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Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients.

ABSTRACT: Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15-20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a "Quasi-paired cohort" method to analyze intestinal metagenome data from immunological responders (IRs) and immunological non-responders (INRs). This method identified significant enrichment for Streptococcus sp. and related lactate-producing bacteria (LAB) in IRs. In a validation cohort, positive correlations between the abundance of these LAB and the post-ART CD4 + recovery was observed, and a prediction model based on these LAB performed well in predicting immune recovery. Finally, experiments using a germ-free mouse model of antibody-induced CD4 + cell depletion showed that supplementation with a lactate-producing commensal Streptococcus thermophilus strongly promoted CD4 recovery. In conclusion, our study identified a group of LAB that was associated with enhanced immune recovery in post-ART HIV-infected patients and promotes CD4 + cell restoration in a mouse model. These findings favour supplementation of LAB commensal as a therapeutic strategy for CD4 + cell count improvement in HIV-infected patients.

SUBMITTER: Lyu W

PROVIDER: S-EPMC8191414 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients.

Lyu Wei W Meng Qingren Q Xiao Jingfa J Li Jing J Wang Jian J Qiu Zhifeng Z Song Xiaojing X Zhu Hua H Shao Changjun C Chu Yanan Y Zhou Qian Q Li Taisheng T Jean-Pierre Routy R Yu Jun J Han Yang Y Kang Yu Y

Computational and structural biotechnology journal 20210511

Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15-20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a "Quasi-paired cohort" method to analyze intestinal metagenome data from immunological ...[more]

PMID: 34141131

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Project description:BackgroundHuman immunodeficiency virus type 1 (HIV-1) infection is characterized by persistent systemic inflammation and immune activation, even in patients receiving effective antiretroviral therapy (ART). Converging data from many cross-sectional studies suggest that gut microbiota (GM) changes can occur throughout including human immunodeficiency virus (HIV) infection, treated by ART; however, the results are contrasting. For the first time, we compared the fecal microbial composition, serum and fecal microbial metabolites, and serum cytokine profile of treatment-naïve patients before starting ART and after reaching virological suppression, after 24 wk of ART therapy. In addition, we compared the microbiota composition, microbial metabolites, and cytokine profile of patients with CD4/CD8 ratio < 1 (immunological non-responders [INRs]) and CD4/CD8 > 1 (immunological responders [IRs]), after 24 wk of ART therapy.AimTo compare for the first time the fecal microbial composition, serum and fecal microbial metabolites, and serum cytokine profile of treatment-naïve patients before starting ART and after reaching virological suppression (HIV RNA < 50 copies/mL) after 24 wk of ART.MethodsWe enrolled 12 treatment-naïve HIV-infected patients receiving ART (mainly based on integrase inhibitors). Fecal microbiota composition was assessed through next generation sequencing. In addition, a comprehensive analysis of a blood broad-spectrum cytokine panel was performed through a multiplex approach. At the same time, serum free fatty acid (FFA) and fecal short chain fatty acid levels were obtained through gas chromatography-mass spectrometry.ResultsWe first compared microbiota signatures, FFA levels, and cytokine profile before starting ART and after reaching virological suppression. Modest alterations were observed in microbiota composition, in particular in the viral suppression condition, we detected an increase of Ruminococcus and Succinivibrio and a decrease of Intestinibacter. Moreover, in the same condition, we also observed augmented levels of serum propionic and butyric acids. Contemporarily, a reduction of serum IP-10 and an increase of IL-8 levels were detected in the viral suppression condition. In addition, the same components were compared between IRs and INRs. Concerning the microflora population, we detected a reduction of Faecalibacterium and an increase of Alistipes in INRs. Simultaneously, fecal isobutyric, isovaleric, and 2-methylbutyric acids were also increased in INRs.ConclusionOur results provided an additional perspective about the impact of HIV infection, ART, and immune recovery on the "microbiome-immunity axis" at the metabolism level. These factors can act as indicators of the active processes occurring in the gastrointestinal tract. Individuals with HIV-1 infection, before ART and after reaching virological suppression with 24 wk of ART, displayed a microbiota with unchanged overall bacterial diversity; moreover, their systemic inflammatory status seems not to be completely restored. In addition, we confirmed the role of the GM metabolites in immune reconstitution.

Project description:BackgroundThere is conflicting evidence on the immunologic benefit of treating helminth co-infections ("deworming") in HIV-infected individuals. Several studies have documented reduced viral load and increased CD4 count in antiretroviral therapy (ART) naïve individuals after deworming. However, there are a lack of data on the effect of deworming therapy on CD4 count recovery among HIV-infected persons taking ART.Methodology/principal findingsTo estimate the association between empiric deworming therapy and CD4 count after ART initiation, we performed a retrospective observational study among HIV-infected adults on ART at a publicly operated HIV clinic in southwestern Uganda. Subjects were assigned as having received deworming if prescribed an anti-helminthic agent between 7 and 90 days before a CD4 test. To estimate the association between deworming and CD4 count, we fit multivariable regression models and analyzed predictors of CD4 count, using a time-by-interaction term with receipt or non-receipt of deworming. From 1998 to 2009, 5,379 subjects on ART attended 21,933 clinic visits at which a CD4 count was measured. Subjects received deworming prior to 668 (3%) visits. Overall, deworming was not associated with a significant difference in CD4 count in either the first year on ART (β = 42.8; 95% CI, -2.1 to 87.7) or after the first year of ART (β = -9.9; 95% CI, -24.1 to 4.4). However, in a sub-analysis by gender, during the first year of ART deworming was associated with a significantly greater rise in CD4 count (β = 63.0; 95% CI, 6.0 to 120.1) in females.Conclusions/significanceEmpiric deworming of HIV-infected individuals on ART conferred no significant generalized benefit on subsequent CD4 count recovery. A significant association was observed exclusively in females and during the initial year on ART. Our findings are consistent with recent studies that failed to demonstrate an immunologic advantage to empirically deworming ART-naïve individuals, but suggest that certain sub-populations may benefit.

Project description:BackgroundCD4+ cell count recovery after effective antiretroviral therapy (ART) is an important determinant of both AIDS and non-AIDS morbidity and mortality. Data on CD4+ cell count recovery after initiation of ART are still limited in Sub-Saharan Africa. The aim of this study was to assess CD4+ cell count recovery among HIV-infected adults initiating ART in an Ethiopian setting.MethodsA retrospective cohort study of HIV-infected adults initiating ART between September 2008 and June 2019 was carried out. CD4+ cell count recovery was defined as an increase in CD4+ cell count of >100 cells/mm3 from baseline or achievement of a CD4+ cell count >500 cells/mm3 at 12 months after ART initiation. Factors associated with CD4+ cell count recovery were evaluated using logistic regression analysis.ResultsOf the 566 patients included in this study, the median baseline CD4+ cell count was 264 cells/mm3 (IQR: 192-500). At 12 months after ART initiation, the median CD4+ cell count increased to 472 cells/mm3, and the proportion of patients with CD4+ cell count < 200 cells/mm3 declined from 28.3 to 15.0%. A total of 58.0% of patients had an increase in CD4+ cell count of >100 cells/mm3 from baseline and 48.6% achieved a CD4+ cell count >500 cells/mm3 at 12 months. Among patients with CD4+ cell counts < 200, 200-350 and >350 cells/mm3 at baseline, respectively, 30%, 43.9% and 61.7% achieved a CD4+ cell count >500 cells/mm3 at 12 months. In multivariable analysis, poor CD4+ cell count recovery (an increase of ≤100 cells/mm3 from baseline) was associated with older age, male sex, higher baseline CD4+ cell count and zidovudine-containing initial regimen. Factors associated with poor CD4+ cell count recovery to reach the level >500 cells/mm3 included older age, male sex and lower baseline CD4+ cell count.ConclusionsCD4+ cell count failed to recover in a substantial proportion of adults initiating ART in this resource-limited setting. Older age, male sex and baseline CD4+ cell count are the dominant factors for poor CD4+ cell count recovery. Novel therapeutic approaches are needed focusing on high risk patients to maximize CD4+ cell count recovery and improve outcomes during therapy.

Project description:Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 primarily targets mucosal compartments during acute infection in vivo. Moreover, early HIV-1 infection causes extensive depletion of CD4+ T cells in the gastrointestinal tract that herald persistent inflammation due to the translocation of enteric microbes to the systemic circulation. Here, we profiled the transcriptome of primary intestinal CD4+ T cells infected ex vivo with transmitted/founder (TF) HIV-1. Infections were performed in the presence or absence of Prevotella stercorea, a gut microbe enriched in the mucosa of HIV-1-infected individuals that enhanced both TF HIV-1 replication and CD4+ T cell death ex vivo. In the absence of bacteria, HIV-1 triggered a cellular shutdown response involving the downregulation of HIV-1 reactome genes, while perturbing genes linked to OX40, PPAR and FOXO3 signaling. However, in the presence of bacteria, HIV-1 did not perturb these gene sets or pathways. Instead, HIV-1 enhanced granzyme expression and Th17 cell function, inhibited G1/S cell cycle checkpoint genes and triggered downstream cell death pathways in microbe-exposed gut CD4+ T cells. To gain insights on these differential effects, we profiled the gene expression landscape of HIV-1-uninfected gut CD4+ T cells exposed to bacteria. Microbial exposure upregulated genes involved in cellular proliferation, MAPK activation, Th17 cell differentiation and type I interferon signaling. Our findings reveal that microbial exposure influenced how HIV-1 altered the gut CD4+ T cell transcriptome, with potential consequences for HIV-1 susceptibility, cell survival and inflammation. The HIV-1- and microbe-altered pathways unraveled here may serve as a molecular blueprint to gain basic insights in mucosal HIV-1 pathogenesis.

Dataset Information

Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients.

Publications

Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients.

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