ncbi.nlm.nih.gov/pubmed/19901984
http://dx.doi.org/10.1371/journal.pone.0007769
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