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, β-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.

mTOR as a multifunctional therapeutic target in HIV infection

“…In agreement with these findings it has also been demonstrated in dendritic cells (DCs) that rapamycin-mediated autophagy induction exerts a better anti-BCG vaccine response [31]. This raises the possibility of therapeutic manipulation of cell signalling to restore autophagy in HIV-1 infection [30].…”

“…Thus, stopping phagocytosis of opportunistic pathogens such as Mycobacterium avium complex, Pneumocystis carinii, Toxoplasma gondii or Candida albicans by peripheral blood monocytes, tissue macrophages and monocyte-derived macrophages following in vivo and in vitro HIV-1 infection has been documented [29]. Late-stage development of opportunistic infections has therefore been attributed to defective monocyte/macrophage signalling and function in HIV-infected individuals [30]. mTOR activation inhibits the destruction of pathogenic microorganisms by macrophages by inhibiting autophagy; rapamycin restores this macrophage inhibition.…”

Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion

“…In particular, IFN-g, TNF-a, IL-1a, and IL-1b increase autophagosome formation in macrophages (3,4,15), whereas IL-4, IL-13, and IL-10 inhibit autophagy (5)(6)(7)(8).…”

Porcine Circovirus Type 2 Induces Autophagy via the AMPK/ERK/TSC2/mTOR Signaling Pathway in PK-15 Cells

“…HCV induces autophagy through the Rab5 and class III PI3K Vps34 pathway (55). Human immunodeficiency virus inhibits autophagy through the Src-Akt and STAT3 pathway (59). We have found that PCV2 induces autophagy in PK-15 cells (68).…”