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The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G

BACKGROUND: The HIV-1 accessory protein known as viral infectivity factor or Vif binds to the host defence factor human APOBEC3G (hA3G) and prevents its assembly with viral particles and mediates its elimination through ubiquitination and degradation by the proteosomal pathway. In the absence of Vif...

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Autores principales: Miller, James H, Presnyak, Vlad, Smith, Harold C
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2222665/
https://www.ncbi.nlm.nih.gov/pubmed/18036235
http://dx.doi.org/10.1186/1742-4690-4-81
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author Miller, James H
Presnyak, Vlad
Smith, Harold C
author_facet Miller, James H
Presnyak, Vlad
Smith, Harold C
author_sort Miller, James H
collection PubMed
description BACKGROUND: The HIV-1 accessory protein known as viral infectivity factor or Vif binds to the host defence factor human APOBEC3G (hA3G) and prevents its assembly with viral particles and mediates its elimination through ubiquitination and degradation by the proteosomal pathway. In the absence of Vif, hA3G becomes incorporated within viral particles. During the post entry phase of infection, hA3G attenuates viral replication by binding to the viral RNA genome and deaminating deoxycytidines to form deoxyuridines within single stranded DNA regions of the replicated viral genome. Vif dimerization has been reported to be essential for viral infectivity but the mechanistic requirement for Vif multimerization is unknown. RESULTS: We demonstrate that a peptide antagonist of Vif dimerization fused to the cell transduction domain of HIV TAT suppresses live HIV-1 infectivity. We show rapid cellular uptake of the peptide and cytoplasmic distribution. Robust suppression of viral infectivity was dependent on the expression of Vif and hA3G. Disruption of Vif multimerization resulted in the production of virions with markedly increased hA3G content and reduced infectivity. CONCLUSION: The role of Vif multimerization in viral infectivity of nonpermissive cells has been validated with an antagonist of Vif dimerization. An important part of the mechanism for this antiretroviral effect is that blocking Vif dimerization enables hA3G incorporation within virions. We propose that Vif multimers are required to interact with hA3G to exclude it from viral particles during their assembly. Blocking Vif dimerization is an effective means of sustaining hA3G antiretroviral activity in HIV-1 infected cells. Vif dimerization is therefore a validated target for therapeutic HIV-1/AIDS drug development.
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spelling pubmed-22226652008-02-01 The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G Miller, James H Presnyak, Vlad Smith, Harold C Retrovirology Research BACKGROUND: The HIV-1 accessory protein known as viral infectivity factor or Vif binds to the host defence factor human APOBEC3G (hA3G) and prevents its assembly with viral particles and mediates its elimination through ubiquitination and degradation by the proteosomal pathway. In the absence of Vif, hA3G becomes incorporated within viral particles. During the post entry phase of infection, hA3G attenuates viral replication by binding to the viral RNA genome and deaminating deoxycytidines to form deoxyuridines within single stranded DNA regions of the replicated viral genome. Vif dimerization has been reported to be essential for viral infectivity but the mechanistic requirement for Vif multimerization is unknown. RESULTS: We demonstrate that a peptide antagonist of Vif dimerization fused to the cell transduction domain of HIV TAT suppresses live HIV-1 infectivity. We show rapid cellular uptake of the peptide and cytoplasmic distribution. Robust suppression of viral infectivity was dependent on the expression of Vif and hA3G. Disruption of Vif multimerization resulted in the production of virions with markedly increased hA3G content and reduced infectivity. CONCLUSION: The role of Vif multimerization in viral infectivity of nonpermissive cells has been validated with an antagonist of Vif dimerization. An important part of the mechanism for this antiretroviral effect is that blocking Vif dimerization enables hA3G incorporation within virions. We propose that Vif multimers are required to interact with hA3G to exclude it from viral particles during their assembly. Blocking Vif dimerization is an effective means of sustaining hA3G antiretroviral activity in HIV-1 infected cells. Vif dimerization is therefore a validated target for therapeutic HIV-1/AIDS drug development. BioMed Central 2007-11-24 /pmc/articles/PMC2222665/ /pubmed/18036235 http://dx.doi.org/10.1186/1742-4690-4-81 Text en Copyright © 2007 Miller et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Miller, James H
Presnyak, Vlad
Smith, Harold C
The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title_full The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title_fullStr The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title_full_unstemmed The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title_short The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G
title_sort dimerization domain of hiv-1 viral infectivity factor vif is required to block virion incorporation of apobec3g
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2222665/
https://www.ncbi.nlm.nih.gov/pubmed/18036235
http://dx.doi.org/10.1186/1742-4690-4-81
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