Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS One. 2014 Mar 7;9(3):e91063. doi: 10.1371/journal.pone.0091063. eCollection 2014.

Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction.

Author information

1
Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Cellular & Integrative Physiology and Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; R. L. Roudebush VA Medical Center, Indianapolis, Indiana, United States.
2
Department of Cellular & Integrative Physiology and Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; R. L. Roudebush VA Medical Center, Indianapolis, Indiana, United States.
3
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
4
Department of Cellular & Integrative Physiology and Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
5
Department of Medicine, Pulmonary Sciences & Critical Care Medicine, University of Colorado, Denver, Colorado, United States of America.
6
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America.
7
Institut de Recherches Cliniques de Montréal University of Montréal, Montréal, Quebec, Canada.
8
Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

Abstract

With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.

PMID:
24608713
PMCID:
PMC3946685
DOI:
10.1371/journal.pone.0091063
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center