CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

437

Immunological Non-Responders Have CD4+ Immunosenescense and Impaired Lymphocyte Cytokine Production Wilhelm A Vos 1 , Adriana Navas 1 , Elise M. Meeder 1 , Albert L. Groenendijk 1 , Marc Blaauw 1 , Louise E. van Eekeren 1 , Twan Otten 1 , Maartje C. Cleophas 1 , Nadira Vadaq 1 , Vasiliki Matzaraki 1 , Kees Brinkman 2 , Jan van Lunzen 1 , Andre J. van der Ven 1 , Willem L. Blok 2 , Janneke E. Stalenhoef 2 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 OLVG, Amsterdam, Netherlands Background: Immunological non-responders (INRs) are people living with HIV (PLHIV) that fail to restore CD4+ T-cell counts despite suppressive antiretroviral therapy (ART). INRs are at a higher risk for non-HIV related mortality and morbidity, such as non-aids malignancies. IL-2 induced CD4+ T-cell count increases did not effect clinical endpoints in previous trials, indicating a persistent qualitative defect despite increases in absolute CD4 counts. Methods: PLHIV with CD42 years of suppressive ART were defined as INRs, and were compared to immunological responders (IRs) with CD4>500 during ART. The 2000HIV study (clinicaltrials NTC03994835) enrolled 1895 PLHIV, which were divided into a discovery and a validation cohort. We used logistic, and rank based regression to analyze clinical data, extensive flow cytometry panels for monocytes, DC-, NK-, B-, CD4+T- and CD8+T- cells, and monocyte, and lymphocyte cytokine production capacity after stimulation with various stimuli in INRs compared to IRs. Analyses were corrected for sex at birth and age (all), seasonality (flow cytometry), and current monocyte/lymphocyte count (cytokine production). Results: The discovery cohort consisted of 62 INRs and 1224 IRs, the validation cohort of 26 INRs and 243 IRs. INRs were older, had more advanced HIV disease before starting ART and more often had a history of non- AIDS related malignancy. INRs had lower absolute CD4+ T-cells in all subsets analyzed. Activated and immunosenescent related subpopulations (HLA-DR+, CD38+; PD1+) were proportionally increased throughout CD4+ T-cell subsets (Figure 1A). CD8+ cells had proportionally increased HLD-DR+ subsets. Results were confirmed in the validation cohort. Monocyte and granulocyte phenotypes were not different between INRs and IRs in both cohorts. Moreover, INRs lymphocytes produced less IL-22 and IFN-γ in response to most stimuli, and less IL-10 and IL-17 to some stimuli (Figure 1B) indicating impaired cytokine production capacity. In contrast, monocyte cytokine production was comparable between INRs and IRs. Findings in the validation cohort were consistent. Proportional CD4+CD38+HLA-DR+ and CD4+PD1+ subsets were inversely correlated to lymphocyte cytokine production. Conclusion: We show an increase in immunosenescence CD4+ subsets and impaired lymphocyte function in INRs in a large cohort of PLHIV. These qualitative immune defects may therefore contribute to the observed increased morbidity in INRs.

study. Out of the 61 men, 47 were HPV-positive, while 24 were HPyV-positive, with 87.5% specifically testing positive for MCPyV. HPV infections were associated with lower IFN-I mRNA levels compared to the HPV-negative group [Mann-Whitney (MW) test, p<0.05]. Notably, IFN-α levels decreased in HPV/ HIV co-infected patients [Jonckheere-Terpstra test (JT), p<0.006]. Furthermore, HPV/HIV co-infections and the presence of Low-grade Squamous Intraepithelial Lesion (LSIL) were associated with lower expression of TLR9 (JT, p<0.026). When comparing HPV/HIV-positive and HPV/HPyVs positive men, IFN-α showed lower mRNA levels in the HPV/HIV group (MW, p<0.037), while IFN-λ2 was more produced in the HPV/HPyVs group (MW, p<0.008). Conclusion: The findings highlight the potential synergy between HIV and HPV infections in compromising mucosal innate immunity and promoting viral co infections, such as HPyVs, in the anal mucosa. Alterations in IFN and TLR-9 genes provide insights into complex mechanisms behind viral persistence, enhancing the understanding of innate immunity, viral infections, and HPV-related malignancies, with implications for future research and therapies. Circulating Acyl-CoA-Binding Protein Abates T-Cell Function in People Living With HIV Stephane Isnard 1 , Léna Royston 1 , Tsoarello Mabanga 1 , Simeng Bu 1 , Carolina A. Berini 2 , Nicole F. Bernard 1 , Julien van Grevenynghe 3 , Guido Kroemer 4 , Jean-Pierre Routy 1 1 McGill University Health Centre Research Institute, Montreal, Canada, 2 McGill University Health Centre, Montreal, Canada, 3 INRS Centre Armand-Frappier Santé Biotechnologie, Laval, Canada, 4 Centre de Recherche des Cordeliers, Paris, France Background: Autophagy, a cytosolic-structure degradation pathway producing energy, allows efficient anti- HIV T-cell responses. Autophagy enables IL21 production in anti-HIV CD4 T-cells, which in turn stimulates lipophagy and enhances CD8 T-cell anti-HIV responses. Extracellular Acyl-CoA-Binding Protein (ACBP) inhibits autophagy, tricarboxyclic acid (TCA) cycle and oxidative phosphorylation in mouse models. Herein, we assessed the levels of circulating ACBP and its influence on T-cell function in people living with HIV (PLWH) on antiretroviral therapy (ART). Methods: Plasma ACBP and cytokines were quantified by ELISA in 50 PLWH on effective ART (mean duration 14.7 years) and 30 controls with similar age. Metabolomic analyses were performed on serum samples by GC-MS (10 participants with high and low ACBP). In vitro, recombinant ACBP (recACBP) was added at increasing concentration up to 10μg/mL on PBMCs from PLWH on ART and controls, T-cell responses were assessed by flow cytometry. Intracellular LC3B was visualized by microscopy. Results: ACBP levels were higher in PLWH on ART compared to controls (median 127.5 vs 78.1 ng/mL, p=0.03), independently of age and sex. In ART-treated PLWH, plasma ACBP levels were neither associated with CD4 nor CD8 T-cell counts, however they correlated with levels of growth factors (EGF, G-CSF, GRO), pro- inflammatory cytokines (IFNα2, IFNγ, IL1β) and homeostatic factors (IL7 and IL15) (r>0.3, p<0.05 for all comparisons). Conversely, ACBP levels were inversely associated with plasma IL21 levels (r=-0.54, p<0.01). PLWH with high ACBP had higher serum levels of TCA intermediates glutamate (2-fold, p=0.02) and α- ketoglutarate (1.5-fold, p=0.09), respectively. We added recACBP to PBMCs stimulated with either anti-CD3 antibodies or HIV Gag, Nef and Env peptides for 16 h, and observed a decrease in IFNγ, IL2 and TNFα production in CD4 and CD8 T-cells (p<0.03 for all). Upon anti-CD3 stimulation, IL17A and IL21 production were also decreased in CD4 T-cells while IL10 levels remained unaffected. RecACBP decreased intracellular levels of the autophagy marker LC3B without affecting cell viability. Conclusion: Higher plasma ACBP levels in PLWH on ART were associated with inflammation, unfit metabolism, and markers of T-cell dysfunction. Our findings indicate that circulating ACBP directly abates autophagy and anti-HIV T-cell functions, compelling the development of circulating ACBP inhibitors aiming at improving anti-HIV T-cell responses in PLWH, towards an HIV cure.

436

Poster Abstracts

CROI 2024 109