title: Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy.
abstract: To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication. Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption. HIVenv(C2-V3),gag(p24) andpol(reverse transcriptase) were sequenced from cell-free HIV RNA and cell-associated HIV DNA in blood and CSF using the Roche 454 FLX Titanium platform. Comprehensive sequence and phylogenetic analyses were performed to search for evidence of unique or differentially represented viral subpopulations emerging in CSF supernatant as compared with blood plasma. Using a conservative definition of compartmentalization based on four distinct statistical tests, nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound. The degree and duration of viral compartmentalization varied considerably between subjects and between time-points within a subject. In 10 cases, we identified viral populations within the CSF supernatant at the first sampled time-point after ART interruption, which were phylogenetically distinct from those present in the paired blood plasma and mostly persisted over time (when longitudinal time-points were available). Our data suggest that an independent source of HIV RNA contributes to viral rebound within the CSF after treatment interruption. The most likely source of compartmentalized HIV RNA is a CNS reservoir that would need to be targeted to achieve complete HIV eradication.
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Sara
authors: S
authors: Gianella
authors: Department of Biology, Temple University, Philadelphia, PA, USA.
authors: Sergei L
authors: SL
authors: Kosakovsky Pond
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Michelli F
authors: MF
authors: Oliveira
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Konrad
authors: K
authors: Scheffler
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Matt C
authors: MC
authors: Strain
authors: Departments of Neurosciences and Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors: Antonio
authors: A
authors: De la Torre
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors: Scott
authors: S
authors: Letendre
authors: Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
authors: Davey M
authors: DM
authors: Smith
authors: Departments of Neurosciences and Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors: Ronald J
authors: RJ
authors: Ellis
keywords: ART interruption; HIV reservoir; central nervous system; viral rebound.