HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Autor:	Vos WAJW; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Internal Medicine and Infectious Diseases, OLVG, Amsterdam, Netherlands., Navas A; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Meeder EMG; Department of Psychiatry, Radboudumc, Radboud University, Nijmegen, Netherlands.; Cognition and Behavior, Donders Institute for Brain, Radboud University, Nijmegen, Netherlands., Blaauw MJT; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Internal Medicine and Infectious Diseases, Elizabeth-Tweesteden Ziekenhuis, Tilburg, Netherlands., Groenendijk AL; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Internal Medicine, ErasmusMC, Erasmus University, Rotterdam, Netherlands.; Department of Medical Microbiology and Infectious diseases, ErasmusMC, Erasmus University, Rotterdam, Netherlands., van Eekeren LE; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Otten T; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Internal Medicine and Infectious Diseases, Elizabeth-Tweesteden Ziekenhuis, Tilburg, Netherlands., Vadaq N; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Matzaraki V; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., van Cranenbroek B; Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands., Brinkman K; Department of Internal Medicine and Infectious Diseases, OLVG, Amsterdam, Netherlands., van Lunzen J; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Joosten LAB; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania., Netea MG; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Blok WL; Department of Internal Medicine and Infectious Diseases, OLVG, Amsterdam, Netherlands., van der Ven AJAM; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Koenen HJPM; Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands., Stalenhoef JE; Department of Internal Medicine and Infectious Diseases, OLVG, Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 May 08; Vol. 15, pp. 1350065. Date of Electronic Publication: 2024 May 08 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1350065
Abstrakt:	Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm 3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm 3 . Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Vos, Navas, Meeder, Blaauw, Groenendijk, van Eekeren, Otten, Vadaq, Matzaraki, van Cranenbroek, Brinkman, van Lunzen, Joosten, Netea, Blok, van der Ven, Koenen and Stalenhoef.)
Databáze:	MEDLINE
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