Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction

Ting Wang, Linden A. Green, Samir Gupta, Chul Kim, Liang Wang, Sharilyn Almodovar, Sonia C. Flores, Igor A. Prudovsky, Paul Jolicoeur, Ziyue Liu, Matthias Clauss

Research output: Contribution to journalArticle

24 Citations (Scopus)

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-kβ 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.

Original languageEnglish
Article numbere91063
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 7 2014

Fingerprint

nef Gene Products
Endothelial cells
endothelium
Endothelium
Endothelial Cells
HIV
endothelial cells
Jurkat Cells
proteins
Monocytes
Cardiovascular Diseases
attractants
Apoptosis
monocytes
therapeutics
cardiovascular diseases
Signal transduction
T-cells
apoptosis
Macaca

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. / Wang, Ting; Green, Linden A.; Gupta, Samir; Kim, Chul; Wang, Liang; Almodovar, Sharilyn; Flores, Sonia C.; Prudovsky, Igor A.; Jolicoeur, Paul; Liu, Ziyue; Clauss, Matthias.

In: PLoS One, Vol. 9, No. 3, e91063, 07.03.2014.

Research output: Contribution to journalArticle

Wang, T, Green, LA, Gupta, S, Kim, C, Wang, L, Almodovar, S, Flores, SC, Prudovsky, IA, Jolicoeur, P, Liu, Z & Clauss, M 2014, 'Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction', PLoS One, vol. 9, no. 3, e91063. https://doi.org/10.1371/journal.pone.0091063
Wang, Ting ; Green, Linden A. ; Gupta, Samir ; Kim, Chul ; Wang, Liang ; Almodovar, Sharilyn ; Flores, Sonia C. ; Prudovsky, Igor A. ; Jolicoeur, Paul ; Liu, Ziyue ; Clauss, Matthias. / Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. In: PLoS One. 2014 ; Vol. 9, No. 3.
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