Inflammation and epithelial cell injury in AIDS enteropathy: involvement of endoplasmic reticulum stress

Abstract

Immunosuppressive lentivirus infections, including human, simian, and feline immunodeficiency viruses (HIV, SIV, and FIV, respectively), cause the acquired immunodeficiency syndrome (AIDS), frequently associated with AIDS enteropathy. Herein, we investigated the extent to which lentivirus infections affected mucosal integrity and intestinal permeability in conjunction with immune responses and activation of endoplasmic reticulum (ER) stress pathways. Duodenal biopsies from individuals with HIV/AIDS exhibited induction of IL-1β, CD3ε, HLA-DRA, spliced XBP-1(Xbp-1s), and CHOP expression compared to uninfected persons (P<0.05). Gut epithelial cells exposed to HIV-1 Vpr demonstrated elevated TNF-α, IL-1β, spliced Xbp-1s, and CHOP expression (P<0.05) together with calcium activation and disruption of epithelial cell monolayer permeability. In addition to reduced blood CD4(+) T lymphocyte levels, viral loads in the gut and plasma were high in FIV-infected animals (P<0.05). FIV-infected animals also exhibited a failure to gain weight and increased lactulose/mannitol ratios compared with uninfected animals (P<0.05). Proinflammatory and ER stress gene expression were activated in the ileum of FIV-infected animals (P<0.05), accompanied by intestinal epithelial damage with loss of epithelial cells and leukocyte infiltration of the lamina propria. Lentivirus infections cause gut inflammation and ensuing damage to intestinal epithelial cells, likely through induction of ER stress pathways, resulting in disruption of gut functional integrity.

Bacterial and Parasitic Agents of Infectious Diarrhoea in the Era of HIV and AIDS - The Case of a Semi Rural Community in South Africa

“…E. bieneusi was not associated with intestinal inflammation in our study, as demonstrated by the lactoferrin test in HIV negative and HIV positive individuals even though most HIV positive individuals without microsporidia had elevated lactoferrin, indicating high level of intestinal inflammation. This could be due to t h e e f f e c t o f H I V i t s e l f a s p r e v i o u s l y demonstrated (Kotler et al, 1993;Maingat et al, 2011). This is in line with some studies where multiple small intestinal biopsies showed atrophy with acute and chronic inflammation in HIV seropositive individuals even without apparent pathogens (Orenstein et al, 1992;Snijders et al, 1995;Idris et al 2010).…”

Intestinal Epithelial Barrier Disruption through Altered Mucosal MicroRNA Expression in Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections

“…These studies found that miRNA depletion was likely due to the inflam- matory environment and not direct infection of T cells (55). Chronic inflammation and increased immune activation in the GI tract during HIV/SIV infection has previously been reported, and it is possible that this is a contributing factor in decreased miRNA expression (18,58). In the present study, we sought to correlate viral loads, CD4 ϩ T cell depletion, and immune activation with loss of specific miRNA expression.…”

Lack of Interleukin-10-Mediated Anti-Inflammatory Signals and Upregulated Interferon Gamma Production Are Linked to Increased Intestinal Epithelial Cell Apoptosis in Pathogenic Simian Immunodeficiency Virus Infection

“…Several different potential mechanisms of intestinal EC apoptosis in SIV/HIV infection have been proposed, including virusinduced apoptosis mediated by the interaction of SIV and GPR15/ Bob, an epithelial associated coreceptor for HIV-1/SIV (39), increased infiltration of perforin-positive mucosal cytotoxic T cells (6), upregulation of inflammatory cytokines by direct interaction of ECs with HIV-1 envelope protein (58), and viral proteinand cytokine-induced endoplasmic reticulum stress (12). In conclusion, this investigation clearly indicated that internalization of IL-10R was a key feature in SIV pathogenesis where the interaction between surface IL-10R and IL-10 might be important in regulating the proinflammatory and Th1 function in SIV-infected InRMs.…”

“…Increased permeability due to compromised barrier function could facilitate gut microbiota crossing the mucosal epithelium and entering circulation (microbial translocation) (10). Epithelial injury and impaired epithelial regeneration are considered key factors in the pathogenesis of AIDS contributing to generalized HIV-induced immune cell activation (9,11,12).…”