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Identification of rare HIV-1–infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression
Andrea Lisco, … , Claire Deleage, Irini Sereti
Andrea Lisco, … , Claire Deleage, Irini Sereti
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e127113. https://doi.org/10.1172/jci.insight.127113.
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Clinical Medicine AIDS/HIV

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

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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/μl, compared with CD4+ increases of 193 cells/μl and 427 cells/μl 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.

Authors

Andrea Lisco, Chun-Shu Wong, Silvia Lucena Lage, Itzchak Levy, Jason Brophy, Jeffrey Lennox, Maura Manion, Megan V. Anderson, Yolanda Mejia, Christopher Grivas, Harry Mystakelis, Peter D. Burbelo, Ainhoa Perez-Diez, Adam Rupert, Craig A. Martens, Sarah L. Anzick, Caryn Morse, Shanna Chan, Claire Deleage, Irini Sereti

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Figure 1

CD4+ T cell trends after ART initiation.

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CD4+ T cell trends after ART initiation.
(A) CD4+ T cell count in immuno...
(A) CD4+ T cell count in immunological responders (IRs), immunological nonresponders (INRs), and extreme immunological decline (EXID) after initiation of ART. The median (red bar), IQR (error bar), and each available CD4+ T cell count measurement (symbols) is presented at each time point for IR (n = 8), INR (n = 15), and EXID (n = 5). (B) The median (red bar), IQR (error bar), and the difference in CD4+ T cell count between week 0 (ART initiation) and week 96 or week 192 (symbols) is presented for each IR (n = 8), INR (n = 15), and EXID (n = 5) subject. Each EXID subject is identified by a different gray-filled shape. *P ≤ 0.05 in the comparison indicated by the black horizontal line as determined by Mann-Whitney U test; ns, nonsignificant difference.

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