HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Nave Patients

Objectives: Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14 enriched monocytes predicted cognitive impairment and brain injury. Methods: We enrolled 61 cART-naı̈ve HIV-infected Thais in a prospective study and measured HIV DNA in CD14 enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results: The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14 + HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14 HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation: Reservoir burden of HIV DNA in monocyte-enriched (CD14) peripheral blood cells increases risk for HAND in treatment-naı̈ve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. Citation: Valcour VG, Ananworanich J, Agsalda M, Sailasuta N, Chalermchai T, et al. (2013) HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naı̈ve Patients. PLoS ONE 8(7): e70164. doi:10.1371/journal.pone.0070164 Editor: Stephen D. Ginsberg, Nathan Kline Institute and New York University School of Medicine, United States of America Received March 18, 2013; Accepted June 15, 2013; Published July 31, 2013 Copyright: 2013 Valcour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by R01-NS053359 (NINDS/NIH SRK), R01-NS061696 (NINDS/NIH VV), R21-MH072388 (NIMH/NIH VV), R01-NS053345 (NINDS/NIH BS), and MD007584 (NIMHD/NIH BS, CS). Added statistical assistance was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant Number UL1 TR000004. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. This work was supported in part by a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, and the U.S. Department of Defense. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] " Membership of the SEARCH 011 Protocol Team is provided in the Acknowledgments.