Document Detail


Susceptibility to virus-cell fusion at the plasma membrane is reduced through expression of HIV gp41 cytoplasmic domains.
MedLine Citation:
PMID:  18400243     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytoplasmic tail of the HIV transmembrane protein plays an important role in viral infection. In this study we analyzed the role of retroviral cytoplasmic tails in modulating the cytoskeleton and interfering with virus-cell fusion. HeLaP4 cells expressing different HIV cytoplasmic tail constructs showed reduced acetylated tubulin levels whereas the cytoplasmic tail of MLV did not alter microtubule stability indicating a unique function for the lentiviral cytoplasmic tail. The effect on tubulin is mediated through the membrane proximal region of the HIV cytoplasmic tail and was independent of membrane localization. Site-directed mutagenesis identified three motifs in the HIV-2 cytoplasmic tail required to effect the reduction in acetylated tubulin. Both the YxxPhi domain and amino acids 21 to 45 of the HIV-2 cytoplasmic tail need to be present to change the level of acetylated tubulin in transfected cells. T-cells stably expressing one HIV-2 cytoplasmic tail derived construct showed also a reduction in acetylated tubulin thus confirming the importance of this effect not only for HeLaP4 and 293T cells. Challenge experiments using transiently transfected HeLaP4 cells and T cells stably expressing an HIV cytoplasmic tail construct revealed both reduced virus-cell fusion and replication of HIV-1(NL4.3) compared to control cells. In the virus-cell fusion assay only virions pseudotyped with either HIV or MLV envelopes showed reduced fusion efficiency, whereas VSV-G pseudotyped virions where not affected by the expression of HIV derived cytoplasmic tail constructs, indicating that fusion at the plasma but not endosomal membrane is affected. Overexpression of human histone-deacetylase 6 (HDAC6) and constitutively active RhoA resulted in a reduction of acetylated tubulin and reduced virus-cell fusion as significant as that observed following expression of HIV cytoplasmic tail constructs. Inhibition of HDAC6 showed a strong increase in acetylated tubulin and increase of virus-cell fusion confirming the correlation between post-translational modification of tubulin and virus-cell fusion. These results thus identify tubulin and its post-translational modification as a new cellular target for interference with HIV-cell fusion.
Authors:
Katharina Malinowsky; Julia Luksza; Matthias T Dittmar
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-04-08
Journal Detail:
Title:  Virology     Volume:  376     ISSN:  0042-6822     ISO Abbreviation:  Virology     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-05-26     Completed Date:  2008-07-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0110674     Medline TA:  Virology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  69-78     Citation Subset:  IM    
Affiliation:
Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Amino Acid Substitution / genetics
Cell Line
Cell Membrane / virology*
Cytoplasm / chemistry
Epithelial Cells / virology
HIV Envelope Protein gp41 / genetics,  metabolism*
HIV-1 / genetics,  physiology*
HIV-2 / genetics,  physiology*
Histone Deacetylases / metabolism
Humans
Mutagenesis, Site-Directed
Mutation, Missense
T-Lymphocytes / virology
Tubulin / analysis
Virus Internalization*
Virus Replication
rhoA GTP-Binding Protein / metabolism
Chemical
Reg. No./Substance:
0/HIV Envelope Protein gp41; 0/Tubulin; EC 3.5.1.98/HDAC6 protein, human; EC 3.5.1.98/Histone Deacetylases; EC 3.6.5.2/rhoA GTP-Binding Protein

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