RESUMEN
PURPOSE OF REVIEW: The purpose of this article is to review age-associated alterations in microbiota composition, diversity and functional features in context of immune senescence, chronic inflammation and comorbidities associated with HIV infection. The overall goal is to assess whether modulating the microbiome will likely improve resilience of the immune system and augment return to health. RECENT FINDINGS: Alteration in the gut microbiota composition diversity and function occur in HIV and aging. Importantly, butyrate producing bacteria are reduced in both HIV and aging individuals. There is increasing relevance of studying metabolomics in the context of HIV-associated non-AIDS comorbidities and aging. Interventional prospects of probiotics, prebiotics and fecal microbiota transplantation in HIV and aging will provide novel therapeutic approaches. SUMMARY: Increasing evidence suggests a significant link in changes in the composition, diversity and functional aspects of intestinal microbiome with normal aging and HIV infection. Data on association of metabolites produced by the microbiome with HIV-associated non-AIDS comorbidities is mounting. The impact of the microbiome alterations on inflammation, immune and organ senescence and mechanisms by which bio-behavioral pathways will exacerbate these outcomes needs to be further evaluated.
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Envejecimiento/patología , Microbioma Gastrointestinal/inmunología , Infecciones por VIH/patología , Microbiota/inmunología , Terapia Biológica/métodos , Disbiosis/patología , Infecciones por VIH/complicaciones , HumanosRESUMEN
BACKGROUND: HIV/hepatitis C-coinfected persons experience more rapid liver disease progression than hepatitis C virus (HCV) monoinfected persons, even in the setting of potent antiretroviral therapy. METHODS: We sought to articulate the role of macrophage activation and inflammation in liver disease progression by measuring serial soluble markers in HIV/HCV-coinfected women. We compared markers measured during retrospectively defined periods of rapid liver disease progression to periods where little or no liver disease progression occurred. Liver disease progression was defined by liver biopsy, liver-related death or the serum markers AST-to-platelet ratio index and FIB-4. Soluble CD14, sCD163, lipopolysaccharide (LPS), tumor necrosis factor (TNF) receptor II, interleukin-6, and chemokine ligand 2 (CCL 2) were measured at 3 time points over 5 years. RESULTS: One hundred six time intervals were included in the analysis: including 31 from liver disease progressors and 75 from nonprogressors. LPS, sCD14, interleukin-6, and CCL2 levels did not differ in slope or quantity over time between rapid liver disease progressors and nonprogressors. TNFRII and sCD163 were significantly higher in liver disease progressors at (P = 0.002 and <0.0001 respectively) and preceding (P = 0.01 and 0.003 respectively) the liver fibrosis outcome in unadjusted models, with similar values when adjusted for HIV RNA and CD4 count. CONCLUSIONS: In women with HIV/HCV coinfection, higher sCD163 levels, a marker of macrophage activation, and TNFRII levels, implying activation of the TNF-α system, were associated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation, and liver disease progression in HIV/HCV coinfection.
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Coinfección/inmunología , Progresión de la Enfermedad , Infecciones por VIH/inmunología , Hepatitis C/inmunología , Activación de Macrófagos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Biomarcadores/sangre , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Hepatitis C/sangre , Hepatitis C/epidemiología , Hepatitis C/patología , Humanos , Interleucina-6/sangre , Hígado/patología , Hígado/virología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Estudios Longitudinales , Persona de Mediana Edad , Factores de Riesgo , Factor de Necrosis Tumoral alfa/sangre , Estados UnidosRESUMEN
HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear.In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI).We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (Pâ<â0.001, coefficient r = -0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV- except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV- groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA- (P = 0.005).HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals.
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Coinfección/complicaciones , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Cirrosis Hepática/virología , Viremia/complicaciones , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/metabolismo , Caspasa 3/metabolismo , Coinfección/inmunología , Estudios Transversales , Femenino , VIH/inmunología , Infecciones por VIH/inmunología , Hepacivirus/inmunología , Hepatitis C/inmunología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/inmunología , Humanos , Interleucina-2/metabolismo , Cirrosis Hepática/inmunología , Persona de Mediana Edad , Viremia/inmunologíaRESUMEN
GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16- natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T-cell immune activation in individuals with HIV infection.
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Linfocitos B/inmunología , Infecciones por Flaviviridae/diagnóstico , Virus GB-C/inmunología , Infecciones por VIH/complicaciones , Hepatitis Viral Humana/diagnóstico , Células Asesinas Naturales/inmunología , Monocitos/inmunología , Antígeno CD56/análisis , Infecciones por Flaviviridae/patología , Infecciones por Flaviviridae/virología , Proteínas Ligadas a GPI/análisis , Hepatitis Viral Humana/patología , Hepatitis Viral Humana/virología , Humanos , Tolerancia Inmunológica , Receptores de IgG/análisisRESUMEN
BACKGROUND: Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS: We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor α (TNF-α) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. RESULTS: While LPS levels did not differ significantly over time between progressors and nonprogressors (P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured (P = .03) and throughout the study period (P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period (P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4(+) T-cell count. CONCLUSIONS: Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis.
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Traslocación Bacteriana , Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Cirrosis Hepática/epidemiología , Cirrosis Hepática/patología , Adulto , Citocinas/sangre , Progresión de la Enfermedad , Femenino , Humanos , Lipopolisacáridos/sangre , Estudios Longitudinales , Persona de Mediana Edad , Plasma/químicaRESUMEN
GBV-C infection is associated with prolonged survival and with reduced T cell activation in HIV-infected subjects not receiving combination antiretroviral therapy (cART). The relationship between GBV-C and T cell activation in HIV-infected subjects was examined. HIV-infected subjects on cART with non-detectable HIV viral load (VL) or cART naïve subjects were studied. GBV-C VL and HIV VL were determined. Cell surface markers of activation (CD38(+)/HLA-DR(+)), proliferation (Ki-67+), and HIV entry co-receptor expression (CCR5+ and CXCR4+) on total CD4+ and CD8+ T cells, and on naïve, central memory (CM), effector memory (EM), and effector CD4+ and CD8+ subpopulations were measured by flow cytometry. In subjects with suppressed HIV VL, GBV-C was consistently associated with reduced activation in naïve, CM, EM, and effector CD4+ cells. GBV-C was associated with reduced CD4+ and CD8+ T cell surface expression of activation and proliferation markers, independent of HIV VL classification. GBV-C was also associated with higher proportions of naïve CD4+ and CD8+ T cells, and with lower proportions of EM CD4+ and CD8+ T cells. In conclusion, GBV-C infection was associated with reduced activation of CD4+ and CD8+ T cells in both HIV viremic and HIV RNA suppressed patients. Those with GBV-C infection demonstrated an increased proportion of naive T cells and a reduction in T cell activation and proliferation independent of HIV VL classification, including those with suppressed HIV VL on cART. Since HIV pathogenesis is thought to be accelerated by T cell activation, these results may contribute to prolonged survival among HIV infected individuals co-infected with GBV-C. Furthermore, since cART therapy does not reduce T cell activation to levels seen in HIV-uninfected people, GBV-C infection may be beneficial for HIV-related diseases in those effectively treated with anti-HIV therapy.
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Infecciones por Flaviviridae/inmunología , Virus GB-C/patogenicidad , Infecciones por VIH/inmunología , Hepatitis Viral Humana/inmunología , Activación de Linfocitos/fisiología , Subgrupos Linfocitarios/inmunología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Femenino , Citometría de Flujo , Virus GB-C/inmunología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Plasmacytoid dendritic cells (pDC) contribute to antiviral immunity mainly through recognition of microbial products and viruses via intracellular Toll-like receptor 7 (TLR7) or TLR9, resulting in the production of type I interferons (IFNs). Although interferons reduce the viral burden in the acute phase of infection, their role in the chronic phase is unclear. The presence of elevated plasma IFN-alpha levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN-alpha could contribute to immune activation. Blocking of IFN-alpha production using chloroquine, an endosomal inhibitor, was tested in a novel in vitro model system with the aim of characterizing the effects of chloroquine on HIV-1-mediated TLR signaling, IFN-alpha production, and T-cell activation. Our results indicate that chloroquine blocks TLR-mediated activation of pDC and MyD88 signaling, as shown by decreases in the levels of the downstream signaling molecules IRAK-4 and IRF-7 and by inhibition of IFN-alpha synthesis. Chloroquine decreased CD8 T-cell activation induced by aldrithiol-2-treated HIV-1 in peripheral blood mononuclear cell cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of the T-cell response, such as indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PDL-1). Our results indicate that TLR stimulation and production of IFN-alpha by pDC contribute to immune activation and that blocking of these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe, well-tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with highly active antiretroviral therapy to control immune activation in HIV-1 infection.