CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusions: IR compensate for bioenergetic and immunological defects via accelerated mitochondrial biogenesis, preserving immune function. In contrast, INR show inadequate compensation, contributing to their distinct immunological profile. Strategies to enhance mitochondrial biogenesis or repair autophagy defects may improve immune function in INR, potentially converting them into IR. Effect of Delayed ART Initiation on Anti-CD4 Autoantibodies in ART-Naive People With HIV Brian P. Epling 1 , Andrea Lisco 1 , Shweta Mistry 2 , Birgit Grund 2 , Jason Baker 2 , Carlos Brites 3 , Julien Gras 4 , Sandy Pillay 5 , Blessing Uche 6 , Peter Burbelo 7 , Irini Sereti 1 , for the INSIGHT START Study Group 1 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 2 University of Minnesota, Minneapolis, MN, USA, 3 Federal University of Bahia, Salvador, Brazil, 4 Hôpital Saint-Louis, Paris, France, 5 Enhancing Care Foundation, Durban, South Africa, 6 Institute of Human Virology Nigeria, Abuja, Nigeria, 7 National Institute of Dental and Craniofacial Research, Bethesda, MD, USA Background: We previously identified autoantibodies to the CD4 molecule (anti-CD4 AAb) in antiretroviral therapy (ART)-naïve people with HIV (PWH) with CD4 counts <100 cells/ µ L by luciferase immunoprecipitation systems (LIPS). The influence of delayed ART initiation on these AAb and their impact on CD4 count after ART initiation is unclear. Methods: In the Strategic Timing of Antiretroviral Treatment (START) trial, ART naïve PWH with CD4>500 cells/ µ L were randomized to start ART immediately (immediate arm) or delay until CD4<350 cells/µL or development of AIDS (deferred arm). In a random subset of participants (pts), we measured anti-CD4 AAb at baseline and month 24 (M24) by LIPS, defining seropositivity (AAb+) as >25000 relative light units. We used logistic regression models to assess associations with baseline AAb+ and to compare treatment groups for AAb+ at M24. To assess the effect of AAb+ on CD4 recovery with ART use, we compared the mean change in CD4 count between baseline AAb+ vs AAb- pts within the immediate arm. Results: Baseline characteristics were similar between arms in the random subset of 1199 pts (600 imm., 599 def.); median age was 36 yrs, median CD4 count was 648 cells/µL. Across all pts at baseline, AAb+ was 41%. AAb+ was independently associated with global region and recent (≤6 months) HIV infection, but not with age, sex, CD4 count, or HIV RNA level ( Figure 1 ). By M24, all pts in the immediate and 33% in the deferred arms had started ART. Among all pts, AAb+ decreased from 41% to 26% in the immediate and from 40% to 31% in the deferred arm (M24 OR (def/imm) 1.91, p<0.001). In pts who were AAb- at baseline, 0.3% (imm) and 4.4% (def) became AAb+ at M24. In the immediate arm, AAb+ decreased from 59% at baseline to 15% at M24 in those with recent HIV infection, versus from 40% to 27% in other pts (p<0.001 for difference). In the immediate arm, there was no difference in CD4 recovery from baseline to M24 between AAb+ and AAb- pts (mean increase of 203 vs 202 cells/ µL respectively). Conclusions: Among pts randomized to immediate ART initiation, anti-CD4 AAb+ was decreased at M24 compared to deferred ART, but AAb+ at baseline was not associated with the rate of CD4 recovery with ART. With immediate ART, AAb+ reverted to negative more commonly in those with recent HIV infection compared to those with longer duration of untreated HIV. These findings indicate that early ART initiation results in reductions in anti-CD4 AAb+, but their pathogenic role in this population remains uncertain.

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CD4-Binding Site Abs Modify the Negative Association Between Cluster A Abs and CD4 Count in PWH Mehdi Benlarbi 1 , Jonathan Richard 2 , Tommaso Clemente 3 , William D. Tolbert 4 , Marc Messier-Peet 1 , Marzena Pazgier 4 , Frank Maldarelli 5 , Antonella Castagna 3 , Madeleine Durand 2 , Andrés Finzi 2 1 Université de Montréal, Montreal, Canada, 2 Centre de Recherche du CHUM, Montreal, Canada, 3 IRCCS San Raffaele Scientific Institute, Milan, Italy, 4 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 5 National Institutes of Health, Bethesda, MD, USA Background: Chronic inflammation and immune dysfunction persist in some people with HIV (PWH), even during antiretroviral therapy (ART). We previously observed that HIV-1 soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies (Abs) are associated with chronic inflammation and immune dysfunction in aviremic participants of the Canadian HIV and Aging cohort. Here, we evaluated whether antibodies targeting the CD4 binding site of gp120 (CD4BS) could prevent CD4 depletion in vitro, and how their presence in the plasma of PWH could affect the negative association between anti-cluster A Abs and CD4 cell counts. Methods: We first evaluated the capacity of CD4BS Abs or plasma from PWH to prevent CD4 depletion in vitro. We next performed a cross-sectional assessment of anti-cluster A Abs and anti-CD4BS Abs in three independent cohorts of PWH. We used generalized least squares linear regression models with random effects (considering clustering within cohorts) to estimate the association between anti-cluster A Abs and CD4 counts. Next, we assessed how this association was affected by the presence or the absence of anti-CD4BS Abs by adding an interaction term to the model. Results: In vitro, we observed that CD4BS Abs blocked the coating of uninfected bystander CD4+ T cell by sgp120 and their elimination by ADCC mediated by plasma from PWH (p<0.0001). Plasma from participants with anti-CD4BS Abs also decreased the coating of CD4+ T cells with sgp120 (p=0.0089) and prevented their ADCC-mediated elimination (p=0.0001). We included 520 participants from three independent cohorts for measurements of anti-cluster A Abs and anti-CD4BS Abs. The mean age of participants was 56, 87% were males, and the median duration of HIV infection was 20.7 years. ~16% of PWH (82/520) had detectable levels of anti-CD4BS Abs. In the total study population, anti cluster A Abs were inversely associated with CD4 cell counts (beta; -18.32 95%CI -32.85 to -3.79, p=0.013). The strength of this association was increased in those without anti-CD4bs Abs (beta; -26.74 95%CI -42.52 to -10.96, p=0.001). This association was not present in PWH with anti-CD4BS Abs (beta; 19.77 95%CI -19.42 to 58.95, p-value for interaction 0.02). Conclusions: Our results suggest that sgp120-mediated immune dysfunction is associated with its capacity to interact with CD4, and that anti-CD4BS Abs negate this capacity, which could lead to novel therapeutic approaches to tackle residual immune dysfunction in PWH. Prevalence and Activity of Anti-Interferon Auto-Antibodies in People Living With HIV Olivia Payne 1 , Andrey Brodskiy 1 , Orest Idilli 1 , Sarah Griffith 1 , Laura McCoy 1 , Marc Lipman 1 , James Brown 2 , Dimitra Peppa 1 , Doug Fink 1 1 University College London, London, UK, 2 Royal Free Hospital, London, UK Background: The interferon (IFN) cytokine family, encompassing subtypes 1-3, is fundamental to control of HIV replication. Anti-IFN auto-antibodies (auto-Abs) have emerged as key determinants of severe acute viral infection but data are limited in chronic virus infections. A single cohort study of people living with HIV (PLWH) has reported anti-Type 1 IFN (T1IFN) auto-Ab prevalence only without characterisation of auto-Ab function. We undertook the first multi centre seroprevalence study of auto-Abs against all three IFN-types in PLWH, testing neutralisation and associations with clinical outcomes. Methods: We conducted a longitudinal observational study using cryopreserved serum samples from two London clinical cohorts (Mortimer Market Centre and Royal Free Hospital). Serum, demographic and HIV-related clinical data were collected from HIV- control (n=75) and from PLWH (n=177) groups. Auto-Ab levels were measured using published GyroLab immunoassay against T1 (IFNα, IFNω), T2 (IFNγ), and T3 (IFNλ1) IFNs. Assay positivity cut-off defined as 2*S.D.+ mean of the control group. IFN neutralisation was tested by HEK293 cell IFN bioassay. Results graphed and analysed in Prism v10.3.1 using Spearman correlation and Mann-Whitney test. Results: Age was comparable between controls (51 years, IQR43-57) and PLWH (50 years, IQR44-54). 52% control donors were male, compared to 85.7% PLWH. Overall, 4.0-5.3% of the control group had detectable auto-Abs across T1-3 IFNs,

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Poster Abstracts

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CROI 2025