HIV-Nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death

Sarvesh Chelvanambi, Natalia Bogatcheva, Mariola Bednorz, Stuti Agarwal, Bernhard Maier, Nathan Alves, Wei Li, Farooq Syed, Manal M. Saber, Noelle Dahl, Hongyan Lu, Richard B. Day, Patricia Smith, Paul Jolicoeur, Andy Yu, Navneet K. Dhillon, Norbert Weissmann, Homer Twigg, Matthias Clauss

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte–activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV 1 patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial–cadherin 1 endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.

Original languageEnglish (US)
Pages (from-to)357-366
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Human Immunodeficiency Virus nef Gene Products
Endothelial cells
Cell death
Cell Death
Endothelial Cells
HIV
Lung
T-cells
Pathology
Apoptosis
Dimercaprol
Peptides
Blood Vessels
Blood
HEK293 Cells
T-Lymphocytes
Macrophages
Inspiratory Capacity
Human Immunodeficiency Virus Proteins
Lung Volume Measurements

Keywords

  • EMAPII
  • Emphysema
  • Endothelial
  • Extracellular vesicles
  • HIV-Nef

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

HIV-Nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death. / Chelvanambi, Sarvesh; Bogatcheva, Natalia; Bednorz, Mariola; Agarwal, Stuti; Maier, Bernhard; Alves, Nathan; Li, Wei; Syed, Farooq; Saber, Manal M.; Dahl, Noelle; Lu, Hongyan; Day, Richard B.; Smith, Patricia; Jolicoeur, Paul; Yu, Andy; Dhillon, Navneet K.; Weissmann, Norbert; Twigg, Homer; Clauss, Matthias.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 60, No. 3, 01.03.2019, p. 357-366.

Research output: Contribution to journalArticle

Chelvanambi, S, Bogatcheva, N, Bednorz, M, Agarwal, S, Maier, B, Alves, N, Li, W, Syed, F, Saber, MM, Dahl, N, Lu, H, Day, RB, Smith, P, Jolicoeur, P, Yu, A, Dhillon, NK, Weissmann, N, Twigg, H & Clauss, M 2019, 'HIV-Nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death', American Journal of Respiratory Cell and Molecular Biology, vol. 60, no. 3, pp. 357-366. https://doi.org/10.1165/rcmb.2018-0089OC
Chelvanambi, Sarvesh ; Bogatcheva, Natalia ; Bednorz, Mariola ; Agarwal, Stuti ; Maier, Bernhard ; Alves, Nathan ; Li, Wei ; Syed, Farooq ; Saber, Manal M. ; Dahl, Noelle ; Lu, Hongyan ; Day, Richard B. ; Smith, Patricia ; Jolicoeur, Paul ; Yu, Andy ; Dhillon, Navneet K. ; Weissmann, Norbert ; Twigg, Homer ; Clauss, Matthias. / HIV-Nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death. In: American Journal of Respiratory Cell and Molecular Biology. 2019 ; Vol. 60, No. 3. pp. 357-366.
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AU - Maier, Bernhard

AU - Alves, Nathan

AU - Li, Wei

AU - Syed, Farooq

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AU - Dahl, Noelle

AU - Lu, Hongyan

AU - Day, Richard B.

AU - Smith, Patricia

AU - Jolicoeur, Paul

AU - Yu, Andy

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