RESUMO
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-1ß, 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-1ß, 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.
Assuntos
Retículo Endoplasmático/metabolismo , Enterite/genética , Células Epiteliais/metabolismo , Enteropatia por HIV/genética , Animais , Complexo CD3/genética , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Gatos , Linhagem Celular Tumoral , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/virologia , Retículo Endoplasmático/imunologia , Enterite/imunologia , Enterite/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Expressão Gênica , Enteropatia por HIV/imunologia , Enteropatia por HIV/virologia , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/fisiologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Cadeias alfa de HLA-DR , Interações Hospedeiro-Patógeno , Humanos , Vírus da Imunodeficiência Felina/imunologia , Vírus da Imunodeficiência Felina/fisiologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Infecções por Lentivirus/genética , Infecções por Lentivirus/imunologia , Infecções por Lentivirus/virologia , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral/imunologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/imunologiaRESUMO
The objective of this study was to determine the initial and subsequent phenotypes of HIV-1 isolated from the blood, duodenal, and colonic biopsies of 51 HIV-1 positive patients followed prospectively over 2 years. Blood and tissues were cocultured with stimulated peripheral blood monocytes, and HIV was analyzed for phenotypic expression of syncytia-induction (SI). A total of 45/51 patients had HIV-1 isolated from the blood and 35/51 had HIV isolated from gastrointestinal tract. In 12/45 patients SI-HIV-1 was isolated from the blood. In 6/12 patients the blood phenotype reverted to the NSI phenotype. SI phenotypes were also isolated from the colon and duodenum of 8/35 patients and reversion from SI to NSI virus phenotype was again observed in gut tissue of 3/8 patients. These results show that gastrointestinal tissues can harbor SI HIV phenotype. Discordant phenotypes can be found in tissue and blood of late-stage patients. Reversion of phenotypic SI expression to NSI may occur in patients receiving monotherapy as antiretroviral treatment. These results suggest that gastrointestinal tissues may act as a separate and distinct site involved in HIV replication and its associated pathogenesis.
