Indiana University-Purdue University Indianapolis (IUPUI) / HIV-associated cardio-pulmonary vascular pathologies such as coronary artery
disease, pulmonary hypertension and emphysema remain a major issue in the HIVinfected
population even in the era of antiretroviral therapy (ART). The continued
production of HIV encoded pro-apoptotic protein, such as Nef in latently HIV-infected
cells is a possible mechanism for vascular dysfunction underlying these diseases. HIVNef
persists in two compartments in these patients: (i) extracellular vesicles (EV) of
plasma and bronchoalveolar lavage (BAL) fluid and (ii) PBMC and BAL derived cells.
Here I demonstrate that the presence of HIV-Nef protein in cells and EV is capable of
stressing endothelial cells by inducing ROS production leading to endothelial cell
apoptosis. HIV-Nef protein hijacks host cell signaling by interacting with small GTP
binding protein Rac1 which activates PAK2 to promote the release of pro-apoptotic cargo
containing EV and surface expression of pro-apoptotic protein Endothelial Monocyte
Activating Polypeptide II (EMAPII). Using this mechanism, Nef protein robustly
induces apoptosis in Human Coronary Artery Endothelial Cells and Human Lung
microvascular endothelial cells. Endothelial specific expression of HIV-Nef protein in
transgenic mice was sufficient to induce vascular pathologies as evidenced by impaired
endothelium mediated vasodilation of the aorta and vascular remodeling and emphysema
like alveolar rarefaction in the lung. Furthermore, EV isolated from HIV patients on ART was capable of inducing endothelial apoptosis in a Nef dependent fashion. Of therapeutic
interest, EMAPII neutralizing antibodies to block EMAPII mediated apoptosis and statin
treatment to ameliorate Nef induced Rac1 signaling was capable of blocking Nef induced
endothelial stress in both in vivo and in vitro. In conclusion, HIV-Nef protein uses a
Rac1-Pak2 signaling axis to promote its dissemination in EV, which in turn induces
endothelial cell stress after its uptake.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/19438 |
| Date | 05 1900 |
| Creators | Chelvanambi, Sarvesh |
| Contributors | Clauss, Matthias, Basile, David, Day, Richard, Yu, Andy |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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