CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

512

Slope of Neutralization Curve is Best Predictor of Viral Decay Response to 3BNC117 at ART Initiation Jesper D Gunst , Henrik Støvring, Marie H. Pahus, Ole S. Søgaard Aarhus University Hospital, Aarhus, Denmark Background: Broadly neutralizing anti-HIV-1 antibodies (bNAbs) are currently being tested as component in long-acting treatment of HIV-1 and curative strategies. bNAb sensitivity of plasma viruses and thus the proviral reservoir is crucial for the clinical outcome. Currently, there is no gold standard for analyzing nor categorizing bNAb sensitivity. Methods: Plasma HIV-1 RNA from 59 eCLEAR ART-naïve participants were analyzed for 3BNC117 sensitivity post hoc using the PhenoSense assay and two genotypic prediction algorithms; the 'HIV screening analysis' developed at Rockefeller University and the 'bNAb-ReP' developed by VRC/NIH. We used mixed-effects linear regression models to calculate the second-phase (day 10 to 24 after ART initiation) plasma HIV-1 RNA decay among individuals receiving 3BNC117 to ART initiation compared to ART alone. A ROC curve was used to explore and identify the optimal characteristic among the three bNAb sensitivity assays for predicting second-phase viral decay. Results: The IC values (≥IC 50 ) on the neutralization curve obtained from the PhenoSense assay may be modelled using the Median Effect Principle. This implies that a logistic model can be used to estimate the slope of log(f_a/ (1-f_a)) as a measure of inhibition increase with respect to 3BNC117 dose. There was a significant faster second-phase viral decay with steeper slope of the neutralization curve (-0.029 change in log(f_a/(1-f_a)) per log 10 3BNC117 concentration, 95% Confidence Interval: -0.049; -0.010, P=0.003). Among the three bNAb sensitivity assays, the slope of the logistic was the best predictor of second-phase viral decay outperforming any IC values or genotypic assessments. The sensitivity and specificity in predicting a faster second-phase viral decay with a slope of 2.25 was 62% and 75%. The next best predictors of plasma viral decay in the second phase were IC 90 <1.2 µg ml−1 with a sensitivity and specificity of 78% and 63% on the PhenoSense assay and a threshold for single envelope sequences of 75% on the bNAb-ReP (90% of all sequences needed to be categorized as sensitive) with a sensitivity and specificity of 77% and 75%. Conclusion: Whilst bNAb sensitivity is crucial for clinical outcome in clinical trials administering bNAbs, so far bNAb sensitivity threshold has been based on expert opinions. Using clinical data from the eCLEAR trial, we have shown that the best predictors of bNAb-mediated effects on plasma HIV-1 RNA decay are the slope of the neutralization curve from the PhenoSense assay. HIV-1 Reservoir Dynamics in Children With Early Treated, Perinatally Acquired HIV: Does Sex Matter? Kavidha Reddy 1 , Chantal Molechan 1 , Moira J. Spyer 2 , Mathias Lichterfeld 3 , Pablo Rojo 4 , Paolo Rossi 5 , Paolo Palma 5 , Carlo Giaquinto 6 , Afaaf Liberty 7 , Mornay Isaacs 8 , Loide Cardoso 9 , Ligia Estevao 10 , Alfredo Tagarro 4 , Thumbi Ndung'u 1 1 Africa Health Research Institute, Durban, South Africa, 2 University College London, London, United Kingdom, 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 4 Hospital Universitario 12 de Octubre, Madrid, Spain, 5 Bambino Gesu Children's Hospital, Rome, Italy, 6 University of Padova, Padova, Italy, 7 University of the Witwatersrand, Johannesburg, South Africa, 8 Stellenbosch University, Cape Town, South Africa, 9 Fundação Ariel Glaser Contra o SIDA Pediátrico, Maputo, Mozambique, 10 Universitat de Barcelona, Barcelona, Spain Background: Eliminating the HIV-1 reservoir is key to an effective HIV cure. Improved understanding of the size and nature of the viral reservoir will help the design of cure strategies. Here, we performed a longitudinal analysis of the total HIV reservoir in early treated, perinatally HIV-infected children. Methods: Participants were infants from the Early AntiRetroviral Treatment in Children (EARTH) Cohort in South Africa, Mozambique, and Mali. HIV was diagnosed shortly after birth, followed by early ART initiation with up to 4 years of follow up. We analysed 34/52 infants, 18 females and 16 males, termed virological controllers with undetectable viral load during at least 12 months of follow up. Proviral DNA was measured from total PBMCs by droplet digital PCR from ART initiation through 4 years. Results: ART was initiated at a median of 34 days of life (IQR, 26.0-73.0) and the median time to viral suppression in virological controllers was 363 days on ART (IQR, 317,0-552,0). There was a positive correlation with baseline viral load and proviral load each measured at ART initiation (p=0.03, r=0.58) and 1 year (p=0.01, r=0.56) and 2 years (p=0.001, r=0.69) of follow up. At ART initiation the median total HIV DNA level was 3.7 log copies/million cells (IQR, 3.2-4.1). The HIV DNA reservoir decreased slowly over the first 6 months (median=3.2 log c/10 6 cells, IQR, 2.6-3.7) of ART with significant decline after 1 year (median=2.6

flowcytometry. Correlations were determined using Pearson's correlations (p<0.05). Results: A mean decline in intact proviral DNA (Fig.1A) and total HIV-DNA load, but not defective proviral DNA and cell-associated US-RNA between 24 and 156 weeks after ART initiation was observed. We measured a positive HIV specific CD4+ and CD8+ T-cell response to at least 3 different viral proteins in the majority of individuals at both time points (Fig.1 B+C). At 24 weeks, intact proviral DNA load was associated with CD4+ T-cell responses to Env (p<0.001, R2=0.96), Gag (p=0.005, R2=0.6), Nef (p<0.001, R2=0.9) and Pol (p=0.002, R2=0.6). At 156 weeks, intact proviral DNA load was correlated with CD8+ T-cell response to Gag (p=0.034, R2=0.59) and Pol (p<0.001, R2=0.77). Moreover, we observed a positive association between the decay of intact proviruses between 24 and 156 weeks with CD4+ T-cell responses to Env (p=0.034, R2=0.64) and Nef (p=0.007, R2=0.76). No associations between T-cell responses and other viral reservoir measurements (defective proviral DNA load, total HIV-DNA and US-RNA) were observed. Conclusion: We detected a positive association between HIV specific T-cell responses and the decay of intact proviral DNA load in individuals treated during AHI. This implies that a potent HIV specific T-cell response, in addition to early ART, leads to a reduction of intact proviral DNA load. This finding potentially provides a promising avenue for cure interventions aimed at reservoir induction in combination with T-cell activating strategies. The figure, table, or graphic for this abstract has been removed. Lower ADCC After 26 Weeks of PEG-IFN-α2b and 2 bNAbs in Otherwise Suppressed HIV-1+ Emmanouil Papasavvas 1 , Jessicamarie Morris 1 , Brian N. Ross 1 , Matthew Fair 1 , Livio Azzoni 1 , Karam Mounzer 2 , Jay R. Kostman 2 , Pablo Tebas 3 , Luis J. Montaner 1 1 Wistar Institute, Philadelphia, PA, USA, 2 Philadelphia FIGHT, Philadelphia, PA, USA, 3 University of Pennsylvania, Philadelphia, PA, USA Background: Previous studies suggested that pegylated interferon α2b (peg IFN-α2b) and the broadly neutralizing antibodies (bNabs) 3BNC117 and 10-1074 may contribute to cure-related strategies. We evaluated the effect of a 26-week immunotherapy course with peg-IFN-α2b+bNAbs in the cytotoxic function and activation of natural killer (NK) cell subsets in persons with HIV infection (PWH) that participated in the BEAT 2 study (NCT03588715). Methods: Fourteen PWH receiving suppressive antiretroviral therapy (ART, <50 HIV-1 copies/ml) underwent ART interruption (ATI) while receiving a 26-week immunotherapy course of peg-IFN-α2b+bNAbs. Peripheral blood mononuclear cells (PBMC) were collected prior to ATI/immunotherapy (ART alone, time-point 1), on ART+4 weeks peg-IFN-α2b (time-point 2), and on ATI+26 weeks peg IFN-α2b+bNAbs (time-point 3). Fresh PBMC were used in 51Cr release assays for assessment of antibody-dependent cell-mediated cytotoxicity (ADCC) against NK-resistant lymphoblastic target cell line prior and after in vitro stimulation with gp120, and for direct cytotoxicity against MHC-cell null cancer target cell line prior and after in vitro stimulation with IFN-α. Cryopreserved PBMC were used for immunophenotypic characterization by flow cytometry of NK cell subsets and of markers associated with NK activation, inhibition or maturation (e.g. CD38, NKp46, NKG2A, Siglec 7, Siglec 9, CD57). Statistics were performed by JMP 15. Results: Immunotherapy did not affect IFN-α-induced NK direct cytotoxicity but resulted in a decrease in gp120-mediated ADDC. Reduced ADCC was observed together with an increase in the cytokine producing CD56hi and in CD56lo/+CD16- % of CD56+ NK cells, and a decrease in the cytotoxic CD56lo/+CD16+ % of CD56+, suggesting that decrease in the expression of Fc receptor CD16 on NK could be associated with lower ADCC function. These findings were supported by a negative correlation between ADCC and CD56lo/+CD16- % of lymphocytes after IFN-α immunotherapy (end of step 2). Finally, the gp120-induced ADCC decrease was observed together with a decrease in the maturation/cytotoxicity marker CD57 in CD56lo/+CD16+ NK cells, despite an increase in activation (CD38, NKp46) and inhibition (NKG2A, Siglec 7) markers. Conclusion: In PWH, combined immunotherapy with peg-IFN-α2b+bNAbs resulted in no effect on IFN-α-induced NK direct cytotoxicity and an unexpected decrease in gp120-induced ADCC and in circulating CD16+ NK cell subsets. The figure, table, or graphic for this abstract has been removed.

Poster Abstracts

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CROI 2024 135