RESUMEN
Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44+ cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4ß7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis.
Asunto(s)
Colon Sigmoide/inmunología , Infecciones por VIH/inmunología , VIH/fisiología , Inmunidad Mucosa , Interleucinas/inmunología , Mucosa Intestinal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Linaje de la Célula , Colon Sigmoide/patología , Colon Sigmoide/virología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Interleucinas/deficiencia , Interleucinas/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/virología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Células Asesinas Naturales/virología , Recuento de Linfocitos , Depleción Linfocítica , Receptores CCR5/inmunología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Colaboradores-Inductores/virología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Interleucina-22RESUMEN
Early and profound CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) may drive Human Immunodeficiency Virus (HIV) immunopathogenesis, and GALT immune reconstitution on highly active antiretroviral therapy (HAART) may be suboptimal. Blood and sigmoid colon biopsies were collected from HAART-treated individuals with undetectable blood HIV RNA for > or =4 years and from uninfected controls. HIV proviral levels and T-cell phenotype/function were examined in both compartments. CD4+ T-cell reconstitution in the sigmoid, including CD4+ T cells expressing CCR5, exceeded that in blood and did not differ from uninfected controls. Sigmoid HIV proviral load was not correlated with CD4+ reconsitution, but was correlated with the degree of mucosal CD8+ T-cell immune activation. Colonic Gag-specific T-cell responses were common, but were not associated with proviral load or immune activation. In this select study population, long-term HAART was associated with complete CD4+ T-cell reconstitution in sigmoid colon. However, colonic immune activation may drive ongoing HIV replication.