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

Authors:
Andrea Lisco
Andrea Lisco
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Silvia Lucena Lage
Silvia Lucena Lage
Centro de Terapia Celular e Molecular (CTC-Mol)
Itzchak Levy
Itzchak Levy
Soroka University Medical Center
Israel
Jason Brophy
Jason Brophy
The Hospital for Sick Children
Canada
Jeffrey Lennox
Jeffrey Lennox
Emory University School of Medicine
United States
Maura Manion
Maura Manion
Case Western Reserve University/University Hospitals Case Medical Center
Cleveland | United States

JCI Insight 2019 Apr 18;4(8). Epub 2019 Apr 18.

Laboratory of Immunoregulation, HIV Pathogenesis Section, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

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.

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Source
http://dx.doi.org/10.1172/jci.insight.127113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538352PMC
April 2019
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