Dataset Information

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

ABSTRACT: HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DR^int/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1^high, TIGIT^high) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

SUBMITTER: Scharf L

PROVIDER: S-EPMC8545800 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

Scharf Lydia L Pedersen Christina B CB Johansson Emil E Lindman Jacob J Olsen Lars R LR Buggert Marcus M Wilhelmson Sten S Månsson Fredrik F Esbjörnsson Joakim J Biague Antonio A Medstrand Patrik P Norrgren Hans H Karlsson Annika C AC Jansson Marianne M

Frontiers in immunology 20211012

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from ...[more]

PMID: 34712231

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Project description:ObjectivePrior hypothesis-driven studies identified immunophenotypic characteristics associated with the control of HIV replication without antiretroviral therapy (HIV controllers) as well as with the degree of CD4 T-cell recovery during ART. We hypothesized that an unbiased 'discovery-based' approach might identify novel immunologic characteristics of these phenotypes.DesignWe performed immunophenotyping on four 'aviremic' patient groups: HIV controllers (n = 98), antiretroviral-treated immunologic nonresponders (CD4 < 350; n = 59), antiretroviral-treated immunologic responders (CD4 > 350, n = 142), and as a control group HIV-negative adults (n = 43). We measured levels of T-cell maturation, activation, dysfunction, senescence, functionality, and proliferation.MethodsSupervised learning assessed the relative importance of immune parameters in predicting clinical phenotypes (controller, immunologic responder, or immunologic nonresponder). Unsupervised learning clustered immune parameters and examined if these clusters corresponded to clinical phenotypes.ResultsHIV controllers were characterized by high percentages of HIV-specific T-cell responses and decreased percentages of cells expressing human leukocytic antigen-antigen D related in naive, central memory, and effector T-cell subsets. Immunologic nonresponders were characterized by higher percentages of CD4 T cells that were TNFα+ or INFγ+, higher percentages of activated naive and central memory T cells, and higher percentages of cells expressing programmed cell death protein 1. Unsupervised learning found two distinct clusters of controllers and two distinct clusters of immunologic nonresponders, perhaps suggesting different mechanisms for the clinical outcomes.ConclusionOur discovery-based approach confirmed previously reported characteristics that distinguish aviremic individuals, but also identified novel immunologic phenotypes and distinct clinical subpopulations that should lead to more focused pathogenesis studies that might identify targets for novel therapeutic interventions.

Project description:BackgroundCurrent clinical balance assessment tools do not aim to help therapists identify the underlying postural control systems responsible for poor functional balance. By identifying the disordered systems underlying balance control, therapists can direct specific types of intervention for different types of balance problems.ObjectiveThe goal of this study was to develop a clinical balance assessment tool that aims to target 6 different balance control systems so that specific rehabilitation approaches can be designed for different balance deficits. This article presents the theoretical framework, interrater reliability, and preliminary concurrent validity for this new instrument, the Balance Evaluation Systems Test (BESTest).DesignThe BESTest consists of 36 items, grouped into 6 systems: "Biomechanical Constraints," "Stability Limits/Verticality," "Anticipatory Postural Adjustments," "Postural Responses," "Sensory Orientation," and "Stability in Gait."MethodsIn 2 interrater trials, 22 subjects with and without balance disorders, ranging in age from 50 to 88 years, were rated concurrently on the BESTest by 19 therapists, students, and balance researchers. Concurrent validity was measured by correlation between the BESTest and balance confidence, as assessed with the Activities-specific Balance Confidence (ABC) Scale.ResultsConsistent with our theoretical framework, subjects with different diagnoses scored poorly on different sections of the BESTest. The intraclass correlation coefficient (ICC) for interrater reliability for the test as a whole was .91, with the 6 section ICCs ranging from .79 to .96. The Kendall coefficient of concordance among raters ranged from .46 to 1.00 for the 36 individual items. Concurrent validity of the correlation between the BESTest and the ABC Scale was r=.636, P<.01.LimitationsFurther testing is needed to determine whether: (1) the sections of the BESTest actually detect independent balance deficits, (2) other systems important for balance control should be added, and (3) a shorter version of the test is possible by eliminating redundant or insensitive items.ConclusionsThe BESTest is easy to learn to administer, with excellent reliability and very good validity. It is unique in allowing clinicians to determine the type of balance problems to direct specific treatments for their patients. By organizing clinical balance test items already in use, combined with new items not currently available, the BESTest is the most comprehensive clinical balance tool available and warrants further development.

Dataset Information

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

Publications

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

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