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...

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Autores principales: Manish K. Gupta, Rafal Kaminski, Brian Mullen, Jennifer Gordon, Tricia H. Burdo, Joseph Y. Cheung, Arthur M. Feldman, Muniswamy Madesh, Kamel Khalili
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/9ad17bb03abc452586a3880c4d4e1833
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Sumario: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.