CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) treatment on intact and defective proviral HIV-1 DNA in people with PHI. Methods: Multicenter, single-arm clinical trial in confirmed PHI individuals (<3 months) starting BIC/FTC/TAF. Reservoir was quantified at baseline (w0) and 48 weeks (w48) after ART initiation. Intact Proviral DNA Assay was used to measure intact and defective HIV-1 proviral DNA in patients’ CD4+ T cells. Fiebig stages were categorized in 2 groups, II-IV and V-VI, respectively. Changes over time in DNA reservoir and comparisons between baseline characteristics were estimated using a mixed-effects linear regression model considering as covariates calendar visit (w0 and w48), Fiebig stage, baseline HIV-1 RNA viral load (VL), subtype (B/non-B) and the interaction between visit and each of the other three variables, and with random effects at participant level. Results: 48/66 (73%) participants with paired samples were included, 92% male, median (IQR) 31.5 (26-41) y.o.; 88% MSM; 62% subtype B and median (IQR) VL was 503500 (155000-1385000) cp/mL. At ART initiation, 13 patients were at Fiebig stages II-IV (27%) and 25 at V-VI (73%). Intact and defective proviral DNA significantly decreased (p<0.001) after 48 weeks of treatment in Fiebig II-IV (from 7376 to 95 and from 13497 to 157 cp/10 6 CD4+ T cells respectively) and in Fiebig V-VI (from 8899 to 458 and from 2119 to 233 cp/10 6 CD4+ T cells respectively) (figure 1). Decay between w0 and w48 was higher in Fiebig II-IV (98.71% in intact and 98.83% in defective viruses) than in Fiebig V-VI (94.86% in intact and 89.01% in defective viruses). Intact/defective ratio in Fiebig II-IV is lower than in Fiebig V-VI both in w0 (0.54 and 4.2 respectively) and in w48 (0.60 and 1.9 respectively). Total proviral DNA decrease was more pronounced in participants with higher VL at w0 (p=0.014), subtype B (p=0.049) and Fiebig stages II-IV (p=0.002); however, these differences were not statistically significant for intact proviral DNA. Conclusions: Reservoir, including intact DNA, significantly decreases at w48, after controlling for Fiebig stage, viral subtype or baseline VL. Starting ART at Fiebig II-IV results in a more pronounced reservoir decay and a lower intact/ defective ratio at both timepoints than at Fiebig V-VI.

DNA in peripheral CD4+ T cells by ddPCR. The inducible reservoir was measured by the VIP-SPOT assay. Reservoir decay was fitted to 2-phase biexponential decay dynamics using nonlinear mixed effects models. Results: By the first week after ART initiation viral load had decreased by 2 logs, and beyond week 12, all participants remained virally suppressed except for a single blip in one individual. Over the first year on ART, both total and intact proviruses exhibited a similar overall decrease, representing the 81.6% and 83.7% reduction from the initial pool, respectively. This contrasts with the massive depletion of 96.6% of cells containing inducible proviruses. Furthermore, the half-life of the inducible reservoir after ART initiation was 2.6 days (95%CI=2.2-3.1 days), while the decay of the proviral reservoir was much slower, with a half-life of 5.1 weeks (95%CI=4.2-6.6). Conclusions: Our findings demonstrate a rapid and specific clearance of cells harboring inducible proviruses within the first days after ART initiation. During this period, the interplay of opposing factors such as the expansion of CD4+ T cells and the restoration of host immune status collectively influences the composition of the long-lived HIV-1 reservoir. These findings support the idea that interventions focused on enhancing CTL responses or modulating viral latency may yield more significant benefits if implemented during this specific timeframe or just before ART initiation. HIV Proviral Populations Differ by Sex and Immune Activation Levels During Antiretroviral Therapy Chuen-Yen Lau 1 , Thuy Nguyen 2 , Matthew A. Adan 1 , Jessica Earhart 1 , Danielle Konlian 1 , Lindsey Adams 1 , Mary Zipparo 1 , Jeanette Higgins 1 , Catherine Rehm 1 , Robert Gorelick 3 , Brian Luke 3 , Frank Maldarelli 1 1 National Institutes of Health, Bethesda, MD, USA, 2 National Cancer Institute at Frederick, Frederick, MD, USA, 3 Frederick National Laboratory for Cancer Research, Frederick, MD, USA Background: Understanding mechanisms driving persistence and clonal expansion of HIV infected cells during antiretroviral therapy (ART) is critical to control of HIV. Most infected cells contain proviruses that are defective for replication, but can express RNA and HIV proteins, including Gag, that may contribute to pathogenesis on ART. Roles of sex, age, and immune status in persistence, and expression of HIV proviral populations during ART are not well understood. To investigate determinants of persistence and expression of HIV proviruses, we analyzed levels of total and gag -deleted proviruses and their RNA expression in the context of clinical and immune parameters in male and female persons with HIV (PWH) undergoing long-term ART. Methods: Clinical information and peripheral blood mononuclear cells (PBMC) were obtained from PWH undergoing ART with HIV RNA <50 c/ml for >3 years (y) in protocols at NIH Clinical Center, Walter Reed, and Womens Interagency HIV Study. Cell-associated HIV LTR and gag RNA and DNA were measured by multiplexed droplet digital PCR, and >20 lymphocyte subsets and activation markers measured by FACS. Univariable analyses were used to select clinical, immunologic, and virologic variables for multivariable modeling of drivers of HIV DNA and RNA levels. Multivariable models were identified based on Bonferroni corrected Pearson p-values and significance. Results: Among 103 PWH, the median age was 50 (range 27-80) y, 37% were female, median CD4 was 674 (range 250-1765) cells/µl, and median ART duration was 14.5 (3-31) y. Total levels of HIV proviruses were not significantly different in males and females, but females had a higher proportion of gag deleted proviruses (p=0.017). HIV gag expression ( gag RNA/ gag DNA levels were >3-fold higher in females (p=0.0004). In males, age positively correlated with total provirus levels, but negatively with total and gag RNA. CD16+CD56+ NK cells positively correlated with levels of LTR and gag RNA per provirus. Regression identified levels of CD8Ro+ cells as strong correlates of levels of proviruses in males and females; roles of other factors (age, NK cells, CD8DR+) in HIV LTR and gag RNA expression were more complex in men and women. Conclusions: Levels of HIV proviruses and CD8 memory cells correlate in all PWH, but relative contributions of other immune and demographic charateristics to HIV persistence and expression in males and females are complex. Sex and age are important considerations for HIV eradication and control strategies.

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Poster Abstracts

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Rapid Clearance of the Inducible HIV-1 Reservoir After Initiation of Antiretroviral Therapy Maria C. Puertas 1 , Lucía Bailón 2 , Victor Urrea 1 , Maria C. Garcia-Guerrero 1 , Yovaninna Alarcón-Soto 3 , Angel Rivero 2 , Beatriz Mothe 3 , José Moltó 2 , Javier Martinez-Pìcado 1 , for the DUALITY Study Group 1 IrsiCaixa, Badalona, Spain, 2 Fundació Lluita contra les Infeccions, Barcelona, Spain, 3 Fundació Lluita contra la SIDA, Badalona, Spain Background: Despite the cumulative expansion of the viral reservoir during untreated HIV-1 infection, it has been recently observed that the intact variants dated close to time of ART initiation predominate in the replicative-competent reservoir. This observation indicates that there is a critical window period immediately following ART initiation that significantly shapes the composition of the proviral reservoir. Still, deeper understanding of the dynamics of the latent reservoir and the factors modulating its composition is needed. Methods: In this prospective study, we evaluated the decay dynamics of the different compartments of the HIV-1 reservoir in a group of 40 ART-naive individuals initiating dolutegravir-based regimens as part of the DUALITY study (Eudra-CT number 2019-002733-10). All participants were male, with most identifying as men who have sex with men (88.6%), and the median age was 31 years [IQR=23-35]. After starting ART, blood sampling was performed at baseline, at weeks 1, 2 and 4, and at months 3, 6 and 12. We quantified proviral

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