CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

520

Vectored Delivery of Closer-to-Germline Antibodies Can Mediate Long-Term SHIV Suppression Jose Martinez-Navio 1 , Sebastian P. Fuchs 1 , Desiree E. Mendes 1 , Claudia Muniz 1 , Paula G. Mondragon 1 , Rachel Zabizhin 1 , Eva Rakasz 2 , Guangping Gao 3 , Jeffrey Lifson 4 , Ronald C. Desrosiers 1 1 University of Miami, Miami, FL, USA, 2 Wisconsin National Primate Research Center, Madison, WI, USA, 3 University of Massachusetts, Worcester, MA, USA, 4 AIDS and Cancer Virus Program, Frederick, MD, USA Background: Delivery of potent broadly neutralizing antibodies by recombinant adeno-associated virus (AAV) vectors can strongly and durably suppress ongoing viral replication after a single vector administration. We have successfully and durably suppressed viral replication in three SHIV-infected monkeys with this approach, including the "Miami monkey" with well over 7 years of plasma viremia below 15 copies/mL of SHIV RNA. However, the generation of anti-drug antibody responses (ADAs) against the AAV-delivered antibodies often limits the efficacy of this approach. Due to extensive affinity maturation, most potent broadly neutralizing antibodies exhibit unusually high levels of somatic hypermutation that can be seen as 'non-self' by the recipient's immune system. To overcome this important challenge, delivery of less extensively mutated (i.e., closer-to-germline) antibodies was evaluated. Methods: In a pilot experiment, four Indian-origin rhesus macaques were experimentally infected with SHIV-AD8. At week 14 post-infection, and with plasma viremias ranging from 5,100 to 130,000 copies/mL of SHIV RNA, all four monkeys received AAV vectors expressing anti-HIV antibodies DH270, PCIN63 and DH511. These antibodies are naturally closer-to-germline than those we had previously used. Results: Three of the four macaques showed high levels (20-320 µg/mL) of two AAV-delivered antibodies through 70 weeks of follow up measurements. Sustained viral load suppression was achieved in two of these three monkeys. Only transient effects on viral load levels were observed in the third monkey suggesting viral escape mutations; sequencing to confirm escape is currently in progress. The fourth monkey showed low levels of AAV-delivered antibodies due to ADAs and little or no virologic suppression. Conclusion: Our results indicate that potent broadly neutralizing antibodies which are closer-to-germline can mediate long-term virologic suppression following gene therapy with AAV vectors with potentially lower incidence of ADA responses, but also highlight the difficulties associated with achieving long-term, antibody-mediated suppression. Ruxolitinib-Mediated HIV-1 Reservoir Decay in A5336 Phase IIa Trial Monica D Reece , Vincent Marconi, Zhan Zhang, Susan P. Ribeiro, Rafick P. Sekaly, Deanna A. Kulpa, Christina Gavegnano Emory University, Atlanta, GA, USA Background: Ruxolitinib is FDA approved for myelofibrosis, polycythemia vera, atopic dermatitis and chronic graft-versus-host disease. We evaluated ruxolitinib's impact on the peripheral HIV-1 reservoir and key immunomodulatory events driving HIV-1 persistence in people with HIV-1 (PWH) in an AIDS Clinical Trial (ACTG) sponsored open-label randomized Phase 2a multi-site trial (n=60). Methods: Inclusion criteria: ≥18 age ≤75, background ART regimen (NNRTI or INSTI without cobicistat for ≥2 years), continuously virologically suppressed, CD4+ T-cell count >350 cells/mm 3 ; no significant medical condition besides HIV or hypertension. Participants were randomized to ruxolitinib 10 mg bid plus ART (n=40) or ART alone (n=20) from week 0 through 5. Both groups were observed through week 12. Cellular markers, integrated DNA, and IPDA were measured on peripheral blood from weeks 0, 5, and 12. A sequential series of Mann-Whitney U tests were performed to understand how biomarker changes across weeks impact reservoir decay. We evaluated 1) biomarkers within the ruxolitinib-treated (RUX) group which were altered from baseline, 2) which markers determined in round 1 were differential versus control (CNT) group, and 3) which of these were associated with participants who experienced reservoir growth or decay independent of treatment. Significance was further confirmed through Benjamini-Hochberg testing to minimize the false discovery rate (15%). Results: Integrated DNA and IPDA reservoir measurements were highly correlated to one another throughout trial. HIV-1 reservoir significantly decayed in the RUX group by week 12 versus CNT (p=0.0471). Cellular markers altered by ruxolitinib, possessing a different expression profile from CNT, and associated with reservoir decay were determined: pSTAT5+ monocytes in low baseline reservoir and total RUX groups at week 12, pSTAT3+ monocytes in low baseline

Conclusion: To our knowledge, this is the largest cohort-based transcriptomic study of host genetic predictors of the HIV reservoir. Further studies are needed to validate these findings, ideally with dedicated functional genomic and intracellular protein assays using longitudinal samples to demonstrate causality of these observed associations. Our findings add important clinical and immunologic data to the limited host genomic HIV reservoir studies to date.

519

Taming the Viral Reservoir Over 3 Decades of Advancements in HIV Treatment Irene González-Navarro 1 , Victor Urrea 1 , Cristina Gálvez 1 , Beatriz Mothe 1 , Lucía Bailón 2 , Maria Salgado 1 , Javier Martinez-Picado 1 1 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 2 Hospital Germans Trias i Pujol, Barcelona, Spain Background: Since the advent of antiretroviral therapy (ART), HIV clinical management has steadily improved, not only because of the availability of more potent and safer drugs, but also due to the recommendations for universal treatment at diagnosis, regardless of disease stage and CD4 count, and efforts to increase HIV diagnose at its earliest stage after HIV acquisition. However, little is known about the effects of such improvements on the establishment of the latent HIV reservoir. Here, we characterize a group of people with HIV (PWH) on ART to determine the influence of multiple factors on the HIV reservoir evolution. Methods: We analyzed the reservoir of 893 PWH treated and virologically suppressed for >3 years by measuring total HIV-DNA in PBMCs by ddPCR. Those with <50 HIV-DNA copies/10 6 PBMCs were classified as LoViReT. 40 demographic, clinical, virologic, and immunologic variables were collected to explore their association with the LoViReT status using the Random Forest machine learning algorithm, along with LOESS and logistic regression, or PCA. Results: 180 (20%) of the 893 PWH were classified as LoViReTs. Minimum CD4 count, maximum viremia during clinical follow-up, shorter time from ART initiation to viral suppression, and longer time on an integrase strand transfer inhibitor (INSTI)-based regimen predicted LoViReT status (classification error=30%). The multiple logistic regression model estimation of the effect of these parameters was: minimum CD4 count OR=1.52 (per 100 cells/μL), maximum viremia OR=0.73 (log 10 plasma HIV-RNA copies/mL), and time to suppression OR=0.59 (years). We further analyzed how those factors vary based on ART start date. We observed a decrease in total HIV-DNA and a greater percentage of LoViReTs when ART was started after 2007. Indeed, time from treatment to suppression changed from 1.7 years in 1998 to <4 months in 2020. Since INSTIs were introduced in 2007, we performed a sub-analysis of the effect of INSTI-based regimens on HIV proviral levels, noting that individuals initiating ART with INSTIs had lower reservoir levels (p=0.001) and shorter times to undetectable viremia (p=2.2x10 -16 ). Conclusion: ART guidelines constant improvement and the introduction of new generation drugs are related to the establishment of lower HIV reservoir levels in PWH and, therefore, to the increase in the LoViReT phenotype among the individuals examined, which could facilitate the future success of medical strategies aimed at achieving a functional cure.

Poster Abstracts

521

CROI 2024 138