Abstract
ObjectivesCognitive 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.MethodsWe 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).ResultsThe 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.InterpretationReservoir 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.
Highlights
Combination antiretroviral therapy suppresses plasma HIV viral RNA to undetectable levels for most patients but fails to universally eliminate reservoirs of HIV DNA. [1] The inability to clear these reservoirs has emerged as the Achilles heel of HIV eradication because withdrawal from treatment allows for rapid new viral replication from these sources
[8] Autopsy reports identify a monocyte/macrophage foundation to cognitive impairment even among Combination antiretroviral therapy (cART) treated subjects, and researchers have shown an association between soluble CD14 and lysosomal proteins secreted by macrophages to cognitive impairment and brain atrophy. [9,10,11,12,13] We test the hypothesis that CD14+ HIV DNA can identify subjects with HAND prospectively in a blinded fashion, and evaluate the mechanistic link to central nervous system (CNS) injury by brain magnetic resonance spectroscopy (MRS) and evaluation of cerebrospinal fluid (CSF) immune activation
The CD14+ HIV DNA reservoir burden was associated with HAND (ANI+mild neurocognitive disorder (MND)+HIV-associated dementia (HAD)) in both univariate (OR = 14.9, p,0.001) and multiple logistic models (OR = 14.5, p = 0.001) adjustment for concurrent CD4+ T-lymphocyte count and plasma HIV RNA (Table 2)
Summary
Combination antiretroviral therapy (cART) suppresses plasma HIV viral RNA to undetectable levels for most patients but fails to universally eliminate reservoirs of HIV DNA. [1] The inability to clear these reservoirs has emerged as the Achilles heel of HIV eradication because withdrawal from treatment allows for rapid new viral replication from these sources. Current neurological research has focused on the brain as a protected site for HIV since not all antiretroviral medications have shown high degrees of central nervous system (CNS) penetration effectiveness (CPE). Our past work focused on the burden of HIV DNA in PBMCs, and those enriched for monocytes as determined by expression of the CD14 cell surface marker. This CD14+ HIV DNA reservoir is proportionally small compared to that found in CD4+ T-lymphocytes; the overall CD14+ reservoir size has been linked to cognitive disorders among both cART-treated and untreated patients in past cross-sectional posthoc correlative studies. This CD14+ HIV DNA reservoir is proportionally small compared to that found in CD4+ T-lymphocytes; the overall CD14+ reservoir size has been linked to cognitive disorders among both cART-treated and untreated patients in past cross-sectional posthoc correlative studies. [4,5,6,7] A recent study linked cART regimens with higher effectiveness in monocytes to better overall cognitive performance, a finding that was independent of CPE. [8] Autopsy reports identify a monocyte/macrophage foundation to cognitive impairment even among cART treated subjects, and researchers have shown an association between soluble CD14 and lysosomal proteins secreted by macrophages to cognitive impairment and brain atrophy. [9,10,11,12,13] We test the hypothesis that CD14+ HIV DNA can identify subjects with HAND prospectively in a blinded fashion, and evaluate the mechanistic link to CNS injury by brain MRS and evaluation of CSF immune activation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
