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Current \u201cshock and kill\u201d strategies are limited by ineffective latency-reversing agents (LRAs) and poor understanding of epigenetic regulation. Here, we identify chromatin assembly factor 1 subunit A (CHAF1A), a histone chaperone enforcing HIV-1 latency, as a therapeutic target regulated by antagonistic post-translational modifications: ubiquitination promotes its degradation, while O-GlcNAcylation stabilizes it. We demonstrate that trifluridine, a Food and Drug Administration-approved antiviral drug, reactivates latent HIV-1 by disrupting O-GlcNAcylation, triggering CHAF1A ubiquitination and proteasomal degradation. Notably, CHAF1A expression increases with age in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells (&gt;60 years), correlating with deeper proviral reservoirs. This age-dependent accumulation inversely associates with reduced O-GlcNAcase levels, suggesting O-GlcNAcylation-mediated stabilization in aging. Our findings establish CHAF1A as both a therapeutic target and an age-stratifying biomarker, advancing trifluridine as a translatable LRA to enhance reservoir clearance in aging populations\u2014a demographic increasingly impacted by HIV-1 persistence.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>HIV-1 latency continues to represent a significant barrier to achieving a cure, particularly in aging populations characterized by expanded viral reservoirs and compromised immune recovery\u2014a challenge further intensified by the absence of therapies specifically designed to target age-related mechanisms. Current latency-reversing agents (LRAs) are insufficient in addressing the metabolic and epigenetic dysregulation that sustains viral persistence in older individuals. In this study, we reveal a dynamic interplay between ubiquitination and O-GlcNAcylation that regulates the stability of CHAF1A, a histone chaperone essential for maintaining HIV-1 latency. We identify trifluridine as a novel LRA capable of disrupting O-GlcNAcylation to degrade CHAF1A, thereby effectively reversing latency in primary cells. This research bridges a critical gap between fundamental virology and clinical gerontology. These findings establish a robust foundation for refining strategies aimed at HIV-1 eradication, with a focus on targeting host metabolic-epigenetic networks to address latency in underserved aging populations.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01518-25","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T14:00:11Z","timestamp":1764770411000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["The crosstalk between ubiquitination and GlcNAcylation of CHAF1A regulates HIV-1 latency and reactivation"],"prefix":"10.1128","volume":"99","author":[{"given":"Tao","family":"Yang","sequence":"first","affiliation":[{"name":"Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, Centre for Infection and Immunity Study (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen 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