Plasma IP-10 Is Increased in Immunological NonResponders and Associated With Activated Regulatory T Cells and Persisting Low CD4 Counts

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Abstract

Objective:

To explore immune mechanisms and identify biomarkers associated with an inadequate immune recovery in patients with HIV with efficient antiretroviral therapy.

Design:

A cross-sectional study of 67 HIV-infected patients on antiretroviral therapy for ≥24 months with HIV RNA ≤20 copies per milliliter; 41 were defined as immunological nonresponders (INR) (CD4 < 400 cells per microliter) and 26 as immunological responders (CD4 > 600 cells per microliter). CD4 counts were also registered 2 years after inclusion.

Methods:

Cytokines, soluble markers of microbial translocation, and tryptophan catabolites were measured in plasma by multiplex assay, ELISA, or mass spectrometry. T-cell activation, differentiation, and regulatory T cells (Tregs) were analyzed by flow cytometry in 2 subgroups with comparable nadir CD4 counts.

Results:

Plasma interferon-inducible protein-10 (IP-10) levels were higher (P < 0.05), the T cells were more activated (CD38+HLA-DR+) (P < 0.05), the naive/effector memory T-cell ratio was lower (P < 0.01) and the proportion of resting Tregs (CD4+CD45RA+FoxP3+) was reduced (P < 0.001) in INR patients compared with immunological responders. INR patients with CD4 counts ≤300 cells per microliter also demonstrated a higher fraction of activated Tregs (aTreg) (CD4+CD147highCD25high) (P < 0.05). In the INR group, the aTreg percentages correlated with plasma IP-10 levels and inversely with CD4 counts (both P < 0.01). IP-10 levels (P < 0.05) and kynurenine/tryptophan ratio (P < 0.01) were negatively associated with the CD4 count 2 years after inclusion.

Conclusion:

Patients with HIV with inadequate CD4 responses had higher levels of IP-10, more activated and differentiated T-cell phenotypes, as well as aTreg, compared with patients with satisfactory CD4 gain. High IP-10 levels were also associated with lower CD4 counts after 2 years.

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