HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy

Sci Rep. 2017 Aug 17;7(1):8572. doi: 10.1038/s41598-017-08736-x.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Animals, Newborn
  • Autophagosomes / metabolism
  • Beclin-1 / metabolism
  • Cell Survival
  • Cells, Cultured
  • HEK293 Cells
  • HIV Infections / blood
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / metabolism
  • HIV-1 / physiology*
  • Humans
  • Macaca mulatta
  • Male
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / virology*
  • Protein Binding
  • Rats, Sprague-Dawley
  • Simian Acquired Immunodeficiency Syndrome / blood
  • Simian Acquired Immunodeficiency Syndrome / metabolism
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / physiology
  • nef Gene Products, Human Immunodeficiency Virus / blood
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Beclin-1
  • nef Gene Products, Human Immunodeficiency Virus