CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

11% (95% CI 4.9%, 24.9%), 7% (95% CI 5.3%, 8.4%) and 6% (95%CI 4.1%, 7.6%) respectively. Of the 993 women who had virologic rebound within 30 weeks and were off ART, 10% experienced grade 2 or higher sign/symptom or laboratory events (3% grade 3 and <1% grade 4). 12 women (1%) experienced any clinical event: 3 bacterial infections, 4 herpes zoster infections, 3 moderate weight loss, 1 fungal nail infection and 1 seborrheic dermatitis. Conclusion: In this large cohort of young, postpartumwomen with high CD4 cell counts, 6% of participants remained virally suppressed at 24 weeks. Serious adverse events during the first 30 weeks off ART were rare. These data suggest that short treatment interruptions in HIV-cure related studies can be done safely in young women with nadir CD4 counts above 350 cells/mm 3 . 338 A5340: BRIEF ATI DOES NOT ALTER THE SIZE OR COMPOSITION OF THE LATENT HIV-1 RESERVOIR Katharine J. Bar 1 , D. B. Salantes 1 , Yu Zheng 2 , Felicity Mampe 1 , Subul A. Beg 3 , Jun Lai 3 , Randall Tressler 4 , Richard A. Koup 5 , James A. Hoxie 1 , Mohamed Abdel- Mohsen 6 , Edgar T. Overton 7 , Robert Siliciano 3 , Janet Siliciano 3 , Pablo Tebas 1 1 University of Pennsylvania, Philadelphia, PA, USA, 2 Harvard University, Cambridge, MA, USA, 3 Johns Hopkins Hospital, Baltimore, MD, USA, 4 NIH, Bethesda, MD, USA, 5 Vaccine Research Center, NIAID, Bethesda, MD, USA, 6 Wistar Institute, Philadelphia, PA, USA, 7 University of Alabama at Birmingham, Birmingham, AL, USA Background: The effect of an analytical treatment interruption (ATI) on the latent reservoir remains unknown. We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI in A5340, a clinical trial investigating the effect of VRC01 during ATI. We also assessed the relatedness of viruses sampled pre-ATI and at rebound. Methods: We quantified total HIV-1 DNA and cell-associated RNA in CD4+T cells and replication competent virus by quantitative virus outgrowth assay (QVOA) in resting memory CD4+T cells from leukopharesis samples collected pre-ATI and 6 months post-ART resuppression in 9 participants. Single genome sequencing-derived gp160 env sequences from plasma virus obtained pre-ART, at first detectable rebound, and from pre- and post-ATI QVOA cultures were analyzed phylogenetically. Select envs were cloned and tested for VRC01 neutralization sensitivity. Results: Participants median ART duration prior to ATI was 4.7 years (range 3.6 to 14.5). The median duration of viremia during ATI was 5 weeks (range 4 to 6) and participants were suppressed on ART for a median of 34 weeks (range 23 to 44) prior to post-ATI sampling. Total DNA, cell-associated RNA, and infectious units per million cells by QVOA were not statistically different pre- and post-ATI (P>0.3, Wilcoxon signed rank test), with median log 10 change of 0.3 copies, 0.08 copies, and -0.05 infectious units per million cells, respectively. In each participant, pre- and post-ATI QVOA sequences fell within the pre-ART plasma phylogeny, but did not specifically align within rebound lineages. Expanded clones comprised 30% to 95% of participants’ reservoirs, with similar frequencies pre- and post-ATI. Thus, sequences showed no evidence for enrichment of rebound viruses post-trial and pre-trial QVOA viruses failed to predict the identity of rebound virus. Pre-ART, rebound and QVOA Envs for each participant had similar IC50s to VRC01. Conclusion: Quantitative and phylogenetic analyses suggest a brief ATI does not expand the latent reservoir. While clonal QVOA populations comprised a substantial fraction of replication competent peripheral latent virus, they did not rebound in vivo upon ATI despite similar VRC01 sensitivities. Results provide reassurance for participants of clinical trials employing ATI and highlight the challenge of accurately characterizing the full range of the replication competent latent reservoir that reactivates in vivo . 339 HIV RESERVOIR ESTABLISHMENT DURING HYPERACUTE CLADE C INFECTION Guinevere Q. Lee 1 , Kavidha Reddy 2 , Kevin Einkauf 1 , Kamini Gounder 2 , Krista Dong 1 , Bruce D. Walker 1 , Xu G. Yu 1 , Thumbi Ndungú 2 , Mathias Lichterfeld 3 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Africa Health Research Institute, Mtubatuba, South Africa, 3 Brigham and Women’s Hospital, Boston, MA, USA Background: Little is known about the establishment of HIV reservoir at the earliest stages of infection. Here, we analyzed clade C HIV-1 reservoir seeding in women identified with hyperacute infections in Durban, South Africa through twice-weekly screening of high-risk individuals. Methods: PBMC were available from two patients detected at Fiebig II: (1) peak viremia 2.6x10 6 HIV-1 RNA copies/mL, treated same day, (2) peak 7.7x10 5 ,

remained untreated, and two patients detected at Fiebig V: (3) peak 130, on-treatment for 7 days, (4) peak 5.7x10 7 , remained untreated. Longitudinal samples were available at 1, 6, and 12-month post-detection. Total PBMC DNA was extracted, diluted for single-template full-HIV-genome PCR, and Illumina deep-sequenced. “Intact” proviral genomes were defined as the absence of deleterious mutations (out-of-frame indels, premature stop codons, large deletions). Results: Immediately post-detection at study baseline, HIV reservoir sizes in patients at Fiebig II was lower than those at Fiebig V (0.8, 2.2 versus 3.4, 31.1 genome-intact HIV per million PBMC), and relative contribution of intact genomes to the total pool of HIV DNA were higher in Fiebig II than V (82%, 100% versus 14%, 35%, Figure1). Also at baseline, no APOBEC3G/3F-hypermutated HIV DNA was detected at Fiebig II, in contrast to 5% and 4% at V. In all four patients, HIV reservoir sizes decreased over a year by ~1-10 fold. Among all 87 genome-intact proviruses detected in all patients over one year, 87-100% of genetic variations were single-base substitutions distributed evenly across the viral genome, suggesting that single-base substitution errors during reverse transcription was the predominant driver leading to early reservoir diversity. This diversity increased over time in untreated patients (median pairwise single-base differences within-sample increased from 0 to 18 and 4 to 39) but decreased in treated patients (from 3 to undetectable, and from 3 to 6 to 0). Of interest, a genome-intact provirus that had a single-base substitution that translated into Y143H, an integrase inhibitor resistance associated mutation, was detected 1-month post-detection from patient 1, whose regimen contained raltegravir since day-zero, indicating early-seeding of a drug-resistant variant. Conclusion: Early HIV reservoirs in PBMC were small and had high levels of sequence homogeneity. Single-base substitutions were the major source of genetic diversity, and early treatment limited diversification.

Poster Abstracts

340 MOLECULAR PROFILE OF HIV-1 RESERVOIRS IN EARLY-TREATED INFANTS FROM BOTSWANA Pilar Garcia Broncano 1 , Kevin Einkauf 1 , Ce Gao 1 , Guinevere Q. Lee 1 , Kenneth Maswabi 2 , Gbolahan Ajibola 2 , Sikhulile Moyo 2 , Terence Mohammed 2 , Thabani Ncube 2 , Joseph Makhema 2 , Kathleen M. Powis 3 , Xu G. Yu 1 , Daniel R. Kuritzkes 4 , Roger L. Shapiro 5 , Mathias Lichterfeld 4 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 3 Massachusetts General Hospital, Boston, MA, USA, 4 Brigham and Women’s Hospital, Boston, MA, USA, 5 Harvard University, Boston, MA, USA Background: Latently HIV-1 infected CD4 T cells represent an extremely small, yet highly durable viral reservoir in infected adults, but the molecular structure and composition of proviral reservoirs in infants with neonatal HIV-1 infection remain unclear. Immediate initiation of antiretroviral therapy (ART) in HIV- infected infants enrolled in the Early Infant Treatment Study (EIT) in Botswana provides an opportunity to evaluate the evolution of HIV-1 reservoirs in the developing neonatal immune system.

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