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Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

ABSTRACT: BACKGROUND:The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID). METHODS:EXID's clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4+ lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies. RESULTS:EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4+ decrease of 157 cells/?l, compared with CD4+ increases of 193 cells/?l and 427 cells/?l in INR and IR, respectively. EXID had reduced naive CD4+ T cells, but similar proportions of cycling CD4+ T cells and HLA-DR+CD38+CD8+ T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL. CONCLUSIONS:EXID is a distinct immunological outcome compared with previously described INR. Anti-CD4+ T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.

SUBMITTER: Lisco A

PROVIDER: S-EPMC6538352 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

Lisco Andrea A Wong Chun-Shu CS Lage Silvia Lucena SL Levy Itzchak I Brophy Jason J Lennox Jeffrey J Manion Maura M Anderson Megan V MV Mejia Yolanda Y Grivas Christopher C Mystakelis Harry H Burbelo Peter D PD Perez-Diez Ainhoa A Rupert Adam A Martens Craig A CA Anzick Sarah L SL Morse Caryn C Chan Shanna S Deleage Claire C Sereti Irini I

JCI insight 20190418 8

<h4>Background</h4>The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID).<h4>Methods</h4>EXID's clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), ...[more]

PMID: 30996137

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Project description:Despite the suppression of viral replication induced by the highly active anti-retroviral therapy (HAART), an increased immune activation and inflammatory state persists in HIV-infected patients, contributing to lower treatment response and immune reconstitution, and development of non-AIDS conditions. The chronic activation and inflammation affect the functionality and differentiation of CD8+ T-cells, particularly reducing their cytotoxic capacity, which is critical in the control of HIV replication. Although previous studies have shown that HAART induce a partial immune reconstitution, its effect on CD8+ T-cells cytotoxic function, as well as its relationship with the inflammatory state, is yet to be defined. Here, we characterized the functional profile of polyclonal and HIV-specific CD8+ T cells, based on the expression of cell activation and differentiation markers, in individuals chronically infected with HIV, under HAART. Compared with seronegative controls, CD8+ T-cells from patients on HAART exhibited a low degranulation capacity (surface expression of CD107a), with consequent low secreted levels and high intracellular expression of granzyme B and perforin. This degranulation defect was particularly observed in those cells expressing the activation marker HLA-DR, which were further characterized as effector memory cells with high expression of CD57. The expression of CD107a, but not of granzyme B and perforin, in CD8+ T-cells from HIV-infected patients on HAART reached levels similar to those in seronegative controls when the treatment duration was higher than 25 months. In addition, the expression of CD107a was negatively correlated with the expression of exhaustion markers on CD8+ T-cells and the plasma inflammatory molecule sCD14. Thus, despite HAART-induced viral suppression, CD8+ T-cells from HIV-infected patients have an alteration in their cytotoxic program. This defect is associated with the cellular activation, differentiation and exhaustion state, as well as with the inflammation levels, and can be partially recovered with a long and continuous treatment.

Dataset Information

Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

Publications

Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

Similar Datasets

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