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...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2009-11-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC2768900?pdf=render |
id |
doaj-1a939f4cea854fcd8a04af98d5e1a052 |
---|---|
record_format |
Article |
spelling |
doaj-1a939f4cea854fcd8a04af98d5e1a0522020-11-25T02:05:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-11-01411e776910.1371/journal.pone.0007769Potent inhibition of HIV-1 replication by a Tat mutant.Luke W MeredithHaran SivakumaranLee MajorAndreas SuhrbierDavid HarrichHerein 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.http://europepmc.org/articles/PMC2768900?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luke W Meredith Haran Sivakumaran Lee Major Andreas Suhrbier David Harrich |
spellingShingle |
Luke W Meredith Haran Sivakumaran Lee Major Andreas Suhrbier David Harrich Potent inhibition of HIV-1 replication by a Tat mutant. PLoS ONE |
author_facet |
Luke W Meredith Haran Sivakumaran Lee Major Andreas Suhrbier David Harrich |
author_sort |
Luke W Meredith |
title |
Potent inhibition of HIV-1 replication by a Tat mutant. |
title_short |
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_sort |
potent inhibition of hiv-1 replication by a tat mutant. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2009-11-01 |
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. |
url |
http://europepmc.org/articles/PMC2768900?pdf=render |
work_keys_str_mv |
AT lukewmeredith potentinhibitionofhiv1replicationbyatatmutant AT haransivakumaran potentinhibitionofhiv1replicationbyatatmutant AT leemajor potentinhibitionofhiv1replicationbyatatmutant AT andreassuhrbier potentinhibitionofhiv1replicationbyatatmutant AT davidharrich potentinhibitionofhiv1replicationbyatatmutant |
_version_ |
1724938827551735808 |