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People with HIV (PWH) and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. The pathophysiology of mycobacterial-IRIS overlaps with primary hemophagocytic lymphohistiocytosis (pHLH). To assess possible genetic predisposition to IRIS, protein-altering variants in genes associated with HLH were evaluated in 82 PWH and mycobacterial infections who developed IRIS (n = 56) or did not develop IRIS (n = 26). Protein-altering variants in cytotoxicity genes were found in 23.2% of IRIS patients compared to only 3.8% of those without IRIS. These findings suggest a possible genetic component in the risk of mycobacterial IRIS in PWH. Clinical Trials Registration. NCT00286767, NCT02147405.
Asunto(s)
Infecciones por VIH , Síndrome Inflamatorio de Reconstitución Inmune , Linfohistiocitosis Hemofagocítica , Tuberculosis , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/complicaciones , Tuberculosis/complicaciones , Tuberculosis/genética , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. METHODS: HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points. RESULTS: HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. CONCLUSIONS: Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.
Asunto(s)
Infecciones por VIH , Síndrome Inflamatorio de Reconstitución Inmune , Linfohistiocitosis Hemofagocítica , Humanos , VIH , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , BiomarcadoresRESUMEN
BACKGROUND: Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T cells involved in antimicrobial responses as well as inflammatory, allergic, and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells. METHODS: We investigated the MAIT cells in patients with idiopathic CD4+ lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections. RESULTS: The numbers, phenotype, and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Administration of interleukin-7 (IL-7) to ICL patients expanded the CD8+ MAIT-cell subset, with maintained responsiveness and effector functions after IL-7 treatment. CONCLUSIONS: ICL patients maintain normal levels and function of MAIT cells, preserving some antibacterial responses despite the deficiency in CD4+ T cells. CLINICAL TRIALS REGISTRATION: NCT00867269.
Asunto(s)
Interleucina-7/uso terapéutico , Linfopenia , Células T Invariantes Asociadas a Mucosa , Infecciones por VIH , Humanos , Recuento de Linfocitos , Linfopenia/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Infección PersistenteRESUMEN
Unbiased plasma proteomics in a matched case-control study of treated people with human immunodeficiency virus (PWH) revealed the complement cascade as being among the top pathways enriched in PWH. Specific complement components, namely C5, associated significantly with non-AIDS comorbidity prevalence, and did so more strongly than previously established predictive biomarkers.
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Complemento C5/análisis , Infecciones por VIH/epidemiología , Envejecimiento , Biomarcadores/sangre , Estudios de Casos y Controles , Comorbilidad , VIH , Seronegatividad para VIH , Humanos , Factores InmunológicosRESUMEN
OBJECTIVE: Characterize autoantibodies and autoimmune diseases in a prospective cohort of patients with Idiopathic CD4 Lymphocytopenia (ICL) a rare immunodeficiency characterized by an absolute CD4+ T count of <300 cells/µl in the absence of HIV or HTLV infection. METHODS: Single-Center prospective study of 67 patients conducted over an 11-year period. Rheumatologic evaluation and measurement of autoantibodies were systematically conducted, and flow cytometry of immune cell subsets was performed in a subset of patients. RESULTS: 54% of referred patients had clinical evidence of autoimmunity, with 34% having at least one autoimmune disease, most commonly autoimmune thyroid disease. 19%, had autoantibodies or incomplete features of autoimmune disease. Patients with autoimmune disease had more elevated serum immunoglobulins, and more effector memory T cells than those without autoimmunity. CONCLUSIONS: Evidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.
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Autoanticuerpos/análisis , Enfermedades Autoinmunes/inmunología , Inmunofenotipificación/métodos , Linfocitopenia-T Idiopática CD4-Positiva/inmunología , Adulto , Anciano , Enfermedades Autoinmunes/complicaciones , Estudios de Cohortes , Enfermedades Transmisibles/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Linfocitopenia-T Idiopática CD4-Positiva/complicaciones , Adulto JovenRESUMEN
Gastrointestinal (GI) immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. In simian immunodeficiency virus (SIV)-infected Asian macaque models of human immunodeficiency virus (HIV) infection, we previously noted that initiation of antiretroviral therapy (ART) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. To determine if ART itself might contribute to dysbiosis or immune dysfunction, we treated healthy rhesus macaques with protease, integrase, or reverse transcriptase inhibitors for 1 to 2 or for 5 to 6 weeks and evaluated intestinal immune function and the composition of the fecal bacterial microbiome. We observed that individual antiretrovirals (ARVs) modestly altered intestinal T-cell proinflammatory responses without disturbing total or activated T-cell frequencies. Moreover, we observed transient disruptions in bacterial diversity coupled with perturbations in the relative frequencies of bacterial communities. Shifts in specific bacterial frequencies were not persistent posttreatment, however, with individual taxa showing only isolated associations with T-cell proinflammatory responses. Our findings suggest that intestinal bacterial instability and modest immunological alterations can result from ART itself. These data could lead to therapeutic interventions which stabilize the microbiome in individuals prescribed ART.IMPORTANCE Dysbiosis of the fecal microbiome is a common feature observed in ARV-treated people living with HIV. The degree to which HIV infection itself causes this dysbiosis remains unclear. Here, we demonstrate that medications used to treat HIV infection can influence the composition of the GI tract immune responses and its microbiome in the nonhuman primate SIV model.
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Disbiosis/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/inmunología , Animales , Antirretrovirales/efectos adversos , Antirretrovirales/farmacología , Modelos Animales de Enfermedad , Disbiosis/virología , Femenino , Intestinos/inmunología , Intestinos/microbiología , Activación de Linfocitos/efectos de los fármacos , Macaca mulatta/metabolismo , Masculino , Microbiota/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/inmunologíaRESUMEN
Lactoferrin modulates mucosal immunity and targets mechanisms contributing to inflammation during human immunodeficiency virus disease. A randomized placebo-controlled crossover clinical trial of recombinant human (rh) lactoferrin was conducted among 54 human immunodeficiency virus-infected participants with viral suppression. Outcomes were tolerability, inflammatory, and immunologic measures, and the intestinal microbiome. The median age was 51 years, and the median CD4+ cell count was 651/µL. Adherence and adverse events did not differ between rh-lactoferrin and placebo. There was no significant effect on plasma interleukin-6 or D-dimer levels, nor on monocyte/T-cell activation, mucosal integrity, or intestinal microbiota diversity. Oral administration of rh-lactoferrin was safe but did not reduce inflammation and immune activation. Clinical Trials Registration: NCT01830595.
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Microbioma Gastrointestinal/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Inmunidad Mucosa/efectos de los fármacos , Lactoferrina/uso terapéutico , Activación de Linfocitos/efectos de los fármacos , Proteínas Recombinantes de Fusión/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Femenino , VIH/efectos de los fármacos , VIH/inmunología , Infecciones por VIH/virología , Humanos , Inmunidad Mucosa/inmunología , Inflamación/tratamiento farmacológico , Inflamación/virología , Interleucina-6/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Microbial translocation occurs after damage to the structural and/or immunological barrier of the gastrointestinal (GI) tract into circulation. Microbial components that trans-locate from the lumen of the GI tract directly stimulate the immune system and contribute to inflammation. When microbial translocation becomes chronic, the inflammation has detrimental consequences. Given that microbial translocation is an important phenomenon in many diseases, defining biomarkers that reliably reflect microbial translocation is critical. Measurement of systemic microbial products is difficult since: 1) robust assays to measure microbial antigens simultaneously are lacking; 2) confounding factors influence assays used to detect microbial products; and 3) biological clearance mechanisms limit their detection in circulation. Thus, host proteins produced in response to microbial stimulation are used as surrogates for microbial translocation; however, many of these proteins are also produced in response to host proteins expressed by dying cells. METHODS: We measured plasma levels of biomarkers associated with GI tract damage, immune responses to microbial products, and cell-death in people living with HIV before and after antiretroviral administration, and in macaque nonhuman primates before and after SIV infection. RESULTS: Proteins secreted during cellular stress (receptor for advanced glycation endproducts-RAGE and high motility group box 1-HMGB1), which can induce sCD14 production in vitro and in vivo, do not associate with elevated levels of biomarkers associated with microbial translocation in progressively HIV-infected individuals and SIV-infected NHPs. CONCLUSIONS: Bystander cell death and generalized inflammation do not contribute to elevated levels of sCD14 observed in HIV/SIV-infected individuals.
RESUMEN
Background: Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Methods: Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1-5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Results: Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Conclusions: Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.
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[This corrects the article DOI: 10.1093/ofid/ofz367.].
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: Chronic HIV-1 infection is associated with lower frequencies and functional impairment of mucosa-associated invariant T (MAIT) cells. We evaluated IL-7 treatment to restore MAIT cells in peripheral blood of chronically HIV-1-infected individuals on antiretroviral therapy. IL-7 led to increased relative and absolute levels of MAIT cells, and this expansion occurred primarily in the CD8 subset. These results suggest that IL-7 may represent a therapeutic intervention for the restoration of MAIT cells in chronic HIV-1 infection.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Factores Inmunológicos/administración & dosificación , Interleucina-7/administración & dosificación , Células T Invariantes Asociadas a Mucosa/inmunología , Membrana Mucosa/inmunología , Adulto , Antirretrovirales/administración & dosificación , Sangre/inmunología , Humanos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression.