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

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.

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

“…The more robust findings for sCD163 as compared to sCD14 suggests that the impact is more likely due to specific monocyte infection than gut microbial translocation. This is consistent with prior studies linking HIV DNA in CD14 + reservoirs to cognition, brain atrophy, and brain inflammation through cytokine analyses and magnetic resonance spectroscopy [40,41]. This study also informs clinical practice in cases where successfully treated patients achieve viral suppression yet have cognitive symptoms.…”

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[183] These preliminary observation warrant further studies on the differential efficacy of ARVs according to target cells: the repeated association between HIV reservoir size (measured as PBMC-or monocyte-associated quantitative HIV DNA) and HAND support the implementation of specific drug strategies in selected patients (those with low CD4+ cells nadir, high HIV RNA zenith and high cumulative viremia for instance). [184,185] …”

HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy

“…[14] A recent analysis of the cART-naïve HIV+ cohort analyzed in the current paper (SEARCH 011) found that high HIV DNA levels in CD14+ monocytes increased the risk of HIV-associated neurocognitive disorders (HAND). [15] As shown by a receiver operator characteristic (ROC) curve, CD14+ HIV DNA ≥ 45 copies/10 6 cells had a sensitivity of 86% and a specificity of 70% for identifying HAND. Furthermore, proton magnetic resonance spectroscopy (MRS) identified markers of brain neuronal injury and glial dysfunction that were positively linked to CD14+ HIV DNA.…”

“…Furthermore, proton magnetic resonance spectroscopy (MRS) identified markers of brain neuronal injury and glial dysfunction that were positively linked to CD14+ HIV DNA. [15] We now examine the relationship of CD14+ HIV DNA to regional brain volumes.…”