CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

543

Evaluation of a Bispecific Antibody Targeting NK Cells for the Elimination of HIV Reservoirs Nerea Sanchez Gaona 1 , David Perea 1 , Adrià Curran 2 , Joaquín Burgos 2 , Jordi Navarro 2 , Paula Suanzes 2 , Vicenç Falcó 2 , Enrique Martín Gayo 3 , Meritxell Genescà 1 , Jorge Carrillo 4 , María Buzón 1 1 Vall d'Hebron Research Institute, Barcelona, Spain, 2 Hospital Universitario de la Vall d’Hebron, Barcelona, Spain, 3 Universidad Autónoma de Madrid, Madrid, Spain, 4 IrsiCaixa Institute for AIDS Research, Badalona, Spain Background: "Shock and kill" strategies for HIV cure involve reactivating latent virus (i.e. using latency reversal agents), followed by immune-mediated clearance. HIV impairs NK function, hampering their ability to eliminate infected cells, highlighting the need for immunotherapies to enhance NK cytolytic activity against HIV. Methods: We designed a tetravalent bispecific antibody (Bi-Ab32/16), which targets the gp120 HIV protein (Ab A32) and CD16a. We assessed its functionality through ADCC and cytotoxicity assays (n=7). Killing of viral reactivated cells (n=4) and changes in the intact proviral DNA (n=5) were evaluated in CD4+ T cells from ART-treated PLWH. Preclinical evaluation was conducted in humanized mice expressing IL15 (NSG-Hu-IL15). HIV-infected mice received ART from 6 to 9 weeks post-infection (wpi) and were randomized (n=6 per group) to receive immunotherapy at 10 mg/kg (Bi-Ab32/16 or A32) from 8 to 10 wpi. Mice were euthanized at 11 and 13 wpi. Immune subsets and NK activation were assessed by flow cytometry. HIV RNA was quantified by RT-qPCR. Results: Bi-Ab32/16 enhanced NK activation, degranulation, and cytotoxicity against HIV-infected cells in vitro (p<0.05). Further, the EC 50 (0.01±0.003 µg/ ml) was 55-fold lower than the parental A32 Ab (0.55±2.5E-5 µg/ml). Following viral reactivation, Bi-Ab32/16 improved killing of HIV-infected cells (median reduction 55%, p<0.01), and mediated the clearance of cells harboring intact proviruses in 3/5 PLWH (median reduction 50.7%). HIV viral loads were detected at 3 wpi (10³-10⁵ copies/ml) in 24/34 animals. HIV-infected mice showed decreased CD4 counts and CD4/CD8 ratios (p<0.05), and increased frequencies of CD16+ NK (p<0.001), which were all normalized after ART initiation (p<0.001). Higher IFNg-expressing NK memory-like subsets were observed at 13 wpi with Bi-Ab32/16 compared to A32 and control groups (p<0.05). However, Bi-Ab32/16 reduced CD16+ NK counts (p<0.05) (Fig.1A), which was inversely associated with infection after ART interruption (p<0.05, r=-0.58). Furthermore, Bi-Ab32/16 animals had a shorter time to viral rebound versus A32 and control groups (p<0.05) (Fig.1B). Conclusion: Bi-Ab32/16 activates NK, enhances ADCC, and diminishes latent HIV infection after viral reactivation in samples from PLWH. However, persistent in vivo NK stimulation with Bi-Ab32/16 reduces CD16+ NK, negatively impacting HIV control. Cellular in vivo therapies involving NK preloaded with Bi-Ab32/16 might offer a promising strategy for HIV elimination.

544

Associations Between Nadir CD4 and Subsequent Immune Measures With Long-Term Cognitive Function Frank Palella 1 , Janeway Granche 2 , Douglas W. Kitch 2 , Katherine Tassiopoulos 2 , Susan L. Koletar 3 1 Northwestern University, Chicago, IL, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 The Ohio State University, Columbus, OH, USA Background: Relationships between immune measures and neurocognition in persons with HIV (PWH) on ART are unclear. Methods: We analyzed data, including nadir and current CD4 cells/μl (CD4), CD4%, and CD4:CD8 ratios, from virally suppressed PWH (HIV RNA <200 copies/ ml >75% of time since ART start) with >2 NPZ3 scores in ALLRT (ACTG 5001) and HAILO (ACTG 5322). We used longitudinal linear mixed models with fixed and random effects to assess associations between NPZ3 (measured ≥96 weeks post ART start, baseline) and immune measures. We adjusted models for age, sex, and race/ethnicity, with and without adjustment for HIV RNA (>200 vs ≤200 copies/ml), type and years of ART use, and HCV infection. Results: Among 885 PWH seen 1/1/2000-12/30/2021, median (Q1, Q3) age at ART start was 44 (39, 48) years, 81% were male, 50% were White, 29% Black, 21% Hispanic or other. CD4 nadir was 0-50 (22%), 51-200 (29%), 201-350 (33%), 351-500 (11%), 501+(5%). Baseline median CD4 was 486, CD4:CD8 0.66 and NPZ3 score -0.10 (Q1, Q3)(-0.70, 0.53). Higher nadir CD4 was associated with higher baseline NPZ3 but slower NPZ3 increase: PWH with nadir CD4 0-50 had mean NPZ3 increases of 0.067 per year (95% CL = (0.056, 0.077); PWH with nadir CD4>501 had smaller increases (0.030 fewer points) per year (95% CL=(-0.054, -0.007)). Adding any time-updated CD4 measure attenuated nadir CD4 associations with NPZ3, often rendering them non-significant. A standard deviation (1SD) (309 cells/µl) increase in maximum CD4 was associated with an increase in NPZ3 score of 0.034 (95% CL=-0.011, 0.080), and a reduction in NPZ3 score slope of -0.007 (-0.013, -0.002). A 1SD (10.4) increase in CD4% was associated with a 0.074 (0.034, 0.113) increase in NPZ3 score and a decrease of -0.009 (-0.015, -0.004) in NPZ3 slope. A 1SD (0.527) increase in CD4:CD8 ratio was associated with an increase in NPZ3 score 0.060 (0.020, 0.099) and reduction in NPZ3 score slope of -0.007 (-0.012, -0.001). When nadir and current CD4 were modeled together, their effects were not statistically significant. Effects were similar in fully-adjusted models; current CD4% and CD4:CD8 remained most strongly associated with current NPZ3 score and change over time; NPZ scores converged at 6-8 years after baseline for the lower 4 nadir CD4 groups. Conclusion: Lower nadir CD4 was associated with lower NPZ3 score at baseline but greater increases over time. Current CD4% and CD4:CD8, but not absolute CD4, had the strongest associations with current NPZ3 score and change over time.

Poster Abstracts

CROI 2024 146