HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation

Neeti Agarwal, Dinakar Iyer, Sanjeet G. Patel, Rajagopal V. Sekhar, Terry M. Phillips, Ulrich Schubert, Toni Oplt, Eric D. Buras, Susan L. Samson, Jacob Couturier, Dorothy E. Lewis, Maria C. Rodriguez-Barradas, Farook Jahoor, Tomoshige Kino, Jeffrey B. Kopp, Ashok Balasubramanyam

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Abstract

Viral infections, such as HIV, have been linked to obesity, but mechanistic evidence that they cause adipose dysfunction in vivo is lacking. We investigated a pathogenic role for the HIV-1 accessory protein viral protein R (Vpr), which can coactivate the glucocorticoid receptor (GR) and co-repress peroxisome proliferator-activated receptor γ (PPARγ) in vitro, in HIV-associated adipose dysfunction. Vpr circulated in the blood of most HIV-infected patients tested, including those on antiretroviral therapy (ART) with undetectable viral load. Vpr-mediated mechanisms were dissected in vivo using mouse models expressing the Vpr transgene in adipose tissues and liver (Vpr-Tg) or infused with synthetic Vpr. Both models demonstrated accelerated whole-body lipolysis, hyperglycemia and hypertriglyceridemia, and tissue-specific findings. Fat depots in these mice had diminished mass, macrophage infiltration, and blunted PPARγ target gene expression but increased GR target gene expression. In liver, we observed blunted PPARα target gene expression, steatosis with decreased adenosine monophosphate- activated protein kinase activity, and insulin resistance. Similar to human HIV-infected patients, Vpr circulated in the serum of Vpr-Tg mice. Vpr blocked differentiation in preadipocytes through cell cycle arrest, whereas in mature adipocytes, it increased lipolysis with reciprocally altered association of PPARγ and GR with their target promoters. These results delineate a distinct pathogenic sequence: Vpr, released from HIV-1 in tissue reservoirs after ART, can disrupt PPAR/GR co-regulation and cell cycle control to produce adipose dysfunction and hepatosteatosis. Confirmation of these mechanisms in HIV patients could lead to targeted treatment of the metabolic complications with Vpr inhibitors, GR antagonists, or PPARγ/PPARα agonists.

Original languageEnglish
Article number213ra164
JournalScience Translational Medicine
Volume5
Issue number213
DOIs
Publication statusPublished - 27 Nov 2013
Externally publishedYes

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Human Immunodeficiency Virus vpr Gene Products
vpr Gene Products
Peroxisome Proliferator-Activated Receptors
Glucocorticoid Receptors
HIV-1
HIV
Lipolysis
Cell Cycle Checkpoints
Gene Expression
Hypertriglyceridemia
Liver
Virus Diseases
Adenosine Monophosphate

ASJC Scopus subject areas

  • Medicine(all)

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Agarwal, N., Iyer, D., Patel, S. G., Sekhar, R. V., Phillips, T. M., Schubert, U., ... Balasubramanyam, A. (2013). HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. Science Translational Medicine, 5(213), [213ra164]. https://doi.org/10.1126/scitranslmed.3007148

HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. / Agarwal, Neeti; Iyer, Dinakar; Patel, Sanjeet G.; Sekhar, Rajagopal V.; Phillips, Terry M.; Schubert, Ulrich; Oplt, Toni; Buras, Eric D.; Samson, Susan L.; Couturier, Jacob; Lewis, Dorothy E.; Rodriguez-Barradas, Maria C.; Jahoor, Farook; Kino, Tomoshige; Kopp, Jeffrey B.; Balasubramanyam, Ashok.

In: Science Translational Medicine, Vol. 5, No. 213, 213ra164, 27.11.2013.

Research output: Contribution to journalArticle

Agarwal, N, Iyer, D, Patel, SG, Sekhar, RV, Phillips, TM, Schubert, U, Oplt, T, Buras, ED, Samson, SL, Couturier, J, Lewis, DE, Rodriguez-Barradas, MC, Jahoor, F, Kino, T, Kopp, JB & Balasubramanyam, A 2013, 'HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation', Science Translational Medicine, vol. 5, no. 213, 213ra164. https://doi.org/10.1126/scitranslmed.3007148
Agarwal, Neeti ; Iyer, Dinakar ; Patel, Sanjeet G. ; Sekhar, Rajagopal V. ; Phillips, Terry M. ; Schubert, Ulrich ; Oplt, Toni ; Buras, Eric D. ; Samson, Susan L. ; Couturier, Jacob ; Lewis, Dorothy E. ; Rodriguez-Barradas, Maria C. ; Jahoor, Farook ; Kino, Tomoshige ; Kopp, Jeffrey B. ; Balasubramanyam, Ashok. / HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. In: Science Translational Medicine. 2013 ; Vol. 5, No. 213.
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AU - Samson, Susan L.

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AU - Lewis, Dorothy E.

AU - Rodriguez-Barradas, Maria C.

AU - Jahoor, Farook

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