Background Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication with occasional asymptomatic episodes of detectable HIV RNA known as asymptomatic (AS) escape. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood.Methods Using a large cohort of PLWH (n=111), including elite controllers (n=4), viral controllers (n=4), ART untreated subjects (n=18), HIV-associated dementia (n=4), ART suppressed (n=16), AS escape (n=19), NS escape (n=35), secondary escape (n=5) subjects, and HIV-negative controls (n=6), we investigated immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection.Results We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape controls. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV env and gag proteins in the CSF of PLWH.Discussion We deployed agnostic tools to study whether there was evidence for a neuroinvasive co-infection and/or autoimmunity in HIV escape syndromes. We more frequently detected EBV DNA and immunoreactivity to self-antigens in NS escape. Whether these additional inflammatory markers are byproducts of an HIV-driven inflammatory process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.### Competing Interest StatementDr. Joseph DeRisi has received grants from the Chan Zuckerberg Biohub, personal fees from the Public Health Company and from Allen & Company; Dr. Michael Wilson has received unrelated grants from Roche/Genentech and Novartis as well as speaking honoraria from Novartis, Takeda, WebMD and Genentech. Drs. Wilson and DeRisi serve as advisors for Delve Bio. Dr. Christopher Bartley has received an honorarium for speaking to the Commonwealth Club and owns shares in NowRx Inc. M. Gisslen has received research grants from Gilead Sciences and Janssen-Cilag and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi, all unrelated to the content of this manuscript.### Funding StatementSupported by grant from NIH/NINDS: R01 R01NS094067 and NS 3R01NS094067-05S1 to Dr. Richard W Price and colleagues, K08NS107619 (MRW) and Westridge Foundation (MRW and IAH). CM Bartley was supported by a Hanna H. Gray Fellowship, Howard Hughes Medical Institute, a President Postdoctoral Fellowship Program, the University of California, and the John A. Watson Scholar Program, UCSF.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The samples used in this study were collected between 2000 and 2018 in the context of HIV research studies at two medical centers: Sahlgrenska University Hospital, Gothenburg, Sweden and Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA. Samples were obtained in the context of established research approved by the local institutional review boards of these institutions. All participants provided informed consent and, if there was a question regarding their capacity to provide fully consent, consent was also obtained from individuals with power of attorney.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAnonymized data not published within this article will be made available by request from any qualified investigator.
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