The brain is an important HIV reservoir. Given its difficult accessibility to quantify viral burden, HIV-specific cerebrospinal fluid (CSF)-antibodies (rather than systemic antibodies) have been suggested as critical biomarkers of HIV-disease in the brain

To define systemic and brain-specific antibody signatures in chronic HIV infection

We applied a Systems Serology approach to thoroughly dissect the antibody profiles (Ig classes and subclasses, Fc-gamma receptors [FcgRs] binding capacity and antibody-mediated innate immunity functions) in the plasma and CSF of 20 chronically infected (11 ART-treated and 9 untreated) HIV+ individuals identified from the CHARTER study.

High titers of HIV-specific antibodies were detected in both plasma and CSF. However, striking brain-specific antibody signatures were identified: 1) unlike plasma antibodies that were of all Ig classes, CSF showed predominantly IgG1, IgG3, and no IgM; 2) CSF-antibodies had lower capacity to activate innate immunity functions and bind FcgRs; 3) CSF-antibodies showed a weak binding to the neonatal FcR (FcRN), which mediates the transport of circulating antibodies to and from the brain; 4) this low FcRN affinity was not observed for antibodies targeting Flu, HSV1, HSV2, CMV and EBV, suggesting a retention of HIV-specific antibodies (but not antibodies to other viruses) within the brain; 5) ART-treatment was associated with higher coordination of humoral responses by plasma-antibodies compared to CSF-antibodies, pointing to a reduced effect of ART in the brain.

These data suggest a unique compartmentalization of subpopulations of antibodies in the CNS during chronic HIV infection, pointing to a functional sieving of antibodies across the blood brain barrier, and provide previously unappreciated insights for the development of next-generation therapeutics targeting the CNS reservoir.