CROI 2025 Abstract eBook

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Poster Abstracts

while their presence abrogated this association (beta; -14.86 95%CI -69.34 to 39.62, p=0.59, p-value for interaction 0.18). Among inflammatory markers, sgp120 was positively associated with Galectin-9 (log beta; 0.07 95%CI 0.00 to 0.13, p=0.025). Conclusions: Our study suggests that sgp120 is associated with immune dysfunction in PWH and raises the intriguing possibility that therapeutic approaches targeting sgp120 could provide immune benefits and mitigate HIV associated immune dysfunction in PWH. Genetic Associations With CD4 Recovery in People With HIV After Initiation of Antiretroviral Therapy Roxane Rohani 1 , Qin Hui 2 , Jennie T. Mather 3 , Lishomwa Ndhlovu 4 , Michael H. Chung 2 , Kris Ann K. Oursler 5 , Boghuma K. Titanji 2 , Todd Hulgan 6 , Brian Agan 7 , Yan V. Sun 2 , Vincent C. Marconi 2 1 Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA, 2 Emory University, Atlanta, GA, USA, 3 Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA, 4 Weill Cornell Medicine, New York, NY, USA, 5 Salem VA Health Care System, Salem, VA, USA, 6 Vanderbilt University Medical Center, Nashville, TN, USA, 7 Uniformed Services University of the Health Sciences, Bethesda, MD, USA Background: CD4+ T-cell recovery varies among people with HIV (PWH) who are virologically suppressed on antiretroviral therapy (ART). Our objective was to identify the genetic predictors of CD4 recovery measured by the slope of longitudinal CD4+ T-cell counts within two years after ART initiation in PWH virologically suppressed on ART. We hypothesized that select single nucleotide polymorphisms (SNPs) would associate with CD4 slope in PWH initiating ART. Methods: A genome-wide association study (GWAS) was performed on samples from PWH in the Million Veteran Program (MVP). HIV infection was defined by 1 inpatient or 2 outpatient HIV ICD codes, or a detectable HIV-1 plasma RNA viral load, or ART prescribed for > 31 days. Individuals had at least 2 CD4 counts: one at baseline (up to 6 months prior to ART) and others within 2 years after ART. We evaluated SNP associations with CD4 slope adjusting for age at ART initiation, sex, and 10 principal components using linear regression. After standard quality control procedures, the TOPMed-imputed SNPs were used in ancestry-specific GWAS of common variants (minor allele frequency>5%). A meta-analysis was conducted to evaluate multi-ancestry associations. We considered P-value of 5x10 -8 as the genome-wide significance (GWS) threshold. Results: A total of 4192 PWH (48% African Americans, 97% male) were included in the GWAS. Mean age at ART initiation was 49 years and mean nadir CD4 count was 358 cells/µl. Median intercept and slope were 394 cells/µl and 0.118 cells/ μL/year, respectively. Although no SNP meeting GWS was identified in the multi-ancestry GWAS of CD4 slope, three common variants were associated at P-value <1x10 -6 , with consistent directionality of association in all three ancestral groups: European, African and Hispanic Americans. One chromosome 7 locus, close to TRIM56 gene (rs7786422, β= -0.0456; p= 2.42 x 10 -7 ), and one chromosome 9 locus, mapped to TOMM5 gene (rs10973430, β= -0.0532; p= 9.11 x 10 -7 ) were associated with diminished CD4 recovery. Conclusions: In the first study of PWH in MVP, we did not identify GWS associations with CD4+ T-cell slope after ART initiation, possibly limited by sample size. However, we found several sub-threshold genetic associations; TRIM56 has inhibitory effects on viral replication, while TOMM5 is part of a complex in mitochondrial outer membrane, acting as an entry point for viral proteins. Replication study in larger sample sizes is needed.

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R5 Tropic HIV Restricts X4 Tropic Virus via Type I IFN Signaling, Limiting Pathogenesis Priya Pal, Bailey Quinn, Sara Nicholson, Hongbo Gao, Liang Shan Washington University, St Louis, MO, USA Background: X4-tropic viruses typically emerge in the late clinical stages of HIV, when the immune system is significantly impaired. As few as two amino acids changes can convert an R5-Tropic virus to an X4-Tropic virus. HIV has an error-prone reverse transcriptase and in the absence of therapy, spontaneous emergence of X4 tropic viruses is expected unless they were specifically restricted. We sought to understand what, if any, immune component was responsible for selective restriction of X4-tropic viruses. Methods: Viral constructs were generated with an NL4-3 consensus background differing only in the envelope which confers tropism. We utilized the MISTRG 6-15 mouse model either transfused with primary CD4+ T cells to compare X4 and R5 tropic viral fitness in the absence of other immune components, or engrafted with CD34+ cells and reconstituted with a human immune system to assess immune mediated restriction of X4-tropic viruses. Using CRISPR Cas9 targeting the type I interferon (IFN) receptor we generated IFNAR KO humanized mice to assess the contribution of type I IFN signaling. Primary CD4+ T cells were cultured to quantify EC50s for type I IFN for both X4 and R5 tropic viruses. Primary plasmacytoid dendritic cells (pDCs) were cultured with various viral constructs and inhibitors to determine key components for IFN release. Results: Using the engrafted MISTRG-6-15 humanized mouse model, we observed R5 dominance in mice infected with both viral tropisms, whereas an X4 dominance was observed in mice only transfused with primary CD4+ T cells, suggesting an innate arm of immunity was responsible for the tropism-specific suppression. Plasma cytokine analysis revealed that only R5 tropic viruses triggered detectable type I IFN levels in infected mice. Furthermore, primary pDCs displayed differential type I IFN release in the presence of R5 and X4 tropic viruses ex vivo . Humanized IFNAR KO MISTRG 6-15 mice infected with a mixture of X4 tropic and R5 tropic viruses lost selective X4 tropic restriction. As a consequence, mice with increased proportions of X4 tropic viruses displayed more rapid CD4 T cell decline. Conclusions: Type I interferon signaling is responsible for selective X4-tropic viral suppression, and this signaling is driven by R5 tropic viruses. This underscores a novel evolutionary tradeoff whereby HIV allows for selective elimination of a subset of viruses, X4-tropic viruses, which would if unchecked result in rapid CD4 decline and host death. Residual HIV Viremia Associates With Reservoir Size, but Not With Immune Activation or Inflammation Twan Otten 1 , Mareva Delporte 2 , Nadira Vadaq 1 , Adriana Navas 1 , Wilhelm A. Vos 3 , Albert L. Groenendijk 4 , Marc J. T. Blaauw 5 , Jéssica dos Santos 1 , Vasiliki Matzaraki 1 , Olivier Richel 1 , Jan van Lunzen 1 , Mihai G. Netea 1 , Niels P. Riksen 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 Erasmus University Medical Center, Rotterdam, Netherlands, 5 Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands Background: Plasma viral loads (VL) in persons with HIV (PWH) taking antiretroviral therapy are generally below the limit of quantification. However, commercial PCR tests differentiate between unquantifiable low, but detectable VL (<40 c/ml, residual viremia, RV) and Target Not Detected (TND). Whether RV drives or is driven by systemic immune activation remains debated. Large studies are lacking, and results are conflicting. In two cohorts of PWH, we

Poster Abstracts

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CROI 2025