HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy

Manish K. Gupta, Rafal Kaminski, Brian Mullen, Jennifer Gordon, Tricia H. Burdo, Joseph Y. Cheung, Arthur M. Feldman, Madesh Muniswamy, Kamel Khalili

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Cardiovascular disease is a leading cause of co-morbidity in HIV-1 positive patients, even those in whom plasma virus levels are well-controlled. The pathogenic mechanism of HIV-1-associated cardiomyopathy is unknown, but has been presumed to be mediated indirectly, owing to the absence of productive HIV-1 replication in cardiomyocytes. We sought to investigate the effect of the HIV-1 auxiliary protein, Nef, which is suspected of extracellular release by infected CD4+ T cells on protein quality control and autophagy in cardiomyocytes. After detection of Nef in the serum of HIV-1 positive patients and the accumulation of this protein in human and primate heart tissue from HIV-1/SIV-infected cells we employed cell and molecular biology approaches to investigate the effect of Nef on cardiomyocyte-homeostasis by concentrating on protein quality control (PQC) pathway and autophagy. We found that HIV-1 Nef-mediated inhibition of autophagy flux leads to cytotoxicity and death of cardiomyocytes. Nef compromises autophagy at the maturation stage of autophagosomes by interacting with Beclin 1/Rab7 and dysregulating TFEB localization and cellular lysosome content. These effects were reversed by rapamycin treatment. Our results indicate that HIV-1 Nef-mediated inhibition of cellular PQC is one possible mechanism involved in the development of HIV-associated cardiomyopathy.

Original languageEnglish (US)
Article number8572
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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Autophagy
HIV-1
Cardiac Myocytes
Quality Control
Cardiomyopathies
Proteins
Sirolimus
Lysosomes
Cardiotoxicity
Primates
Cell Biology
Molecular Biology
Homeostasis
Cardiovascular Diseases
HIV
Viruses
Morbidity
T-Lymphocytes
Serum

ASJC Scopus subject areas

  • General

Cite this

Gupta, M. K., Kaminski, R., Mullen, B., Gordon, J., Burdo, T. H., Cheung, J. Y., ... Khalili, K. (2017). HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. Scientific Reports, 7(1), [8572]. https://doi.org/10.1038/s41598-017-08736-x

HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. / Gupta, Manish K.; Kaminski, Rafal; Mullen, Brian; Gordon, Jennifer; Burdo, Tricia H.; Cheung, Joseph Y.; Feldman, Arthur M.; Muniswamy, Madesh; Khalili, Kamel.

In: Scientific Reports, Vol. 7, No. 1, 8572, 01.12.2017.

Research output: Contribution to journalArticle

Gupta, MK, Kaminski, R, Mullen, B, Gordon, J, Burdo, TH, Cheung, JY, Feldman, AM, Muniswamy, M & Khalili, K 2017, 'HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy', Scientific Reports, vol. 7, no. 1, 8572. https://doi.org/10.1038/s41598-017-08736-x
Gupta MK, Kaminski R, Mullen B, Gordon J, Burdo TH, Cheung JY et al. HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. Scientific Reports. 2017 Dec 1;7(1). 8572. https://doi.org/10.1038/s41598-017-08736-x
Gupta, Manish K. ; Kaminski, Rafal ; Mullen, Brian ; Gordon, Jennifer ; Burdo, Tricia H. ; Cheung, Joseph Y. ; Feldman, Arthur M. ; Muniswamy, Madesh ; Khalili, Kamel. / HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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