CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

487

Mitochondrial Gene Variants Influence VARS2, HIV Reservoir, and CD4+ T Cells in HIV Controllers Victoria Rios Vazquez 1 , Vasiliki Matzaraki 1 , Suzanne D. E. Ruijten 1 , Mareva Delporte 2 , Wilhelm A. Vos 3 , Marc J. T. Blaauw 4 , Louise E. van Eekeren 1 , Albert L. Groenendijk 5 , Leo Joosten 1 , Mihai G. Netea 1 , Willem Blok 3 , Jan van Lunzen 1 , Jéssica dos Santos 1 , Linos Vandekerckhove 2 , Andre van der Ven 1 , for the 2000HIV Human Functional Genomics Partnership Program 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 HIV Cure Research Center, Ghent University, Ghent, Belgium, 3 OLVG, Amsterdam, Netherlands, 4 Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands, 5 Erasmus University Medical Center, Rotterdam, Netherlands Background: Mitochondria are crucial for cellular energy metabolism and immune regulation, but their role in spontaneous HIV control remains unclear. We hypothesized that single nucleotide polymorphisms (SNPs) in mitochondrial-related genes influence HIV control. Methods: SNP-set enrichment analysis was conducted to determine if SNPs in autosomal mitochondrial-related genes are enriched in HIV-control associated SNPs compared to the rest of the genome, using GWAS summary statistics from Europeans in the 2000HIV cohort ( NCT03994835 ). This analysis included 67 HIV controllers and 1,176 non-controllers. Functionally relevant SNPs were prioritized using expression quantitative trait loci (eQTL) data. The effect of prioritized SNP genotypes on gene expression and total HIV reservoir DNA copies/million CD4+ T cells in PBMCs was tested using linear regression. Flow cytometry and single-cell expression data were used to explore immune activation and gene expression at single cell level. Co-expression network and pathway enrichment analyses were performed to explore relationships between prioritized genes and pathways. Results: SNP-set enrichment analysis revealed significant enrichment in mitochondrial genes associated with HIV control (P<1e-5, Figure 1A ). Prioritization with eQTLs identified six independent SNPs and four mitochondrial-related genes. Three independent SNPs near VARS2 ( rs4713462 , rs28436034 , rs9266658 ) significantly associated with HIV control, higher VARS2 expression, and lower viral reservoirs (P<0.05, Figure 1B ). VARS2 expression negatively correlated with total reservoir DNA (P<0.05, R 2 =0.01) and positively with CD4 counts (P<0.05, R 2 =0.14). Flow cytometry showed VARS2 expression positively associated with T cell activation (memory subsets) and negatively with granulocyte and monocyte activation. Single-cell expression data showed VARS2 highly expressed in T cells. Co-expression analysis revealed VARS2 co expressed with genes enriched (P<0.01) in mitochondrial tRNA processing and suppression of pro-inflammatory pathways. Conclusions: Our findings highlight the role of mitochondrial-related genetic variants affecting VARS2 expression, essential for mitochondrial protein synthesis, in HIV reservoir size and immune pathways in European HIV controllers. VARS2 expression linked to heightened T cell activation, reduced innate immune activation, and lower viral reservoirs. This suggests that higher VARS2 expression promotes effective viral control and a protective role in long term HIV control. The figure, table, or graphic for this abstract has been removed. Clinical and Virologic Outcomes of an ART Interruption in Treated Controllers and Non-Controllers Isaac E. Avila-Vargas 1 , Antonio Rodriguez 1 , Tony R. Figueroa 1 , Thomas Dalhuisen 1 , Meghann Williams 1 , Marin Ewing 1 , Monika Deswal 1 , Elnaz Eilkhani 1 , Viva Tai 1 , Rebecca Hoh 1 , Rachel Rutishauser 1 , Amelia N. Deitchman 1 , Steven G. Deeks 1 , Lillian B. Cohn 2 , Michael Peluso 1 , for the SCOPE-ATI Study Team 1 University of California San Francisco, San Francisco, CA, USA, 2 Fred Hutchinson Cancer Center, Seattle, WA, USA Background: The early host-virus interactions immediately post-ART (the “intercept”) likely determine how well the immune system can control HIV. Deep investigation of this early period may lead to novel cure strategies or a potential biomarker of future rebound versus control. Here, we explored the early viral dynamics of spontaneous and post-intervention control. Methods: We conducted an intensive analytic treatment interruption (ATI) in 20 PWH: 13 ART-suppressed non-controllers and 7 ART-treated PWH known to be controllers prior to ART. HIV RNA was measured 3 times/week post-ART. ART was resumed for most when an HIV RNA >1000 cpm was confirmed. We also studied individuals who did or did not control HIV after a combination immunotherapy intervention (n=10). HIV control was generally defined as

<1000 cpm. The viral load data were modeled using a linear mixed effects model. Results: Within the ATI study, the median age was 59 years (range 32-75); 25% were cis- or trans-women. Among those starting ART when rebound was confirmed (“brief ATI”), CD4/CD8 ratio declined slightly (median 1.2 to 1.0, p=0.002), but this resolved with ART restart. No acute retroviral syndrome and no transmissions occurred; all participants re-suppressed within 1 month of ART restart. The median duration of viremia was 7 (range 3-13) days. Controllers exhibited a longer time-to-rebound than non-controllers (38 vs 15 days, p=0.0036), and longer duration between first detected signal and quantifiable rebound (21 vs 8 days, p=0.1). During rebound (Fig A), the daily increase in plasma HIV RNA level was significantly lower in controllers than non-controllers (0.03 log/day vs 0.24 log/day, p<0.0001, Fig B). The delay in rebound and the more gradual rate of viral load increase observed within these controllers was similar to that observed in the recent UCSF-amfAR combination immunotherapy trial in which 7 of 10 individuals achieved post-intervention control (0.02 log/ day). Conclusions: Individuals destined to control HIV spontaneously or after immunotherapy exhibit evidence of control immediately post-ART, even before HIV RNA is detected. The delay in rebound and slow rate of increase suggest that for immune control to be achieved, the responses need to be present and functional just as the virus begins to spread. Intense studies on the biology of the intercept period could lead to novel cure strategies and the identification of a biomarker that might predict when virus will rebound and how well that virus will be controlled. The figure, table, or graphic for this abstract has been removed. HIV-1 Post-Treatment Control Occurs Despite HLA-Escape Mutations in the Intact Reservoir Efthimios A. Deligiannidis 1 , Behzad Etemad 1 , Radwa Sharaf 1 , Prerana Shrestha 1 , Sofia Cohen 1 , Flavio Mesquita 2 , Yijia Li 3 , Jesse Fajnzylber 1 , Colline Wong 1 , Joseph J. Eron 4 , Ian Frank 5 , Jeffrey M. Jacobson 6 , Zabrina L. Brumme 7 , Jonathan Li 1 1 Brigham and Women's Hospital, Boston, MA, USA, 2 Harvard University, Cambridge, MA, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5 University of Pennsylvania, Philadelphia, PA, USA, 6 Case Western Reserve University, Cleveland, OH, USA, 7 Simon Fraser University, Burnaby, Canada Background: HIV-1 post-treatment controllers (PTCs) can maintain viral suppression despite stopping ART while having a detectable intact proviral reservoir. The mechanisms of post-treatment control remain unclear, but there’s evidence that cell-mediated immunity may play a role. The impact of HIV-specific T cell responses is reflected by evolving HLA-escape mutations within the proviral reservoir. In this study, we evaluated the evolution of HLA-escape mutations within the intact reservoir of PTCs and post-treatment non-controllers (NCs) during an analytical treatment interruption (ATI). Methods: We extracted longitudinal PBMC DNA from PTCs and NCs from ACTG ATI trials from both the pre-ATI (on ART) and post-ATI (off ART) time points. Near full-length single-genome sequences were obtained at pre- and post-ATI time points (median 95 and 56.5 weeks for PTCs and NCs at the post-ATI time point). We performed HLA typing and determined the frequency of both adapted and possibly adapted HLA-escape mutations normalized to gene length and the proportion of HLA-escape mutations relative to the potential sites where such mutations could occur for all intact proviruses. Results: We obtained more than 400 intact proviral sequences for longitudinal time points from 13 participants (5 PTCs, 8 NCs). Amongst intact proviruses across all participants, the numbers of adapted and possibly-adapted HLA escape mutations normalized to gene length were more commonly identified in the accessory genes (highest in rev , tat , vpr ) than structural genes ( gag , pol ) or env . PTCs were able to maintain viral control despite the presence of HLA-escape mutations both at the pre-ATI and post-ATI time points. The distribution of HLA-escape mutations across the various genes was similar between PTCs and NCs both when analyzed by the frequency of mutation normalized by gene length and by the proportion of HLA-escape mutations relative to the potential sites of escape. Conclusions: PTCs can maintain viral control despite the presence of HLA escape mutations within the intact proviral landscape, in contrast to NCs who exhibit virologic failure with similar HLA-escape mutation frequencies. Additional studies are needed to assess the strength of HIV-specific T cell

Poster Abstracts

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