Alcohol and HIV decrease proteasome and immunoproteasome function in macrophages: implications for impaired immune function during disease.
Proteasomes (proteinase complexes, PR) and immunoproteasomes (IPR) degrade damaged proteins and affect protein processing required for antigen presentation by mononuclear phagocytes. These critical immune processes are attenuated during progressive HIV-1 infection and are affected by alcohol abuse. To investigate the mechanisms underlying these functional changes, we measured PR and CYP2E1 activities [an ethanol (EtOH) metabolizing enzyme] and reactive oxygen species (ROS) in human monocyte-derived macrophages (MDM) following HIV-1 infection and EtOH treatment. We observed progressive declines of PR activity and PR/IPR contents in HIV-1-infected MDM. PR activity and IPR expression increased after IFN-gamma stimulation but reduced after HIV-1 infection. EtOH inhibited both IFN-gamma-induced PR and IPR. Paradoxically, EtOH attenuated PR catalytic activity in infected MDM and suppressed viral replication. Elevated ROS followed EtOH exposure and paralleled decreased PR activity. The latter was restored by anti-oxidant. The data support the notion that HIV-1 infection and EtOH may work in concert to affect immune function including antigen presentation and thereby affect disease progression.
Liver Study Unit, The Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
James
J
Haorah
David
D
Heilman
Casey
C
Diekmann
Natalia
N
Osna
Terrence M
TM
Donohue
Anuja
A
Ghorpade
Yuri
Y
Persidsky
D000437:Alcoholism / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000276:immunology; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology / Q000378:metabolism; D005470:Fluorometry; D015658:HIV Infections / Q000201:enzymology / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology
D017382:Reactive Oxygen Species; C071313:LMP-2 protein; D007371:Interferon-gamma; D019392:Cytochrome P-450 CYP2E1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex