CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

were phenotypically sensitive to TAB, 10 (45%) to ZAB, 9 (41%) to both bNAbs, and 2 (9%) to neither. Of 24 participants with virologic suppression, 67% were phenotypically sensitive to TAB, 54% to ZAB, 42% to both bNAbs, and 5 (21%) to neither. The proportion of participants with sensitivity to both bNAbs was similar (p=0.99) in viremic participants (9/22 [41%]) compared to those with virologic suppression (10/24 [42%]). Nonsignificant correlations between phenotypic sensitivity to bNAbs and age, years of ART, CD4+ cell count, HIV-RNA, type of ART regimen at the sample collection, viral tropism and HIV subtype. There were marginal correlations between phenotypic sensitivity to TAB and years since HIV diagnosis (Spearman r= 0.287, p=0.053) and phenotypic sensitivity to ZAB and CD8+cell count (Spearman r= -0.317, p=0.049). Conclusion: A significant number of the analyzed 4DR-PWH were found to have virus susceptible to TAB and ZAB. These data provide proof-of-concept that selected multidrug-resistant PWH may be candidates for future trials investigating bNAbs-containing regimens to achieve or maintain virologic suppression.

cytometry. For comparison, we included a control group of 27 ART-naïve viremic PLWH. We determined the sensitivity of infectious viral isolates obtained from the participants against 8 bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and 2 anti-CD4 antibodies (ibalizumab and anti-domain 1 CD4 antibody UB-421) using a TZM-bl-based neutralization/ suppression assay. Results: There was no significant difference in plasma viremia between the study participants with MDR HIV and the control group (P=0.2929). However, the CD4+ T cell counts of the MDR HIV group were significantly lower than those of the control group (P<0.0001). The level of intact HIV proviral DNA was comparable between the two groups (P=0.5895). Levels of activation and exhaustion markers PD-1 (P=0.0019), TIGIT (P=0.0222), 2B4 (P=0.0015), CD160 (P=0.0015), and CD38+/HLA-DR+ (P=0.0138) were significantly lower in the CD8+ T cells of the MDR HIV group. The infectious viral isolates from each study participant with MDR HIV were resistant (IC 80 >10µg/ml or % suppression <80.7%) to at least 2 bNAbs (average 4 bNAbs per participant); however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of study participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to the antibody. Notably, none of the 93 infectious viral isolates obtained from the study participants were resistant to UB-421. Conclusion: The data from our study has direct clinical implications. Our data suggest that the therapeutic options for heavily treatment-experienced PLWH with MDR viruses could be potentially expanded to include HIV-specific bNAbs and UB-421, an avenue that has not been explored until now.

Poster Abstracts

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Studying Dual Role of Glycosylation in Resistance to Broadly Neutralizing Antibodies In Vitro Teresa Murphy , Rebecca Lynch, Gabe Galeotos George Washington University, Washington, DC, USA Background: Broadly neutralizing antibodies (bNAbs) provide a useful tool for HIV cure strategies because of their ability to target conserved regions on the envelope (Env) protein in the context of both virions and infected cells. One of the most well studied bNAbs is the CD4 binding site (CD4bs) antibody, VRC01 and related antibodies. Multiple clinical trials infusing VRC01 into people living with HIV (PWH) demonstrated transient viral suppression. The major obstacle to more effective treatment with bNAbs continues to be viral escape. A deeper understanding of escape pathways from VRC01-class antibodies in genetically diverse samples is needed Methods: We developed an in vitro viral escape assay to test bNAb and Env combinations. Ex vivo CD4+ T cells were infected with infectious molecular clone 246.F3-NL4.3 (AC) in the presence of varying concentrations of VRC01. Cultures were maintained with suboptimal concentrations of bNAbs to induce escape. Replication kinetics were monitored by p24 every 3 days. Every 14 days, target cells were replenished and cultures tested for genotypic and phenotypic measures of bNAb resistance. This was accomplished by single genome sequencing envs and by TZM-bl neutralization assay. Individual mutations were then tested for their contribution to resistance to CD4bs bNAbs by pseudovirus neutralization assay using mutated env plasmids. Results: Using our viral escape assay, we observed both previously published and novel escape mutations. Complete resistance to VRC01 was detected in 246. F3 by day 45. A mutation at position N276 that eliminated the glycan conferred complete resistance to VRC01, despite canonically increasing sensitivity. To study the neutralization profile of this mutation in various subtypes, it was inserted into 12-virus global panel of envs and tested for sensitivity compared to wildtype against a panel of CD4bs bNAbs. This mutation was shown to both increase resistance or sensitivity depending on the envelope and bNAb in question, emphasizing a dual role of this glycan in VRC01 class neutralization. Conclusion: Our data demonstrate that our viral escape assay can highlight novel pathways, such as the loss of glycan 276 conferring complete resistance to VRC01 in 246.F3 env. The role of this glycan in escape was demonstrated to be dependent on both the context of the env as well as the bNAb. This finding emphasizes the importance of studying viral escape with a genetically diverse library to develop a deeper understanding of various pathways.

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Teropavimab and Zinlirvimab Sensitivity in People Living With MDR HIV-1: PRESTIGIO Registry Data Vincenzo Spagnuolo 1 , Laura Galli 1 , Aiyappa Parvangada 2 , Keith J. Dunn 2 , Filippo Lagi 3 , Roberta Gagliardini 4 , L. Sarmati 5 , Annamaria Cattelan 6 , Andrea Giacomelli 7 , Maria Mercedes Santoro 5 , Maurizio Zazzi 8 , Christian Callebaut 2 , Antonella Castagna 9 , Laurie VanderVeen 2 1 San Raffaele Scientific Institute, Milan, Italy, 2 Gilead Sciences, Inc, Foster City, CA, USA, 3 Azienda Ospedaliero Universitaria Careggi, Firenze, Italy, 4 Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, 5 University of Rome Tor Vergata, Rome, Italy, 6 University of Padova, Padova, Italy, 7 Luigi Sacco University Hospital, Milan, Italy, 8 University of Siena, Siena, Italy, 9 San Raffaele Vita-Salute University, Milan, Italy Background: Broadly neutralizing antibodies (bNAbs) are being investigated as long-acting antiviral therapies, but sensitivity to bNAbs in persons with multidrug-resistant HIV is unknown. Here, we characterized sensitivity to teropavimab (GS-5423; 3BNC117-LS; TAB) and zinlirvimab (GS-2872; 10-1074-LS; ZAB) in people living with 4-class drug-resistant HIV (4DR-PWH). Methods: Multicenter, observational study using plasma or peripheral blood mononuclear cells collected from 50 4DR-PWH (25 with HIV-1 RNA > 1000 copies/mL matched by age, sex, nadir CD4+ and years on ART to 25 virologically suppressed [HIV-1 RNA < 50 copies/mL]) enrolled in the PRESTIGIO Registry (NCT04098315) with a documented 4DR (NRTI, NNRTI, PI and INSTI). Phenotypic sensitivity to bNAbs was determined using the PhenoSense Monoclonal Antibody assay (Monogram), with susceptibility defined as IC 90 ≤2 µg/mL. Descriptive statistics are used to present results. Spearman's rank test used for associations between phenotypic susceptibility and clinical variables. Results: Characteristics of included individuals with analyzed samples were indicative of extensive treatment history (Table1). Of 46/50 (92%) participants with PhenoSense mAb assay results, 35 (76%) were phenotypically sensitive to TAB, 23 (50%) to ZAB, and 19 (41%) to both bNAbs; 7 (15%) had phenotypic resistance to both bNAbs. Of 22 viremic participants, 19 (86%)

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