Alcohol and HIV decrease proteasome and immunoproteasome function in macrophages: implications for impaired immune function during disease

Abstract

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-c stimulation but reduced after HIV-1 infection. EtOH inhibited both IFN-c-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.

Descriptive systematic review of sub-Saharan African studies on the association between alcohol use and HIV infection

“…In particular, proteasomes and immunoproteasomes, critical immune processes attenuated during progressive HIV-1 infection, are affected by alcohol abuse. Studies with human monocyte-derived macrophages support the notion that HIV-1 infection and alcohol may act synergistically to affect antigen presentation and in so doing, affect disease progression (Hao rah et al, 2004). Further evidence of the role of alcohol consumption as a cofactor in the immunopathogenesis of HIV disease comes from another in vitro study which found that alcohol inhibited natural killer (NK) cell-mediated innate immunity against HIV (Zhang et al, 2005).…”

“…Furthermore, evidence from clinical and laboratory studies has indicated that alcohol abuse may accelerate HIV disease progression (Bagby, Zhang, Purcell, Didier & Nelson, 2006;Hao rah et al, 2004;Miguez, Shor-Posner, Morales, Rodriguez & Burbano, 2003;Samet et al, 2007). In particular, proteasomes and immunoproteasomes, critical immune processes attenuated during progressive HIV-1 infection, are affected by alcohol abuse.…”

Alcohol Abuse Enhances Neuroinflammation and Impairs Immune Responses in an Animal Model of Human Immunodeficiency Virus-1 Encephalitis

“…60 Re-active oxygen species generation was linked to ethanol metabolism in neural cells 61 and macrophages resulting in IPR dysfunction. 22 Indeed, brain tissue of ethanol-fed mice featured higher levels of nitrotyrosine indicating enhanced oxidative damage. Activation of brain macrophages is a process involving environmental cues (like systemic or brain infections) and cell signals from injured neurons or other neural cells.…”

“…21 Both HIV-1 and ethanol inhibited IPR expression and activity in human MDMs in vitro. 22 In vivo studies showed decreased PR activity after administration of high doses of ethanol, 55 and a reduced amount of CD8 ϩ T cells and impaired immune responses were seen in LMP2-and LMP7-deficient mice. 56,57 Similarly in the present in vivo study, ethanol-fed hu-PBL-NOD/SCID mice with HIVE showed decreased LMP2 and LMP7 levels in the spleen, suggesting IPR dysfunction.…”

“…We demonstrated that both HIV-1 and ethanol diminish PR activity and IPR content in MDMs, and therefore, may contribute to dysfunction in the HIVinfected host. 22 To further study the effects of ethanol on IPR content in vivo, we preformed Western blot analysis of IPR subunits, LMP2, and LMP7 on protein extracts derived from spleen. The IPR expression (LMP2 and LMP7) was adjusted to human CD45 (reflecting number of human cells) in the samples and expressed as the ratio of target protein immunoreactivity to that of internal standard ␣-actin.…”