CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Both groups experienced a significant increase in the level of intact HIV proviral DNA following ATI. After the re-initiation of ART (Post-ATI), the intact HIV DNA burden in the A/E group normalized to the baseline level (P=0.1245) by Week 24. However, in the Chronic group, the level of intact HIV DNA remained elevated at Post-ATI Week 24 and 52 (P=0.0069 and P=0.0042, respectively) compared to that of baseline. There was no difference in the residual plasma viremia between the baseline and Post-ATI Week 24 in the A/E group (P=0.1556). However, in the Chronic group, the level of residual plasma viremia was significantly higher at Post-ATI Week 24 compared to baseline (P=0.0181). There were significant increases in the levels of soluble PD-L1 (P=0.0066) and perforin (P=0.0094) from baseline to Post-ATI Week 24 in the Chronic but not in the A/E group. Conclusion: We conclude that ATI differentially affects the dynamics of the HIV reservoir, residual plasma viremia, and certain biomarkers following the re-initiation of ART in PLWH who initiated ART during the acute/early versus chronic phase of infection. Thus, delineating the underlying mechanisms by which the A/E group achieved faster normalization compared to the Chronic group of immunologic and virologic markers could be informative for the development of future therapies. Immune Responses and HIV Reservoir Evolution From Pre-ART to 5 Years Into Post-Treatment Control Leah Carrere 1 , Miriam Rosás-Umbert 2 , Benjamin Bone 1 , Giacomo S. Frattari 2 , Isabelle Roseto 1 , Xiaodong Lian 1 , Martin Tolstrup 2 , Ce Gao 1 , Mariane H. Schleimann 2 , Xu G. Yu 1 , Jesper D. Gunst 2 , Mathias Lichterfeld 1 , Ole S. Søgaard 2 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Aarhus University, Aarhus, Denmark Background: In the randomized-controlled eCLEAR study focusing on the administration of the broadly neutralizing antibody 3BNC117 at the time of ART initiation, one post-treatment controller was identified. He initiated ART and 3BNC117 during primary HIV-1 infection (plasma viral load of 188,945 copies/mL and CD4 counts of 470 cells/mm 3 ) and has had sustained virologic control for 5.3 years following ART interruption (ATI). However, immunological and virological mechanisms in this post-treatment controller are poorly understood. Methods: Viral reservoir cells were evaluated using quantitative in vitro viral outgrowth assays, duplex ddPCR (3dPCR), near full-genome proviral sequencing (FLIP-Seq) and matched integration site and proviral sequencing (MIP-Seq). Single cell transcriptome, surface protein and T-cell receptor profiling of 14,230 CD4 T cells were performed with the 10x platform. HIV-1-specific CD8 T cells were analyzed using the activation-induced marker (AIM) assay. Results: The person did not have any known protective HLA alleles and plasma samples repeatedly tested negative for antiretroviral drugs. Replication competent proviruses were detected during ATI at a frequency of 0.2-0.5 infectious units/ million CD4 T cells. Intact proviruses/million CD4 T cells declined during ATI. PreART intact proviruses were predominantly (85%) located in ordinary genic locations, although 2 clones of intact proviruses in ZNF genes on chromosome 19 were already observed at this time. During the ATI stage, two large clones of intact proviruses were observed, one integrated in the centromere region of chromosome 4, and one in the peri centromere region of chromosome Y; one single provirus integrated in the centromere region of chromosome 9 was also noted. A strong HIV-1-specific CD8 T response towards Gag was maintained during the ATI, whereas responses towards Pol, Nef and Env decreased. Single cell analysis showed widespread CD4 T cell activation during ATI compared to pre-ATI and upregulation of cytotoxic and antiviral markers (GZMA, CX3CR1, APOBEC3G) by a subset of highly clonally expanded Th1 CD4 T cells. Conclusion: Post-treatment control in this individual was associated with persistence of genome-intact HIV-1 proviruses that grew out under in vitro tissue culture assays but not under physiological in vivo conditions. This is possibly due to a strong immune-mediated selection of intact proviruses in heterochromatin locations that may have a weaker ability to drive rebound in vivo.

484

Common T-Cell Features Predicting Time to Rebound in Interventional and Non-Interventional Treatment Tongcui Ma 1 , Ashley F. George 1 , Reuben Thomas 1 , Min-Gyoung Shin 1 , Mauricio Montano 1 , Satish K. Pillai 2 , Katherine S. Pollard 1 , Rajesh T. Gandhi 3 , Jonathan Z. Li 4 , Davey M. Smith 5 , Steven G. Deeks 6 , Ole S. Søgaard 7 , Martin Tolstrup 7 , Warner C. Greene 1 , Nadia R. Roan 1 1 Gladstone Institutes, San Francisco, CA, USA, 2 Vitalant Research Institute, San Francisco, CA, USA, 3 Massachusetts General Hospital, Boston, MA, USA, 4 Brigham and Women's Hospital, Boston, MA, USA, 5 University of California San Diego, La Jolla, CA, USA, 6 University of California San Francisco, San Francisco, CA, USA, 7 Aarhus University Hospital, Aarhus, Denmark Background: Immunological features predicting time-to-rebound during analytical treatment interruption (ATI) may differ between cohorts, and be impacted by whether or not therapeutic interventions were used. Here, we used CyTOF to identify shared and unique pre-ATI features of T cells associated with time-to-rebound in the non-interventional ACTG A5345 cohort and 3 interventional Danish cohorts. Methods: A 40-parameter CyTOF T cell phenotyping panel was applied on pre-ATI blood specimens from 33 chronic-treated and 11 acute-treated individuals from the non-interventional ACTG A5345 cohort, and 3 chronic treated Danish cohorts receiving therapy prior to ATI: CLEAR (Panobinostat intervention, n=9), TEACH (TLR9 agonist intervention, n=9), and REDUC (therapeutic vaccination + romidepsin intervention, n=16). Clustering analysis was performed to identify T cell phenotypes associated with time-to-rebound upon ATI. Results: Using cluster-resolution optimization, nine and five clusters were identified from the A5345 and the 3 collective Danish cohorts, respectively. Cluster 9 from A5345 and Cluster 3 from TEACH were both significantly (p<0.01) positively associated with longer time-to-rebound. Cluster 9 consisted of memory T cells expressing high levels of the T resident memory (Trm) marker CD103, and high levels of the homeostatic proliferation marker CD127 and the Th17 marker CCR6. As Cluster 9 consisted of both CD4+ and CD8+ T cells, we split it into subclusters 9a (CD8+) and 9b (CD4+). Cluster 9a expressed high levels of the pro-survival factor BIRC5, and low levels of the integrin component CD29. By contrast, Cluster 9b expressed low levels of BIRC5 and high levels of the co-stimulatory molecule CD28. Cluster 3 from the Danish cohorts consisted of CD8+ T cells expressing high levels of BIRC5 and low levels of CD29. These cells also expressed high levels of CXCR4 and CCR7, suggesting homing to inflamed and lymphoid tissues. Our observation that CD8+ T cells from both A5345 Cluster 9a and Danish Cluster 3 expressed high levels of BIRC5 and low levels of CD29 suggest that phenotypic features predicting longer time-to-rebound can be shared among non-interventional and interventional ATI cohorts. Conclusion: CD8+ T cells expressing high levels of BIRC5 and low levels of CD29 predict longer time-to-rebound in both interventional and non-interventional ATI cohorts. These "pro-survival" CD8+ T cells may be better able to survive during the early post-ART period and thereby slow down viral rebound upon ATI. Dynamics of the Intact HIV Reservoir During ART Following Analytical Treatment Interruption Maegan R Manning , Jana Blazkova, Jesse S. Justement, Victoria Shi, Brooke D. Kennedy, M. A. Rai, Catherine A. Seamon, Kathleen R. Gittens, Michael C. Sneller, Susan Moir, Tae-Wook Chun National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Background: To assess efficacy, clinical trials evaluating therapeutic agents aimed at achieving HIV cure or sustained virologic remission require analytical treatment interruption (ATI). It has been shown that ATI results in the expansion of HIV reservoirs in people living with HIV (PLWH) with rebounding plasma viremia; however, the dynamics of the intact HIV reservoir during ART in PLWH who underwent ATI has not been fully delineated. We conducted longitudinal measurements of intact HIV proviral DNA, residual plasma viremia, and biomarkers before ATI and following re-initiation of ART in PLWH who participated in previous ATI trials. Methods: We studied two cohorts of PLWH who initiated ART during the acute/early (A/E, n=25) or the chronic (Chronic, n=19) phase of infection. We determined the levels of intact HIV proviral DNA, residual plasma viremia, and biomarkers before and during ATI, and 24 and 52 weeks following the re-initiation of ART. Levels of intact HIV DNA were determined using the intact proviral DNA assay (IPDA). Residual plasma viremia was measured using an automated instrument. Levels of plasma biomarkers were measured by an automated ELISA.

486

Poster Abstracts

485

CROI 2024 126