Unbiased serology reveals autoimmunity and HIV antibody signatures in HIV CNS Escape

Abstract

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.

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

“…Here, we report for the first time AnkG autoantibodies in the CSF of two patients with neurological illness. Because case 1 is living with HIV, we verified that AnkG autoantibodies were not secondary to his HIV status ( 8 ). Albeit extremely rare, these data suggest that, like myriad other antibodies targeting the AIS and NoR, AnkG autoantibodies are biomarkers of neurological autoimmunity.…”

“…Case 1 CSF IgG colocalized with AnkG at the AIS and NoR, thereby confirming AIS-NoR immunoreactivity ( Figure 2B ). A review of TBIF results from a separate study revealed that none of 46 CSF samples from people living with HIV produced AIS/NoR immunostaining ( 8 ).…”

“…Because of case 1's HIV status, we reviewed PhIP-Seq data from 33 HIV CSF samples ( N = 15 well-controlled and N = 18 untreated HIV) and found that neither AnkG nor epitope AnkG 937−958 were enriched above negative controls ( 8 ). Furthermore, a BLAST search revealed that this epitope does not harbor sequence similarity to HIV arguing against molecular mimicry.…”