Dataset Information

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

ABSTRACT:

Background

Human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce.

Methods

We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals.

Results

INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid-binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17-producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs.

Conclusions

Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

SUBMITTER: Meyer-Myklestad MH

PROVIDER: S-EPMC8844596 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

Meyer-Myklestad Malin Holm MH Medhus Asle Wilhelm AW Lorvik Kristina Berg KB Seljeflot Ingebjørg I Hansen Simen Hyll SH Holm Kristian K Stiksrud Birgitte B Trøseid Marius M Hov Johannes Roksund JR Kvale Dag D Dyrhol-Riise Anne Margarita AM Kummen Martin M Reikvam Dag Henrik DH

The Journal of infectious diseases 20220201 4

<h4>Background</h4>Human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce.<h4>Methods</h4>We investigated circulating ...[more]

PMID: 33216130

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Project description:BackgroundImmunological nonresponders (INRs) living with HIV are at increased risk of co-infection and multiple tumors, with no effective strategy currently available to restore their T-cell immune response. This study aimed to explore the safety and efficacy of thymosin α1 in reconstituting the immune response in INRs.MethodsINRs with CD4 + T cell counts between 100 and 350 cells/μL were enrolled and received two-staged 1.6 mg thymosin α1 subcutaneous injections for 24 weeks (daily in the first 2 weeks and biweekly in the subsequent 22 weeks) while continuing antiretroviral therapy. T cell counts and subsets, the expression of PD-1 and TIM-3 on T cells, and signal joint T cell receptor excision circles (sjTREC) at week 24 were evaluated as endpoints.ResultsTwenty three INRs were screened for eligibility, and 20 received treatment. The majority were male (19/20), with a median age of 48.1 years (interquartile range: 40.5-57.0) and had received antiretroviral therapy for 5.0 (3.0, 7.3) years. Multiple comparisons indicated that CD4 + T cell count and sjTREC increased after initiation of treatment, although no significant differences were observed at week 24 compared to baseline. Greatly, levels of CD4 + T cell proportion (17.2% vs. 29.1%, P < 0.001), naïve CD4 + and CD8 + T cell proportion (17.2% vs. 41.1%, P < 0.001; 13.8% vs. 26.6%, P = 0.008) significantly increased. Meanwhile, the proportion of CD4 + central memory T cells of HIV latent hosts (42.7% vs. 10.3%, P < 0.001) significantly decreased. Moreover, the expression of PD-1 on CD4 + T cells (14.1% vs. 6.5%, P < 0.001) and CD8 + T cells (8.5% vs. 4.1%, P < 0.001) decreased, but the expression of TIM-3 on T cellsremained unaltered at week 24. No severe adverse events were reported and HIV viral loads kept stable throughout the study.ConclusionsThymosin α1 enhance CD4 + T cell count and thymic output albeit as a trend rather than an endpoint. Importantly, it improves immunosenescence and decreases immune exhaustion, warranting further investigation.Trial registrationThis single-arm prospective study was registered with ClinicalTrials.gov (NCT04963712) on July 15, 2021.

Project description:ObjectiveAnkylosing spondylitis (AS) patients often present with microscopic signs of gut inflammation. We used proteomic techniques to identify the differentially expressed proteins (DEPs) in the colon tissues of patients with AS and patients with gut inflammation, and then used investigated the influence of NMRAL1 protein on inflammatory cytokines to explore its potential role in the pathogenesis of AS and gut inflammation.MethodsColonic mucosal tissues were collected from four different groups: healthy individuals (group A), patients with gut inflammation only (group B), patients with AS only (group C), and patients with AS combined with gut inflammation (group D). A total of 20 samples were processed for proteomic analysis, wherein proteins were extracted using SDT lysis, followed by separation via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The proteins were digested using the filter-aided sample preparation (FASP) method and then analyzed using a timsTOF Pro mass spectrometer. The resulting peptide data were used to identify differentially expressed proteins (DEPs) across the different groups. To further explore the inflammation-related function of NMRAL1 protein, the murine monocyte/macrophage cell line RAW264.7 was used. NMRAL1 mRNA expression levels were assessed via RT-qPCR, and inflammatory cytokine levels (TNF-α, IL-1β, IL-17 and IL-23) were measured using ELISA following NMRAL1 siRNA transfection in LPS-treated macrophages.ResultsWe collected colonic mucosa specimens from 20 patients, including groups A,B, C and D with 5 patients in each group. We established a database of DEPs and identified 107 (63 upregulated and 44 downregulated) between group B and group A, 78 (16 upregulated and 62 downregulated) between group D and group C, 45 (8 upregulated and 37 downregulated) between group D and group B, and 57 (33 upregulated and 24 downregulated) between group C and group A. Further analysis revealed that the NmrA-like family domain containing 1 (NMRAL1) protein was identified as a DEP specifically associated with group D. The results of in vitro results showed a significant decrease in NMRAL1 mRNA expression in LPS-treated cells (P<0.001), which was further reduced in NMRAL1 siRNA-transfected cells (P<0.0001), confirming successful transfection. ELISA results revealed that the levels of key inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-23) were significantly elevated in the LPS-treated model group (P<0.0001, P<0.001), but these levels were significantly decreased after NMRAL1 siRNA transfection (P<0.0001, P<0.01, P<0.05).ConclusionNMRAL1 is identified as a key differentially expressed protein in AS patients with gut inflammation. Knockdown of NMRAL1 significantly reduced the levels of inflammatory cytokines, suggesting its potential role in the pathogenesis of AS and gut inflammation, and as a possible therapeutic target.

Dataset Information

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

Background

Methods

Results

Conclusions

Publications

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

Similar Datasets

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