Functional Compartmentalization of Antibodies in the Central Nervous System During Chronic HIV Infection
Marianna Spatola, Carolin Loos, Deniz Cizmeci, Nicholas E. Webb, Matthew J. Gorman, Evan Rossignol, Sally Shin, Dansu Yuan, Laura Fontana, Shibani S. Mukerji, Douglas A. Lauffenburger, Dana Gabuzda, Galit Alter
Abstract
The central nervous system (CNS) has emerged as a critical HIV reservoir. Thus, interventions aimed at controlling and eliminating HIV must include CNS-targeted strategies. Given the inaccessibility of the brain, efforts have focused on cerebrospinal fluid (CSF), aimed at defining biomarkers of HIV-disease in the CNS, including HIV-specific antibodies. However, how antibodies traffic between the blood and CNS, and whether specific antibody profiles track with HIV-associated neurocognitive disorders (HAND) remains unclear. Here, we comprehensively profiled HIV-specific antibodies across plasma and CSF from 20 antiretroviral therapy (ART) naive or treated persons with HIV. CSF was populated by IgG1 and IgG3 antibodies, with reduced Fc-effector profiles. While ART improved plasma antibody functional coordination, CSF profiles were unaffected by ART and were unrelated to HAND severity. These data point to a functional sieving of antibodies across the blood-brain barrier, providing previously unappreciated insights for the development of next-generation therapeutics targeting the CNS reservoir.