Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS

Abstract

Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used 1 H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non-CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte-depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte-depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

“…(5 mg/kg) on 8 and 12 dpi. 17,21 Complete blood cell counts and flow cytometry to monitor leukocyte populations and CD8 þ lymphocyte depletion were performed before infection and weekly thereafter. Blood and cerebrospinal fluid were sampled weekly, and CNS and other tissues were collected at necropsy.…”

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

“…CD8 ϩ cell depletion in humanized mice was used to accelerate brain disease as of previously published data for SIV infected nonhuman primate models. [32][33][34][35]37,51,52 Depletion of CD8 ϩ cells after productive infection significantly increased peripheral and brain viral load, migration of human cells into the CNS, and formation of MGC in meninges as well as diffusing glial reactions. In two cases, as a result of CD8 ϩ cell depletion and CD4 ϩ cell activation, mice developed severe meningoencephalitis, acute glial activation, and phagocytosis of neurons by microglial cells.…”

Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Suppresses Rho GTPases in Human Brain Microvascular Endothelial Cells and Inhibits Adhesion and Transendothelial Migration of HIV-1 Infected Monocytes

“…HIV-1 encephalitis is characterized by monocyte and macrophage accumulation in affected brain tissue (48). Perivascular macrophages serve as a source of neurotoxins and viral reservoir, and they are a driving force of chronic inflammation providing chemokines and homing cues for circulating HIV-1 infected cells (49,50). A pool of perivascular virusinfected macrophages is derived from monocytes migrating across the BBB and suppression of monocyte infiltration may ameliorate neuronal demise (50).…”

“…Perivascular macrophages serve as a source of neurotoxins and viral reservoir, and they are a driving force of chronic inflammation providing chemokines and homing cues for circulating HIV-1 infected cells (49,50). A pool of perivascular virusinfected macrophages is derived from monocytes migrating across the BBB and suppression of monocyte infiltration may ameliorate neuronal demise (50). PPAR␥ stimulation significantly diminished adhesion and migration of HIV-1 infected monocytes across BMVEC monolayers.…”