title: HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3.
abstract: Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, beta-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1(+) patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Grol
authors.forename: Cecilia
authors.initials: C
authors.lastname: Subauste
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Andrade
authors.forename: Koh
authors.initials: K
authors.lastname: Fujinaga
authors.forename: Julie
authors.initials: J
authors.lastname: Nelson
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D019013:CD40 Antigens / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D014122:Toxoplasma / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus