CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: 2109 HIV-uninfected MSM and transgender women in Lima, Peru were followed for 2 years with monthly HIV testing by serology and RNA. Participants diagnosed with acute (HIV RNA+/ seronegative) or recent (seropositive with a negative test within 3 months) HIV infection were enrolled and followed for up to 10 years with frequent specimen collection. The time of HIV acquisition (estimated date of detectable infection [EDDI]) was estimated using a published algorithm based on the timing, results, and uncertainty windows of all HIV tests. We measured the ability of plasma samples from 12 participants, who initiated ART at 24 weeks after diagnosis, to mediate elimination of HIV-1 infected cells by ADCC in the absence and presence of the potent indoline CJF-III-288 CD4mc using a FACS-based ADCC assay. Finally, we analyzed the specificity of CD4-induced (CD4i) nnAbs present in these samples by ELISA. Results: Longitudinal plasma samples, before acquisition, at diagnosis and at multiple time points up to 86 weeks after EDDI were examined. We found that plasma samples collected as early as 3 to 5 weeks after EDDI can mediate ADCC in presence of the CJF-III-288 CD4mc. Recognition HIV-1-infected cells and ADCC progressively increased over time, reaching a plateau by 14-29 weeks after EDDI. ADCC activity increased concomitantly with the elicitation of anti-gp120 CD4i Abs and improved over time with the appearance of anti-gp41 cluster I Abs. Conclusions: Our results show that CD4i nnAbs able to eliminate HIV-1-infected cells are elicited within a few weeks after HIV acquisition and suggest that CD4mc might be used as an early intervention with potential utility to decrease HIV reservoir seeding and reduce reservoir size. Sustained Post-Rebound HIV Remission With Enhanced T-Cell Immunity After LS-bNAbs: A Case Report John Frater 1 , Julie Fox 2 , Ming J. Lee 1 , Mohammed Altaf 1 , Marcilio Jorge Fumagalli 3 , Anna Kaczynska 3 , Timothy Tipoe 1 , Penny Zacharopoulou 1 , Carla Nel 1 , Louise Terry 4 , Mathias Lichterfeld 5 , Daniel Bradshaw 6 , Marina Caskey 3 , Michel Nussenzweig 3 , Sarah Fidler 7 , for the RIO Trial Investigators 1 University of Oxford, Oxford, UK, 2 King's College London, London, UK, 3 The Rockefeller University, New York, NY, USA, 4 Guy's and St Thomas' NHS Foundation Trust, London, UK, 5 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 6 Public Health England, London, UK, 7 Imperial College London, London, UK Background: Non-human primate (NHP) models of HIV cure using HIV-specific broadly neutralising antibodies (bNAbs) describe viral control after an initial period of rebound, attributable to HIV-specific T cell responses – a ‘vaccinal effect’. There are examples of viral control after bNAbs in human studies, but no cases of post-bNAb viral rebound followed by sustained suppression, which may indicate new immunity. Methods: We report a 38-yr old male participant enrolled in the RIO trial. At HIV seroconversion in 2017 he had an initial HIV VL of 55,338 copies/ml before commencing ART 18 days later. Virally suppressed on ART until enrolling into RIO in 2021, he received a placebo infusion and stopped ART; his HIV VL rebounded 4 weeks later (peak 6225 copies/ml). He then received one dose of dual bNAbs (10-1074LS; 3BNC117LS) and ART for 6 months. ART was then stopped again 24 weeks later for a second TI. HIV VL rebounded within 5 weeks and viraemia was sustained for 20 weeks (peak 1893 copies/ml). He then spontaneously controlled (<20 copies/ml) and has maintained aviraemia for 80 weeks since (Figure). During this period bNAb PK levels were both <10ug/ml and ART agents were undetectable in plasma. We present HIV reservoir measures (Q4PCR), HIV Env sequencing and T cell responses measured by ELISPOT, proliferation, AIM and CBA to explore the mechanisms of remission. Results: The participant showed relative sensitivity to 10-1074 at baseline (4/22 resistant SGA Env sequences; IC80s 0.31-2.2ug/ml) and rebounded during the 2nd TI with 100% resistant sequences (IC80s >50ug/ml) after bNAbs. He developed new T cell responses to a sub-dominant C*07:01 epitope in Nef (KRQDILDLWVY) and a dominant likely B42:01-restricted epitope in Gag p24 (GPAHKARVL) which peaked 37 weeks after TI (400 spots/10 6 ), but then waned. Control was associated with increased Gag-specific CD8 T cell proliferation (4.5% at peak vs 0.8% at baseline), Gag-specific CD4 AIM responses (0.4% at peak vs 0% at baseline) and Granzyme B, IL-2 and TNFa by CBA after Gag stimulation. We detected no autologous antibody neutralisation prior to bNAbs. Reservoir size decreased from 2.1 to 0.58 intact proviral DNA copies/million CD4 T cells at baseline versus 37 weeks post-2nd TI (Q4PCR). We will report analyses of integration sites, serology and viral outgrowth.

Conclusions: This is the first reported example of remission following a period of rebound after bNAb dosing and non-therapeutic bNAb levels, consistent with the vaccinal effect seen in NHP studies.

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Sustained T-Cell Mediated Immunity After LS-bNAbs in the RIO Trial: A Vaccinal Effect Mohammed Altaf 1 , Timothy Tipoe 1 , Carla Nel 1 , Helen Brown 1 , Nicola Robinson 1 , Simon Collins 2 , Ming J. Lee 3 , Penny Zacharopoulou 1 , Louise-Rae Cherrill 3 , Emanuela Falaschetti 3 , Michel Nussenzweig 4 , Marina Caskey 4 , Sarah Fidler 4 , John Frater 3 , for the RIO Trial Investigators 1 University of Oxford, Oxford, UK, 2 HIV i-Base, London, UK, 3 Imperial College London, London, UK, 4 The Rockefeller University, New York, NY, USA Background: T cell immunity may explain sustained viral control off ART after bNAbs in non-human primates, but evidence from human trials is limited. Proof of a bNAb-induced ‘vaccinal effect’ requires evidence of both enhanced HIV-specific immunity and associated viral control. The RIO trial facilitated analysis of participants receiving two LS-bNAbs (10-1074 & 3BNC117) followed by analytical treatment interruption (ATI). Methods: 68 participants (on ART within 3/12 of primary HIV) were randomised 1:1 to receive two LS-bNAbs (Arm A) or placebo (Arm B) and ATI. T cell immunity was measured by gamma-interferon ELISPOT with HIV full genome 15-mer overlapping peptides, proliferation (Cell Trace Violet) and Activation Induced Marker (AIM) assays (CD25, OX40, 41BB, CD69), the latter two using pooled peptides (Gag, Pol, Env, Nef). 32 Arm A participants were assayed at pre-bNAb baseline and then, if VL suppressed <200 RNA copies/ml, at 12 (n=25), 20-24 (n=18) and 36 (n=6) weeks after bNAb dosing. Assay data were compared using Wilcoxon matched-pairs signed rank analyses. Survival analyses split assay data at medians (log-rank test). Results: BNAbs resulted in viral control for at least 20 weeks in 65% of participants in Arm A. After bNAb dosing and ATI, proliferation of HIV Gag specific CD4+ and CD8+ T cells increased between Weeks 0 and 12 (2.4 vs 4.1%; P=0.006 and 8.5 vs 13.1%; P=0.008, respectively), sustained to Week 36 (P=0.03 for both). HIV Gag-specific AIM+ CD4+ T cells significantly increased between Weeks 0 and 12 (0.13 vs 0.21%; P=0.05). Gag ELISpot responses significantly increased from baseline (134 sfu/10 6 PBMCs) through Week 12 (210 sfu/10 6 PBMCs; P=0.006) to Week 24 (235 sfu/10 6 PBMCs; p=0.024). Gag responses were dominant, with only weak evidence for shifts in responses to other major HIV proteins (Pol, Nef, Env). 12 weeks after dosing, there was enrichment for CD8+ effector memory cells, and inflation of Th1 cells (P=0.01) with associated increases in expression of both Th1 HLA DR/CD38 (P=0.04) and memory CD4+ and CD8+ T betHi/EomesLo (P=0.04 and P=0.008, respectively). At time of submission, there was evidence for an association between baseline CD8+ T cell proliferation to Gag and viral control (HR 1.92; P=0.097), most marked in participants who remained suppressed >15 weeks after bNAb dosing (HR 3.72; P=0.004). Conclusions: In RIO, after dosing with two LS-bNAbs and an ATI, there was increased Gag-specific T cell immunity in aviraemic participants which was associated with viral control.

Poster Abstracts

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