O1-17. CSF Anti-HIV Antibody Decline by Early Antiretroviral Therapy Suggests Reduced HIV Persistence in the CNS

Magnus Gisslén [1], Steven G. Deeks [2], Lars Hagberg [1], Hiroyu Hatano [2], Serena Spudich [3], Richard W. Price [4], Peter D. Burbelo [5]
Affiliates: [1] Department of Infectious Diseases, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. [2] Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA. [3] Department of Neurology, Yale University, New Haven, CT. [4] Department of Neurology, UCSF, San Francisco, CA. [5] Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD.

Background
Despite the effectiveness of antiretroviral therapy (ART) in reducing HIV to levels below clinical detection in cerebrospinal fluid (CSF), HIV likely persists in the central nervous system (CNS) in treated individuals.  Using anti-HIV antibodies as markers of persistent CNS infection, CSF and blood antibodies were examined in untreated early, treated early and treated late infection to determine the impact of active viral replication on the evolution of HIV antibodies.

Methodology
Using archived samples, luciferase immunoprecipitation systems (LIPS) was applied to measure levels of antibodies against seven recombinant HIV proteins in paired CSF and blood in uninfected controls (n=12) and HIV-infected individuals, before and after long-term treatment of early infection (n=10) and chronic infection (n=10). We also studied two individuals who failed pre-exposure prophylaxis (PrEP), individuals without ART followed longitudinally from early infection (n=10) and the cured Berlin patient.

Results
During untreated early infection, longitudinal sampling revealed the emergence of anti-HIV antibodies robustly in blood by approximately day 40 of infection and then attaining similar levels 2 weeks later in CSF; levels then remained steadily elevated.  ART initiated during early infection markedly lowered antibody levels in CSF, but to a lesser extent in blood.  Treatment initiated during PrEP prevented the appearance of anti-HIV antibodies in both CSF and serum. Despite >10 years of suppressive ART, subjects with chronic infection demonstrated only relatively small reductions of HIV antibodies in CSF and serum. As previously reported, serum antibody profile of the Berlin patient almost resembled uninfected controls, and similarly low antibody levels were found in the CSF as well.

Conclusions
To the extent that CSF and blood antibodies indicate the persistence of HIV, very early treatment reduces systemic, but to a much greater degree the CNS reservoir.  These data suggest it takes longer to establish a reservoir in CNS than blood, and that early treatment has the capacity to preserve long-term CNS integrity.