HIV DNA reservoir increases risk for cognitive disorders in cART-naïve patients.
OBJECTIVE
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-naïve 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.


CONCLUSIONS
Reservoir burden of HIV DNA in monocyte-enriched (CD14(+)) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS.
Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA. vvalcour@memory.ucsf.edu
Victor G
VG
Valcour
Jintanat
J
Ananworanich
Melissa
M
Agsalda
Napapon
N
Sailasuta
Thep
T
Chalermchai
Alexandra
A
Schuetz
Cecilia
C
Shikuma
Chin-Yuan
CY
Liang
Supunee
S
Jirajariyavej
Pasiri
P
Sithinamsuwan
Somporn
S
Tipsuk
David B
DB
Clifford
Robert
R
Paul
James L K
JL
Fletcher
Mary A
MA
Marovich
Bonnie M
BM
Slike
Victor
V
DeGruttola
Bruce
B
Shiramizu
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D003072:Cognition Disorders / Q000175:diagnosis* / Q000209:etiology; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D060885:Multiplex Polymerase Chain Reaction; D015999:Multivariate Analysis; D011446:Prospective Studies; D012372:ROC Curve; D012044:Regression Analysis; D012307:Risk Factors
D016207:Cytokines; D004279:DNA, Viral; D018950:Lipopolysaccharide Receptors