CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

EHMT2, CEACAM3, CC2D1B, RHOA and HMOX1 provide significant advantages for viral replication fitness. Knock-out studies confirmed that GRN, CEACAM3 and CIITA inhibit HIV-1 in primary CD4+ T cells. Several factors were identified with high reproducibility in our virus-driven screen but not in common overexpression or knock-down assays. Finally, lack of the nef gene increased selection of sgRNAs targeting SERINC5 and identified IFI16 as putative Nef target. Subsequent analysis confirmed that Nef attenuates the inhibitory effects of IFI16. Conclusion: We established an innovative, robust and highly versatile virus driven approach that allows the identification of antiviral factors by turning HIV-1 into “traitors” revealing their cellular opponents. Immunoregulatory Pathways Predict Mortality More Strongly in People With Versus Without HIV Samuel R Schnittman 1 , Rebecca Abelman 2 , Gabriele B. Beck-Engeser 2 , Noah Aquino 2 , Gabrielle C. Ambayec 2 , Carl Grunfeld 2 , Edward Cachay 3 , Joseph J. Eron 4 , Michael S. Saag 5 , Robin M. Nance 6 , Joseph A. Delaney 6 , Heidi M. Crane 6 , Adam Olshen 2 , Peter W. Hunt 2 , for the CFAR Network of Integrated Clinical Systems (CNICS) Network 1 Massachusetts General Hospital, Boston, MA, USA, 2 University of California San Francisco, San Francisco, CA, USA, 3 University of California San Diego, San Diego, CA, USA, 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5 University of Alabama at Birmingham, Birmingham, AL, USA, 6 University of Washington, Seattle, WA, USA Background: While people with HIV (PWH) on suppressive antiretroviral therapy (ART) have higher levels of inflammation and are at greater risk for morbidity and mortality than the general population, the immunologic pathways most strongly linked to this excess HIV-associated risk remain incompletely characterized. Methods: The first available plasma sample after 1/1/2010 was selected from a random sample of all PWH from 8 CNICS sites with ≥6 months of ART-mediated viral suppression. Plasma was assessed for 363 detectable inflammatory proteins (Olink Inflammation I Explore Panel). The relationship between each protein and all- cause mortality was assessed via Cox proportional hazards modeling, adjusted for VACS index (1.0) and CNICS site, controlling for the false discovery rate (FDR) via the Benjamini-Hochberg method. To identify pathways more relevant in PWH than in the general population, adjusted hazard ratios (aHR) were compared to published UK Biobank (UKB) data, which reported the association between the same Olink panel and all-cause mortality in 47,600 participants from the general population via FDR-corrected multivariate Cox modeling. Results: Among 922 PWH in CNICS, median age was 47 and 18% were women. Median current and nadir CD4 counts were 579 cells/mm 3 and 245 cells/mm 3 , respectively. Over a median follow-up time of 9 years, 103 deaths occurred. After adjustment and FDR correction, 147 (40%) proteins were associated with an increased (N=140) or decreased (N=7) hazard of death in CNICS (all FDR corrected P<0.05, Figure A). Compared to the same proteins assessed in UKB, higher levels of 48 proteins were uniquely associated with increased mortality in CNICS (N=21) or had an aHR at least 50% higher among PWH than in the UKB general population (N=27) (Figure B). While some of these HIV-associated mortality predictors were pro-inflammatory (IFNg, IFNgR1, IL- 18R1, and IL-15), the largest cluster comprised immunoregulatory proteins linked to suppressing T, NK, and myeloid cell activation (CD276, CD58, CD48, ITGB6, CLEC4G, and KLRD1) or pro-fibrotic and endothelial cell regulatory processes. Conclusion: While numerous pro-inflammatory proteins are associated with mortality in both PWH and the general population, immunoregulatory rather than pro-inflammatory proteins were preferentially associated with mortality risk in PWH. Whether the immunoregulatory response to inflammation is an important causal mediator of increased morbidity and mortality in treated PWH should be explored.

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Oral Abstracts

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HIV-1 Soluble gp120 Is Associated With Immune Dysfunction in Individuals on Antiretroviral Therapy Mehdi Benlarbi 1 , Jonathan Richard 2 , Carl Chartrand-Lefebvre 1 , Marc Messier Peet 2 , Andrew Clark 3 , Walther Mothes 4 , Daniel E. Kaufmann 2 , Frank Maldarelli 5 , Nicolas Chomont 2 , Cécile Tremblay 2 , Ralf Duerr 6 , Marzena Pazgier 7 , Madeleine Durand 2 , Andrés Finzi 2 , for the Canadian HIV and Aging Cohort Study 1 Université de Montréal, Montreal, Canada, 2 Centre de Recherche du CHUM, Montreal, Canada, 3 ViiV Healthcare, London, United Kingdom, 4 Yale University, New Haven, CT, USA, 5 National Cancer Institute, Bethesda, MD, USA, 6 New York University, New York, NY, USA, 7 Uniformed Services University of the Health Sciences, Bethesda, MD, USA Background: Chronic inflammation persists in some people living with HIV (PLWH), even during ART, and is associated with premature aging. The gp120 subunit of HIV-1 Env can shed from viral and cellular membranes, persists in plasma and tissues, and has been suggested to exert immunomodulatory properties. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies (Abs), previously linked to CD4 depletion in vitro, could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. Methods: We developed a novel assay to specifically detect plasmatic sgp120. We performed a cross-sectional assessment of sgp120 and anti-cluster A Abs in individuals from CHACS. We evaluated their associations with immune parameters (CD4 counts, CD4:CD8 ratios) and IL-6. In a subgroup participating in a cardiovascular imaging sub-study, we also studied the association between sgp120, anti-cluster A Abs, and sub-clinical cardiovascular disease, measured by computed tomography coronary angiography. Measures of association were obtained using linear regression models, adjusted for the following clinically-defined potential confounders: age, sex, smoking, low/high-density lipoproteins, diabetes, hypertension, nadir CD4, and duration of antiretroviral therapy. Results: We included 386 participants for measurements of sgp120 and anti-cluster A Abs, 157 of whom also had measurements of IL-6, and 145 of whom took part in the cardiovascular imaging sub-study. The mean age of participants was 55.8, 90% were males, and 82% were Caucasian. The median duration of HIV infection was 18.3 years. sgp120 was detected in 107/386 (28%). Anti-cluster A Abs were inversely associated with CD4 cell counts (adjusted beta -15.29 95%CI -26.74 to -3.84, p=0.009) and CD4:CD8 ratio (adjusted beta -0.055 95%CI -0.080 to -0.030, p=0.004). The strength of these associations was increased in the subset with high sgp120. sgp120 was associated with increased

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CROI 2024