Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS

Abstract

Despite the advent of highly active anti-retroviral therapy HIV-associated neurocognitive disorders (HAND) continue to be a significant problem. Furthermore, the precise pathogenesis of this neurodegeneration is still unclear. The objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (SIV) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. The effect of SIV infection in 23 adult rhesus macaques was investigated using an accelerated NeuroAIDS model. Disease progression was modulated either with combination anti-retroviral therapy (cART, 4 animals) or minocycline (7 animals). Twelve animals remained untreated. Viral loads were monitored in the blood and cerebral spinal fluid, as were levels of activated monocytes in the blood. Neuronal injury was monitored in vivo using magnetic resonance spectroscopy. Viral RNA was quantified in brain tissue of each animal postmortem using reverse transcription polymerase chain reaction (RT-PCR), and neuronal injury was assessed by immunohistochemistry. Without treatment, viral RNA in plasma, cerebral spinal fluid, and brain tissue appears to reach a plateau. Neuronal injury was highly correlated both to plasma viral levels and a subset of infected/activated monocytes (CD14+CD16+), which are known to traffic the virus into the brain. Treatment with either cART or minocycline decreased brain viral levels and partially reversed alterations in in vivo and immunohistochemical markers for neuronal injury. These findings suggest there is significant turnover of replicating virus within the brain and the severity of neuronal injury is directly related to the brain viral load.

Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals

“…Asymptomatic CSF virus escape has also been documented by lumbar punctures 19 . Combination antiretroviral therapy decreases brain viral load, improves immunohistochemical markers of neuronal injury in primates 20 , and is associated with a reduction of neurodegeneration in humans 21 . The low CNS bioavailability of antiretrovirals (e.g., protease inhibitors, such as atazanavir) has been implicated in higher CSF HIV-1 RNA load, together with the accumulation of resistance mutations in the CNS 22 .…”

Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression

“…Natural history studies of acute SIV infection that apply brain neuroimaging combined with post-mortem pathological analysis have yielded varying results. These studies (typically ≤ 14 days post-SIV infection, peak viremia 11-12 days post infection (dpi)) have differed with respect to the infecting SIV strain used and whether the animals are experimentally immunosuppressed by CD8+ T lymphocyte depletion (anti-CD8 monoclonal antibody infusions) to enhance virus replication and accelerate CNS pathogenesis (1,(3)(4)(5)(6). In a study using SIV mac251 (SIV swarm containing both T lymphocyte-and macrophage-tropic SIV strains), neuroimaging evidence for transient neuronal injury (N-acetyl-aspartate [NAA] loss) and glial inflammation (increased choline/creatinine) in frontal cortex was observed (14 dpi) (7).…”

“…Such T lymphocyte depletion after SIV mac251 inoculation can result in progressive irreversible neuronal injury and death in the frontal cortex and basal ganglia over 8 weeks ( 11 ). A comprehensive analysis of this accelerated SIV neuropathogenesis model revealed (i) progressive and irreversible frontal cortex neuronal injury (synaptophysin and NAA loss), (ii) an association between frontal cortex SIV RNA levels and neuronal injury, and (iii) attenuation of progressive neuronal injury with the use of antiretroviral drugs to suppress SIV replication ( 5 ). In this model, there is no evidence for recovery from neuronal injury, although a limited neuroprotective effect of host CD8 + T lymphocyte responses, presumably through control of SIV replication, is suggested.…”

Longitudinal trajectories of brain volume in combined antiretroviral therapy treated and untreated simian immunodeficiency virus-infected rhesus macaques

“…Laboratory data were acquired at baseline (before inoculation), a week postinfection, 2, 5, 8, 12, 24, 36, and 48 wpi. These time points were set in consideration of the virus reported to be detectable in the CNS a week after infection [ 29 ] and physiological condition. Viral load in plasma and CSF were detected by measuring SIV RNA levels (extracted by TRIzol) by reverse transcription-PCR (RT-PCR) as previously described.…”