Dataset Information

Reconstitution of intestinal CD4 and Th17 T cells in antiretroviral therapy suppressed HIV-infected subjects: implication for residual immune activation from the results of a clinical trial.

ABSTRACT:

Introduction

During HIV infection the severe depletion of intestinal CD4+ T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4+ T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers.

Methods

This longitudinal single-arm pilot study evaluates CD4+ T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4+ T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4+ Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA.

Results

Eight months of cART increased intestinal CD4+ and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4+ T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4+ T-cell recovery.

Conclusion

Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4+ T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4+ and of CD8+ T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals.

Trial registration

ClinicalTrials.gov NCT02097381.

SUBMITTER: d'Ettorre G

PROVIDER: S-EPMC4207675 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reconstitution of intestinal CD4 and Th17 T cells in antiretroviral therapy suppressed HIV-infected subjects: implication for residual immune activation from the results of a clinical trial.

d'Ettorre Gabriella G Baroncelli Silvia S Micci Luca L Ceccarelli Giancarlo G Andreotti Mauro M Sharma Prachi P Fanello Gianfranco G Fiocca Fausto F Cavallari Eugenio Nelson EN Giustini Noemi N Mallano Alessandra A Galluzzo Clementina M CM Vella Stefano S Mastroianni Claudio M CM Silvestri Guido G Paiardini Mirko M Vullo Vincenzo V

PloS one 20141023 10

<h4>Introduction</h4>During HIV infection the severe depletion of intestinal CD4+ T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4+ T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers.<h4>Methods</h4>This longitudinal single-arm pilot study evaluates CD4+ T cells, including Th1 and Th17, in gut and blood and soluble markers for i ...[more]

PMID: 25340778

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Project description:ObjectivesImmune non-responders (INR) have poor CD4 recovery and are associated with increased risk of serious events despite antiretroviral therapy (ART). A clinically relevant definition for INR is lacking.MethodsWe conducted a retrospective analysis of three large cohorts: Infectious Disease Clinic at the Atlanta Veterans Affairs Medical Center, the US Military HIV Natural History Study and Infectious Disease Program of the Grady Health System in Atlanta, Georgia. Two-stage modeling and joint model (JM) approaches were used to evaluate the association between CD4 (or CD4/CD8 ratio) slope within two years since ART initiation and a composite endpoint (AIDS, serious non-AIDS events and death) after two years of ART. We compared the predictive capacity of four CD4 count metrics (estimated CD4 slope, estimated CD4/CD8 ratio slope during two years following ART initiation and CD4 at 1 and 2 years following ART initiation) using Cox regression models.ResultsWe included 2,422 patients. Mean CD4 slope (±standard error) during two years of ART was 102 ± 2 cells/μl/year (95% confidence interval: 98-106 cells/μl/year), this increase was uniform among the three cohorts (p = 0.80). There were 267 composite events after two years on ART. Using the JM approach, a CD4 slope ≥100 cells/μL/year or CD4/CD8 ratio slope >0.1 higher rate per year were associated with lower composite endpoint rates (adjusted hazard ratio [HR] = 0.80, p = 0.04 and HR = 0.75 p<0.01, respectively). All four CD4 metrics showed modest predictive capacity.ConclusionsUsing a complex JM approach, CD4 slope and CD4/CD8 ratio slope the first two years after ART initiation were associated with lower rates of the composite outcome. Moreover, the uniformity observed in the mean CD4 slope regardless of the cohort suggests a common CD4 response pattern independent of age or CD4 nadir. Given the consistency observed with CD4 slope, availability and ease of interpretation, this study provides strong rationale for using CD4 gains <100 cells/μl/year to identify patients at risk for adverse events.

Dataset Information

Reconstitution of intestinal CD4 and Th17 T cells in antiretroviral therapy suppressed HIV-infected subjects: implication for residual immune activation from the results of a clinical trial.

Introduction

Methods

Results

Conclusion

Trial registration

Publications

Reconstitution of intestinal CD4 and Th17 T cells in antiretroviral therapy suppressed HIV-infected subjects: implication for residual immune activation from the results of a clinical trial.

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