CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Results: We included 11 ES (6 females, 5 males) and 15 LS (7 females, 8 males) with a median of 8 specimens per participant over a median of 17.3 years of VS. Median age at VS and duration of VS were 0.6 and 17.6 years for ES, and 2.7 and 16.5 years for LS. PBMCs were primarily collected from 5 to <15 years of VS. The median limit of detection for the IPDA with a median of 500,000 cells analyzed was 2 copies/million PBMCs. Total and intact proviruses were lower in ES compared to LS (Figure1). From 5 to <10 and 10 to <15 years of VS, median total HIV-1 DNA was 20.0 and 28.0 copies/million PBMCs in ES compared to 113.2 and 103.3 copies/million PBMCs in LS. Median intact HIV-1 DNA from 5 to <15 years of VS was undetectable in ES, and detectable at 6.3-6.4 copies/million PBMCs in LS. Median total HIV-1 DNA among ES females was lower from 5 to <10 years and higher from 10 to <15 years of VS compared to ES males. LS females had higher median total HIV-1 DNA from 5 to <15 years of VS compared to LS males. Median intact HIV-1 DNA was undetectable for both ES females and males. However, LS females had higher median intact HIV-1 DNA from 5 to <15 years of VS compared to LS males. Estimated mean slopes of total HIV-1 DNA from 5 to <15 years were similar by sex among ES but differed among LS: total HIV-1 DNA increased by 2.4% per year for females and decreased by 5.6% per year for males. Mean slopes of intact HIV-1 DNA for ES females, ES males, and LS males were uncertain due to a high percent of undetectable values, complicating comparisons by sex. Intact HIV-1 DNA decreased over VS for LS females. Conclusion: We observed HIV-1 reservoir size to be smaller by age 5 years with early VS maintained through young adulthood. Among LS youth, we identified sex differences in the reservoir size with relevance to ART-free remission.

Conclusion: The proviral landscape at birth of neonates with in utero HIV-1 and quantifiable HIV-1 DNA includes a mix of intact, defective, and hypermutated proviruses, indicating in utero HIV-1 replication. Intact proviruses share >99.8% sequence identity through Step 2. These findings suggest early formation of abundant intact HIV-1 DNA populations, which could establish reservoirs that pose challenges to HIV-1 remission. CMV Coinfection Drives T-Cell Differentiation but Not Reservoir Size Among Children With HIV Yves Fougère 1 , Jason Brophy 2 , Ari Bitnun 3 , Michael T. Hawkes 4 , Lindy Samson 3 , Mi-Suk Kang Dufour 1 , Christian Renaud 1 , Stanley Read 3 , Hinatea K. Dieumegard 1 , Madeleine Aby Diallo 1 , Jade Canape 1 , Soren Gantt 1 , Hugo Soudeyns 1 , Fatima Kakkar 1 1 Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada, 2 Children's Hospital of Eastern Ontario, Ottawa, Canada, 3 University of Toronto, Toronto, Canada, 4 University of Alberta, Edmonton, Canada Background: CMV co-infection is common among children living with HIV (CLWH), though its impact on HIV disease control is not clear. The objective of this study was to determine the impact of CMV co-infection on HIV reservoir size and T cell subset distribution among CLWH. Methods: CLWH followed in the prospective, multicenter Canadian EPIC4 cohort from 2014-2018 were included if they were on cART for ≥ 1 year with sustained viral suppression (SVS)). CMV serostatus (IgG) was determined using ArchitectTM CMIA assay. HIV-1 reservoir size was estimated by measuring total HIV-1 DNA by PCR in unsorted peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+T cells using a prostration analog stimulation assay. For 65 participants, CD4+ and CD8+ naïve-memory-effector T cell subsets were examined using flow cytometry. Results: Of 226 CLWH enrolled in EPIC4, 108 met sub-study inclusion criteria; of these, 82.4% were CMV+ at baseline. There were no significant differences in total HIV-1 DNA (median = 1.70 vs 1.71 log 10 HIV DNA copies per 106 cells) or inducible cell-free HIV-1 RNA (median = 0.79 vs 0.60 log 10 HIV RNA copies per 106 cells) between CMV+ and CMV- participants, both on univariate and multivariate analysis adjusting for age, age at treatment initiation, duration of SVS, and peak lifetime HIV viral load. However, while frequencies of total CD8+ T cells and CD8+ T central memory (TCM) cells were similar among CMV+ and CMV- children (39.7vs 31.8%, and 2.5 vs 2.9%, respectively), CMV+ children exhibited significantly lower frequencies of CD8+ T naïve (TN) cells (54.6 vs 70.9%, p = 0.003), and significantly higher frequencies of CD8+ T effector memory (TEM) cells (6.8 vs 4.6%, p = 0.047) and CD8+ T terminally differentiated effector (TEMRA) cells (19.5 vs 9.6%, p = 0.003). No differences in total, TN or TCM cell frequencies were observed in CD4+ T cells between CMV+ and CMV- participants, but CMV+ participants had a significantly higher frequency of CD4+ TEM cells (5.7 vs 3.7%, p = 0.005). This difference remained significant after adjustment for age, age at HIV treatment initiation, and age at HIV viral suppression. Conclusion: CMV co-infection was not significantly associated with HIV reservoir size in CLWH, but significantly affected the naïve-memory-effector profile of CD4+ and CD8+ T cells. These results suggest that CMV co-infection may alter the differentiation and maturation of CD4+ and CD8+ T cells in CLWH independent of achievement of SVS. Reservoir Size and Dynamics by Age at Virologic Suppression and Sex in Youth With Perinatal HIV-1 Priya R Khetan 1 , Wendy Yu 2 , Kunjal Patel 2 , Joseph Szewczyk 1 , Adit Dhummakupt 1 , Sandra Burchett 3 , Russell Van Dyke 4 , Deborah Persaud 1 , for the Pediatric HIV/AIDS Cohort Study (PHACS) 1 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Boston Children's Hospital, Boston, MA, USA, 4 Tulane University, New Orleans, LA, USA Background: Studies on HIV-1 reservoir size and dynamics in youth with perinatal HIV-1 with long-term viral suppression (VS) are limited. Methods: We identified longitudinal peripheral blood mononuclear cells (PBMC) specimens among youth with perinatal HIV-1 in the PHACS AMP study who were early-suppressed (ES) at <1 year of age or late-suppressed (LS) at 1-5 years of age and maintained VS. LS were matched to ES by age at last specimen, percent without viral blips, and sex. HIV-1 reservoir size was assessed with the Intact Proviral DNA assay (IPDA). Data were summarized by age at VS, sex, and duration of VS. HIV-1 DNA slopes over follow-up were estimated using linear mixed-effects models.

955

Poster Abstracts

957

Latency Reversal Effects of TLR7 Agonist and HDACi in Long-Standing Perinatal HIV-1 Infection Kristen E Kelly 1 , Adit Dhummakupt 1 , Joseph Szewczyk 1 , Weiqiang Zhou 2 , Hongkai Ji 2 , Ya Hui Chen 1 , Thuy Anderson 1 , Elise T. Ohene-Kyei 1 , Allison Agwu 1 , Deborah Persaud 1 1 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: Latency reversing agents (LRAs) such as TLR agonists and histone deacetylase inhibitors (HDACi) reactivate proviral latency in adults. We examined the LRA effects of the TLR7 agonist, GS-9670 singly and in combination with the HDACi, SAHA, in a cohort of children and young adults living with perinatal HIV-1 (CYALPH) to inform latency reversal strategies for this population. Methods: Peripheral blood mononuclear cells (PBMCs) and purified CD4 T cells from a cohort of 8 CYALPH, median age 17.0[IQR, 16.7-20.3] yrs, with median virologic suppression of 13.3[8.2-16.3] yrs were stimulated ex-vivo with GS-9620 singly and in combination with SAHA for 96 hrs. Concomitant stimulation with PHA/PMA/Ionomycin (PPI) and DMSO were performed to assess proviral reactivation under maximal T cell stimulation and vehicle control. Proviral reactivation was determined by multiply spliced HIV-1 RNA (msRUPM) with the Tat/Rev Limiting Dilution Assay. Total, intact and defective proviral HIV-1 DNA was quantified by multiplex ddPCR, cell-surface marker and histone acetylation expression by flow cytometry, culture supernatant for 9 cytokines with the MSD platform and p24 by SIMOA. Results: The median total HIV-1 DNA load was 262[IQR, 52-485.2] copies per million(cpm) CD4s; the 5 subtype B participants had 13[0-26.1] intact cpm, 4.96% of total HIV-1 DNA. PBMCs stimulated with GS-9620 plus SAHA showed reactivation in only 2 of 6 participants. In CD4 T cells, PPI stimulation increased msRUPM in 6[75%] participants to 13.2[7.7-20.4]; with DMSO, msRUPM was

956

CROI 2024 303