Duration of Initial Viremia Modulates Functional Properties of HIV-specific T Cell Receptors

Duration of Initial Viremia Modulates Functional Properties of HIV-specific T Cell Receptors | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Duration of Initial Viremia Modulates Functional Properties of HIV-specific T Cell Receptors Bruce Walker, Funsho Ogunshola, Nishant Singh, Vincent Butty, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6668459/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Virus-specific CD8+ T cells are crucial in controlling chronic human viral infections such as HIV-1, but the effect of persistent antigen exposure on T cell repertoire formation is not well understood. In this study, we examined epitope-specific CD8+ T cell repertoires in people living with HIV-1, where duration of viremia following hyperacute infection was modulated by the time of initiation of continuous suppressive antiretroviral therapy (ART). After ART-induced suppression of viremia in persons expressing the same HLA class I allele, we analyzed the impact of early (n=6) versus delayed (n=6) ART initiation on the clonotypic composition, cross-reactivity, functional avidity and memory differentiation profile of the HIV-specific T cell repertoire restricted by HLA-B*58:01. Using a panel of barcoded tetramers, we mapped T cell receptor (TCR) clonotypes specific for three dominant epitopes and their variants. Both groups exhibited polyclonal TCR repertoires with evidence of cross-reactivity, which was significantly enriched in donors with prolonged antigen exposure. Within this cohort, broadly cross-reactive clonotypes capable of recognizing all autologous variants were identified, but these were rare (<1%). Early ART initiation preserved repertoires characterized by higher-avidity TCRs and a relative enrichment of transitional memory CD8+ T cell subsets. These functional differences were not associated with differences in TRBV gene sharing, indicating that ART timing shapes repertoire quality and memory differentiation without altering TRBV gene bias. These findings demonstrate how antigen suppression dynamics differentially shape the breadth, functional sensitivity, and memory composition of the HIV-specific TCR repertoire, with implications for T cell-directed immunotherapies and HIV cure strategies. Health sciences/Biomarkers/Predictive markers Biological sciences/Immunology/Infectious diseases/HIV infections Full Text Additional Declarations Yes there is potential Competing Interest. M.E.B. is a founder, consultant, and equity holder of Kelonia Therapeutics and Abata Therapeutics and received research funding from Pfizer Inc. unrelated to this work. Supplementary Files Suppmaterial1.xlsx Ex vivo transcriptional profiling raw data SuppTableonepitopesequences.xlsx Autologous epitope sequences Suppinformation.xlsx TCR Sequences Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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