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Genetic and phenotypic analyses of CSF and blood in treated participants show drug-resistant T-tropic HIV-1 replication in CD4+ T cells driving NSE and NSE-high, supporting CNS-focused failure and specialized treatment.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/neurosymptomatic-cerebrospinal-fluid-escape-is-a-central-nervous-systemfocused-form-of-antiretroviral-therapy-treatment-failure/419965/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/neurosymptomatic-cerebrospinal-fluid-escape-is-a-central-nervous-systemfocused-form-of-antiretroviral-therapy-treatment-failure/419965.png","ImageObject",300,407,{"name":42,"@type":43},"Alexandar","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-04","2026-09-28",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is neurosymptomatic CSF escape (NSE) in people with HIV-1?","Question",{"text":63,"@type":64},"NSE describes people with HIV-1 who develop new central nervous system symptoms and signs along with higher HIV-1 RNA levels in CSF than in blood during antiretroviral therapy.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How is NSE-high (NSE-h) distinguished from NSE?",{"text":68,"@type":64},"NSE-h refers to NSE participants who also have systemic treatment failure criteria, particularly with higher plasma HIV-1 RNA levels (>500 copies/mL), indicating a more severe virologic pattern in blood.",{"name":70,"@type":61,"acceptedAnswer":71},"What drives NSE and NSE-h according to the study’s findings?",{"text":72,"@type":64},"Both are driven by replication of drug-resistant HIV-1 in CD4+ T cells in the CNS, with NSE-h showing higher CSF viral loads reflecting more 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Central Nervous System–Focused Form of Antiretroviral Therapy Treatment Failure  \nLaura P. Kincer,1 Ameet Dravid,2, Shuntai Zhou,1, Riccardo Vercesi,3 Serena Spudich,4 Magnus Gisslén,5,6 Richard W. Price,7 Paola Cinque,3, and Sarah B. Joseph1,8,9,  \n1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 2Department of Medicine, Poona Hospital and Research Center and Noble hospitals and Research Center, Pune, India, 3Unit of Neurovirology and Unit of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy, 4Department of Neurology, Yale University, New Haven, Connecticut, USA, 5Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, 6Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden, 7Department of Neurology, University of California San Francisco, San Francisco, California, USA, 8Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, and 9UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA  \nBackground. During antiretroviral therapy, people with HIV-1 (PWH) occasionally present with new symptoms and signs of central nervous system (CNS) injury accompanied by higher HIV-1 RNA levels in cerebrospinal fluid (CSF) than in blood, a condition defined as neurosymptomatic CSF escape (NSE) . PWH meeting these general criteria but with plasma HIV-1 RNA levels >500 copies/mL have typically been assumed to be experiencing systemic treatment failure without special consideration for HIV-1 dynamics in the CNS. Thus, people with CNS-focused treatment failure may receive suboptimal treatment, targeted at controlling replication in the periphery, not the CNS.  \nMethods. We genetically and phenotypically characterized HIV-1 RNA in the CSF and blood of PWH (N = 9) undergoing antiretroviral therapy who met definitions of NSE and systemic treatment failure, and we defined them as having NSE high (NSE-h) .  \nResults. While plasma viral loads were higher during NSE-h than NSE, the conditions have many shared features, including elevated CSF:plasma viral load ratios, higher CSF white blood cell counts, and drug-resistant T-tropic HIV-1 replicating in the CNS. During NSE-h, HIV-1 populations in blood and CSF were genetically equilibrated, indicating that they were not independently replicating in both compartments.  \nConclusions. NSE and NSE-h are driven by replication of drug-resistant HIV-1 in CD4+ T cells in the CNS, with NSE-h having higher CSF viral loads reflecting more HIV-1 replication. This suggests that people presenting with neurologic symptoms and treatment failure may be experiencing CNS-focused treatment failure that could require specialized treatment.  \nIn the absence of antiretroviral therapy (ART), people with HIV-1 (PWH) typically have detectable HIV RNA in the cerebrospinal fluid (CSF) but at lower concentrations than in the plasma [ 1]. While HIV RNA levels may differ, their dynamics are often similar in the 2 compartments, with HIV RNA consistently becoming detectable within a few weeks after virus acquisition [2] and decaying to undetectable levels within a few months after initiation of ART [3, 4]. However, after initiating ART, some people—particularly those with lower CD4+ T-cell counts and/or  \nReceived 30 July 2025; accepted 13 October 2025; published online 24 October 2025  \nCorrespondence: Sarah B. Joseph, PhD, 22-065 Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295 ([sbjoseph@email.unc.edu](sbjoseph@email.unc.edu)) .  \nOpen Forum Infectious Diseases®  \n© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Soc","cbCaiayaKanBERVd","https://ap.wps.com/l/cbCaiayaKanBERVd","pdf",9038686,"English","# Background\n# Methods\n# Results\n# Conclusions","[{\"question\":\"What is neurosymptomatic CSF escape (NSE) in people with HIV-1?\",\"answer\":\"NSE describes people with HIV-1 who develop new central nervous system symptoms and signs along with higher HIV-1 RNA levels in CSF than in blood during antiretroviral therapy.\"},{\"question\":\"How is NSE-high (NSE-h) distinguished from NSE?\",\"answer\":\"NSE-h refers to NSE participants who also have systemic treatment failure criteria, particularly with higher plasma HIV-1 RNA levels (\\u003e500 copies/mL), indicating a more severe virologic pattern in blood.\"},{\"question\":\"What drives NSE and NSE-h according to the study’s findings?\",\"answer\":\"Both are driven by replication of drug-resistant HIV-1 in CD4+ T cells in the CNS, with NSE-h showing higher CSF viral loads reflecting more replication.\"}]","Neurosymptomatic Cerebrospinal Fluid Escape Is a Central Nervous System–Focused Form of Antiretroviral Therapy Treatment Failure | PDF",1790618971,25]