CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

detected in the latent HIV-1 reservoir prior to ART interruption significantly correlates (p=0.0150) with the time to viral rebound. Conclusion: We report that autologous IgG antibodies can neutralize inducible, replication-competent HIV-1 prior to an ATI, and higher percentages of variants susceptible to anAbs are associated with a longer time to rebound post ART. These results suggest that inducing a potent immune response against anAb-resistant virus could eventually lead to sustained virological control in the absence of ART. The mQVOA may serve as a useful pre-screening tool for selective ATI enrollment. Lastly, ATI studies using time to viral rebound as an outcome measurement should consider the anAb response when designing trials and interpreting results. Plasma Correlates of Rebound After Discontinuation of ART in Persons Living With HIV-1 (PLWH) Malika A Boudries 1 , Dan H. Barouch 1 , Boris D. Juelg 2 , Victoria E. Walker Sperling 1 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA Background: The discovery of biomarkers that predict viral rebound after ATI would significantly contribute to the HIV cure field. Further, the discovery of biomarkers predicting viral rebound after ART discontinuation will inform and guide ATI studies to understand who is more likely to experience a viral rebound and could help select participants for ART interruption studies to make ART discontinuation safer and more effective. Methods: We initiated a multi-center, open-label trial of three monthly intravenous (IV) administration of 20 mg/kg each of PGT121, PGDM1400, and VRC07-523LS (n=12) in persons living with HIV-1 (PLWH) following discontinuation of antiretroviral therapy (ART). ART was interrupted 2 days after the first broadly neutralizing monoclonal antibodies (bNAb) infusion. We collected plasma from all participants two days before ATI, multiple times off ART, and after rebound. We conducted high-throughput transcriptomics, proteomics, and metabolomics at all time points in all participants. Results: We investigated protein signatures modulated after ATI, before detectable rebound (VL< 200cp/ml), and after rebound (VL>200cp/ml) compared with baseline (pre-ATI). We observed a significant increase (FDR q value < 0.05) of T cells, immune activation, and proinflammatory signatures preceding detectable rebound (VL<200 cp/ml) that were augmented after rebound. Signatures of activated proinflammatory macrophage M1, response to interferon-alpha and gamma as well as proinflammatory cytokines and chemokines (CXCL10, CXCL9, TNFRSF1B, CD14, CSF1) were elevated before detectable rebound compared with pre-ATI. Metabolic pathways show dysregulation or a decrease after analytical treatment interruption (ATI) and before detectable rebound, indicating metabolic changes associated with the rebound virus (Fig 1). Conclusion: Our preliminary observations highlight the role of proinflammatory signatures and macrophages as potential plasma biomarkers to predict imminent rebound following ATI.

(n=26), who initiated ART not containing MVC; and Control 2 (n=21), who had undetectable HIV-RNA on ART and switched to a MVC-containing regimen. Cases and Control 1 groups were matched by age, sex, and the number and type of drugs in ART regimen (excluding MVC). We determined the HIV reservoir size by measuring integrated HIV-DNA in stored PBMCs. We estimated the HIV reservoir variation with multivariate linear regression models adjusted for age, baseline CD4 counts, baseline HIV-RNA and baseline HIV-DNA. Results: Pre-ART, median CD4 counts (cells/mm 3 ) were 96 (IQR: 36.5-204.0) in Cases and 351.5 (IQR: 237.0-494.0) in Control 1, and 456.0 (IQR: 264.5-598.5) prior MVC inclusion in Control 2. Pre-ART, the HIV reservoir size (median copies of integrated HIV/million cells) was 2368.0 [IQR: 38.6-9101.0] in Cases and 1583.0 [IQR: 97.3-5720.0] in Control 1. After a median of 79.7 weeks (IQR: 72.0-116.0) from ART initiation, the HIV reservoir size decreased significantly in both groups (97.5 [IQR: 5.4-552.9] in Cases and 720.5 [IQR: 72.6-2578.0] in Control 1, p<0.01). Control 2 group displayed an HIV reservoir size of 661.3 [IQR: 130.0-4499.0] and 416.0 [IQR: 31.2-965.5] before and after switching to a MVC containing regimen, respectively (p<0.01). Multivariate analysis showed that Cases had a 12-fold and 11-fold greater HIV reservoir decline than Control 1 and Control 2, respectively (p<0.01). Conclusion: Administering an LRA during ART initiation with detectable viremia more effectively reduces the HIV reservoir size than in patients with undetectable viral load. This finding can inform the design of clinical trials based on the shock and kill strategy.

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Poster Abstracts

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The Fraction of HIV Reservoir Variants Neutralized by Autologous IgG Correlates With Time to Rebound Mauro A Garcia 1 , Junlin Zhuo 1 , Joseph Varriale 1 , Anna Farrell-Sherman 2 , Jun Lai 1 , Anthony Abeyta-Lopez 1 , Natalie F. McMyn 1 , Rebecca Hoh 3 , Michael J. Peluso 3 , Francesco R. Simonetti 1 , Steven G. Deeks 3 , Lillian Cohn 2 , Robert F. Siliciano 1 , Janet M. Siliciano 1 1 The Johns Hopkins University, Baltimore, MD, USA, 2 Fred Hutchinson Cancer Center, Seattle, WA, USA, 3 University of California San Francisco, San Francisco, CA, USA Background: During untreated infection, HIV-1 rapidly evolves to escape contemporaneous, autologous neutralizing antibodies (anAbs). At the time of ART initiation, archived reservoir isolates may be sensitive or resistant to anAbs. Factors such as time to rebound, and the genotype of rebound virus are difficult to predict amongst analytical treatment interruption (ATI) cohorts. Elucidating the factors that govern these phenomena can inform cure strategies aiming for ART-free virologic control. We hypothesize that (1) anAb-resistant virus detected in the reservoir prior to an ATI may be identical, or genetically similar, to virus that rebounds post ART, and (2) higher percentages of anAb-sensitive reservoir variants may be associated with a longer time to rebound post ART. Methods: Among 9 study participants who underwent an ATI without intervention, we measured inhibition of outgrowth by contemporaneous anAbs in a modified quantitative viral outgrowth assay (mQVOA). The mQVOAs were conducted using donor-derived resting CD4+ T (rCD4) cells isolated prior to the ATI. These rCD4 cells were activated by PHA, then cultured in the presence of contemporaneous autologous IgG, HIV-negative donor IgG, or no IgG for 14 days. Viral outgrowth was scored by HIV-1 p24 ELISA. Results: With samples obtained prior to the ATI, we observed donor-to-donor variation in the ability of contemporaneous autologous IgG to neutralize inducible, replication-competent reservoir isolates. In the cohort analyzed, the fraction of outgrowth isolates neutralized by anAbs ranged from 0 to 44%, and it was observed that participants with more neutralizable reservoir variants had delayed times to viral rebound. Overall, the fraction of anAb-sensitive viruses

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