Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy

Abstract

The central nervous system (CNS) HIV reservoir is an obstacle to achieving an HIV cure. The basal ganglia harbor a higher frequency of SIV than other brain regions in the SIV-infected rhesus macaques of Chinese-origin (chRMs) even on suppressive combination antiretroviral therapy (ART). Since residual HIV/SIV reservoir is associated with inflammation, we characterized the neuroinflammation by gene expression and systemic levels of inflammatory molecules in healthy controls and SIV-infected chRMs with or without ART. CCL2, IL-6, and IFN-γ were significantly reduced in the cerebrospinal fluid (CSF) of animals receiving ART. Moreover, there was a correlation between levels of CCL2 in plasma and CSF, suggesting the potential use of plasma CCL2 as a neuroinflammation biomarker. With higher SIV frequency, the basal ganglia of untreated SIV-infected chRMs showed an upregulation of secreted phosphoprotein 1 (SPP1), which could be an indicator of ongoing neuroinflammation. While ART greatly reduced neuroinflammation in general, proinflammatory genes, such as IL-9, were still significantly upregulated. These results expand our understanding of neuroinflammation and signaling in SIV-infected chRMs on ART, an excellent model to study HIV/SIV persistence in the CNS.

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection

“…In PWH, regardless of cART treatment, osteopontin was found to be elevated in the plasma ( 134 ). In the basal ganglia of SIV-infected monkeys, osteopontin mRNA was highly expressed compared to that in the uninfected animals or those with viral suppression by cART ( 135 ). In another study in PWH, osteopontin was found to be increased in the brain and CSF, and importantly, shown to enhance HIV replication in primary human macrophages ( 136 , 137 ).…”

Morphine Suppresses Peripheral Responses and Transforms Brain Myeloid Gene Expression to Favor Neuropathogenesis in SIV Infection

“…In PWH, regardless of cART treatment, osteopontin was found to be elevated in the plasma (117). In the basal ganglia of SIV-infected monkeys, osteopontin mRNA was highly expressed compared to that in the uninfected animals or those with viral suppression by cART (118). In another study in PWH, osteopontin was found to be increased in the brain and CSF, and importantly, shown to enhance HIV replication in primary human macrophages (119, 120).…”

Lymphoid tissues contribute to plasma viral clonotypes early after antiretroviral therapy interruption in SIV-infected rhesus macaques

“…The number of SIV copies was normalized to diploid genome cell equivalents co-determined by qRT-PCR using the TaqMan RNase P Detection Reagents Kit (Applied Biosystems, catalog no. 4316831) ( 12 , 53 ). The tissue qRT-PCR DNA and RNA assay sensitivity was 10 copies per million cells.…”