CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

494

Loss of Virological Control 32 Years After HIV-1 Diagnosis in an Exceptional Elite Controller Sara Frances 1 , Anna Pons-Grífols 2 , Carmen Gasca Capote 3 , Virginia Sandonís 1 , Edwards Pradenas 2 , Cristina Moral-Turón 3 , Ester Aparicio 2 , Mar Vera 4 , Jorge Del Romero 5 , Benjamin Trinité 2 , Ezequiel Ruiz-Mateos 3 , Julià Blanco 2 , María Pernas 1 , Concepción Casado 1 1 Instituto de Salud Carlos III, Madrid, Spain, 2 IrsiCaixa, Badalona, Spain, 3 Instituto Biomedicina de Sevilla, Sevilla, Spain, 4 Centro Sanitario Sandoval, Madrid, Spain, 5 Centro Sandoval, Madrid, Spain Background: HIV-1 Exceptional Elite Controllers (EEC) maintain undetectable viremia and halt disease progression more than 20 years after infection in the absence of treatment and may be considered as functionally cured. However, loss of control in these individuals is unknown. In this study we performed a detailed, longitudinal characterisation of the HIV-1 reservoir, viral evolution and immune (B- and T-cell) response in an EEC that unexpectedly lost viral control 32 years after diagnosis. Methods: The participant was HIV-1-diagnosed in 1985 and was clinically followed since 1990. A comprehensive virological and immunological study was performed on longitudinal available samples (n=16) between 19 and 37 years after diagnosis (Figure 1). We assessed reservoir integrity by IPDA and single genome amplification; evolution and dynamics of viral quasispecies; infectivity and fusogenicity of isolated Env clones; autologous neutralizing capacity and HIV-1-specific cellular immune response. Results: This EEC (HLA: B39:01/B44:02 and heterozygous CCR5Δ32) had undetectable viral load (VL) for 31 years since diagnosis, except for four transient episodes ≤150 copies/mL. In December 2016, the EEC lost viral control and started ART in October 2021. During the control period, the DNA reservoir was dominated by defective virus (>95%) mainly in the 5'LTR, and by a homogeneous viral quasispecies consisting predominantly of sequences highly similar to the most recent common ancestor (MRCA). For all Env clones analysed (n=9), genetic distance to MRCA was positively correlated with functionality, defined by both infectivity and fusogenicity. Autologous neutralisation against this dominant ancestral Env was observed in all samples analysed (before and after loss of control), as well as an HIV-1-specific Gag immune response. Despite this, extensive sampling during the control period identified evident fluctuations in reservoir size and integrity, viral populations and signs of quasispecies evolution (estimated by env divergence and sequence diversity). These fluctuations were also reflected in the immune response analysed. Conclusions: This large longitudinal characterisation of a case of loss of control after 32 years, suggests that persistent virological control is not necessarily associated with a steady-state scenario, but may be highly dynamic and involve both virological and immunological changes that will define the outcome of exceptional control. The figure, table, or graphic for this abstract has been removed. Effect of ART Start Time, ART Duration, and Elite Control on HIV Transcription Cordelia M. Isbell 1 , Julie Janssens 1 , Sun Jin Kim 1 , Sonia Bakkour Coco 2 , Rebecca Hoh 1 , Jennifer A. Nichols 3 , Xutao Deng 2 , Mars Stone 2 , Janet L. Huie 3 , Steven G. Deeks 1 , Michael P. Busch 2 , Steven Yukl 1 , Adam Wedrychowski 4 , for the RAVEN Study Group 1 University of California San Francisco, San Francisco, CA, USA, 2 Vitalant Research Institute, San Francisco, CA, USA, 3 Jan Biotech, Inc, Ithaca, NY, USA, 4 San Francisco VA Medical Center, San Francisco, CA, USA Background: It remains unclear how HIV transcription varies with timing of ART initiation, duration of ART, and elite controller status. Methods: To investigate these questions, we performed a blinded, cross sectional analysis of 98 PBMC samples from 36 Reservoir Assay Validation and Evaluation Network (RAVEN) program participants, including 4 ART-naïve elite controllers and 32 ART-suppressed participants with HIV (PWH) stratified by timing of ART start (16 early, 16 chronic) and duration of ART suppression (10 short, 8 intermediate, 14 long). Cell associated (CA) initiated (TAR), 5’-elongated (R-U5-pre-Gag), mid-elongated (Pol), distal (Nef), completed (PolyA), and multiply spliced (Tat-Rev) HIV-1 RNAs were measured by RT-ddPCR and normalized to cellular transcription and HIV DNA. Results: No differences were observed between the early and chronic treated PWH in CD4+ or CD8+T cell counts, HIV DNA, or plasma viral load (VL) on ART. Compared to early and chronic treated PWH, elite controllers tended to have higher CD8+T cell counts (P=0.0008 and 0.064, respectively), lower HIV

predicted a higher likelihood of achieving the PTC phenotype. Conversely, markers associated with a lower OR (p<0.05) for PTCs included IL-27 (OR=0.5), a cytokine promoting chronic inflammation; IL-17A/F (OR=0.4), which drives intestinal inflammation via Th17 activation; PD1 (OR=0.24), a contributor to immune exhaustion; and AGRP (OR=0.16), linked to metabolic stress. Conclusions: PTCs exhibit a distinct profile of host factors associated with balanced immune regulation and reduced metabolic stress. Future studies are warranted to investigate the mechanistic contributions of these factors to the PTC phenotype and to explore their predictive value in multi-marker models for accurate identification of potential PTCs. The figure, table, or graphic for this abstract has been removed. Population-Specific T-Cell Responses and Virologic Control After Analytical Treatment Interruption Shelly Karuna 1 , Pei-Chun Yu 1 , Doug Grove 1 , Jorge Gallardo Cartagena 2 , John MacRae Thays 3 , Fatima Laher 4 , Sufia Dadabhai 5 , Jorge Sanchez 3 , Catherine Orrell 6 , Myron Cohen 7 , M. Juliana McElrath 1 , Lawrence Corey 1 , Katharine Bar 8 , Allan Decamp 1 , Stephen C. De Rosa 1 , for the AMP ATI Africa and Peru Study Teams 1 Fred Hutchinson Cancer Center, Seattle, WA, USA, 2 Centro de Investigaciones Tecnológicas Biomédicas y Medioambientales, Lima, Peru, 3 Asociacion Civil Impacta Salud y Educacion, Lima, Peru, 4 Perinatal HIV Research Unit, Soweto, South Africa, 5 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 6 University of Cape Town, Cape Town, South Africa, 7 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 8 University of Pennsylvania, Philadelphia, PA, USA Background: Early ART initiation and broadly neutralizing anti-HIV antibodies (bnAbs) are associated with later ART-free HIV control more frequently in African women with clade C HIV compared to men with clade B HIV. T cells may mediate HIV control, but data among women are limited. We thus measured T cell responses in women and MSM+TG during analytical treatment interruption (ATI). Methods: Eligible participants had acquired HIV within ~8wks of receiving VRC01 bnAb or placebo in the AMP HIV prevention efficacy trials, initiated ART early, and were virally suppressed ≥1 year. ART was paused under intensive monitoring (ATI), then reinitiated for CD4<250, VL>1000 for 4wks without 0.5log decline, or participant/clinician request. We assessed HIV-specific T cell responses (IFN-γ and/or IL-2 expression) by intracellular cytokine staining after stimulation with peptide pools to all HIV proteins. We calculated total response as the sum across responses to each protein. Results: Eleven women in southern Africa and 17 MSM+TG in Peru stopped ART. Median time to confirmed VL>200 was 5.4 weeks (range 2.3-112) in women and 4.3 weeks (0.1-18) in MSM+TG. Maximum HIV-specific CD8+ & CD4+ T cell responses during ATI did not differ by VRC01 vs. placebo in either cohort, but in women, the increase in CD8+ from baseline was greater for Gag (10-fold; p=0.024) and Vif (4.6-fold; p=0.024) in those who received VRC01 in AMP. HIV-specific CD4+ responses were low (max <0.5%) compared to CD8+ responses (mainly 1-5%, max 15%) during ATI. Time to ART re-initiation did not correlate with CD8+ (Spearman r=0.5; p=0.18) or CD4+ (r=0.45; p=0.23) responses. Two of 11 women (18%; 95% CI 5.1-47.7%) maintained VL<200 off ART for ≥32 weeks (“controllers”); no MSM+TG (0/17; 95% CI 0.0-18.4%) exhibited control on ATI. Compared to non-controllers, both controllers had higher frequency CD8+ responses to Env (≥0.8% of CD8+ cells) & Pol (≥10%) and, for the VRC01-recipient controller, also to Gag (4%). Both controllers’ HIV-specific CD8+ responses preceded viral rebound; non-controllers’ CD8+ responses followed rebound. Both controllers & non-controllers had HLA alleles associated with protection (eg, B*14:02, B*44:03, B*58:01, DRB1*13-DQB1*06) &/or susceptibility (eg, B*58:02). Conclusions: Differences in CD8+ (but not CD4+) responses may partly explain why the proportion of controllers differs between Peruvian MSM+TG (0%) and African women (18%) in this post-AMP ATI. Study of T cell responses may identify biomarkers that predict control on ATI.

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Poster Abstracts

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CROI 2025 125