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CD4?CD73? T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression.

ABSTRACT: The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4? T cells in HIV-1 infection is unclear.We evaluated the frequency and numbers of CD4?CD39? and CD4?CD73? T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP by ectoenzyme-expressing CD4? T cells, whereas cyclic adenosine monophosphate (cAMP) levels were measured using enzyme immunoassay. Suppression of T-cell function by exogenous ADO and CD4?CD73? T cells was tested by flow cytometry.CD39 and CD73 are expressed in different CD4? T-cell subsets. CD4?CD73? T cells do not express CD25 and FOXP3, and their frequency and numbers were lower in HIV-1-positive individuals regardless of virologic suppression (P=0.005 and P<0.001, respectively). CD4?CD73? numbers inversely correlated with CD4?CD38?DR? (P=0.002), CD8?CD38?DR? T-cell frequency (P=0.05), and plasma CRP levels (P=0.01). Both subsets are required for hydrolysis of exogenous ATP to ADO and can increase CD4? T-cell cAMP levels when incubated with exogenous ATP. Low-level viremia did not correlate with activated T-cell frequency. In vitro, ADO suppressed T-cell activation and cytokine expression. CD4?CD7? T cells suppressed T-cell proliferation only in the presence of exogenous 5'-AMP.The ADO-producing CD4?CD73? subset of T cells is depleted in HIV-1-positive individuals regardless of viral suppression and may play a key role in controlling HIV-1-associated immune activation.

SUBMITTER: Schuler PJ

PROVIDER: S-EPMC3939796 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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CD4⁺CD73⁺ T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression.

Schuler Patrick J PJ Macatangay Bernard J C BJ Saze Zenichiro Z Jackson Edwin K EK Riddler Sharon A SA Buchanan William G WG Hilldorfer Benedict B BB Mellors John W JW Whiteside Theresa L TL Rinaldo Charles R CR

AIDS (London, England) 20130601 10

<h4>Background</h4>The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4⁺ T cells in HIV-1 infection is unclear.<h4>Methods</h4>We evaluated the frequency and numbers of CD4⁺CD39⁺ and CD4⁺CD73⁺ T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP b ...[more]

PMID: 24005375

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Project description: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). 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. 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. 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.

Project description:BackgroundDuring antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear.MethodsHIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements.ResultsBetween 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3-4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed.ConclusionsVL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

Dataset Information

CD4?CD73? T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression.

Publications

CD4⁺CD73⁺ T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression.

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