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HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy.

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.

SUBMITTER: Gupta MK

PROVIDER: S-EPMC5561171 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy.

Gupta Manish K MK Kaminski Rafal R Mullen Brian B Gordon Jennifer J Burdo Tricia H TH Cheung Joseph Y JY Feldman Arthur M AM Madesh Muniswamy M Khalili Kamel K

Scientific reports 20170817 1

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 ...[more]

PMID: 28819214

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HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy.

Publications

HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy.

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