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. 2022 Jan 13;14(1):139.
doi: 10.3390/v14010139.

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

Antonio Solis-Leal  1 , Summer Siddiqui  2 , Fei Wu  1   3 , Mahesh Mohan  1 , Wenhui Hu  4 , Lara A Doyle-Meyers  2 , Jason P Dufour  2 , Binhua Ling  1   2   3   5
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Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy

Antonio Solis-Leal et al. Viruses. .

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.

Keywords: antiretroviral therapy; central nervous system; human immunodeficiency virus; immune activation; neuroinflammation; non-human primates; reservoir; rhesus macaques; simian immunodeficiency virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Differential cytokine and chemokine levels in plasma of the different groups of chRMs. The scatter graphs show the distribution observed in the plasma of each group for the cytokines and chemokines: (A) CCL2, (B) IL-6, (C) CXCL10, and (D) IFN-g. (* p < 0.05, ** p < 0.01).
Figure 2
Figure 2
Differential cytokine and chemokine levels in CSF of chRMs. The scatter graphs show the distribution observed in the CSF of the experimental groups for the cytokines (A) CCL2, (B) IL-6, (C) CXCL10, and (D) IFN-g. (* p < 0.05, ** p < 0.01). Non-parametric Mann-Whitney tests.
Figure 3
Figure 3
Association of levels of cytokine and chemokine between the CSF and plasma of SIV-infected chRMs with ART (right panels) or without ART (left panels). (A,B), (C,D), (E,F) and (G,H) show CCL2, IL-6, CXCL10, and IFN-γ levels respectively.
Figure 4
Figure 4
CSF/Plasma ratio difference between Untreated and ART groups. The graphs show the distribution observed in the CSF/Plasma ratio of the experimental groups for (A) CCL2, (B) IL-6, (C) CXCL10, and (D) IFN-γ (** p < 0.01).
Figure 5
Figure 5
Profiling of gene expression in the basal ganglia of SIV+ chRMs with antiretroviral therapy (ART) or without ART (Untreated). The fold-changes of gene expression in the ART and Untreated groups were shown separately in comparison with the healthy control group.
Figure 6
Figure 6
Gene expression changes in the basal ganglia found exclusively in either the Untreated group or the ART group, compared to the healthy control. (A) Genes upregulated only in the Un treated group compared to the healthy control group. (B) Genes up/downregulated only in the ART group compared to the healthy control group. Red or green borders in the bar graphs represent upregulation or downregulation respectively compared to the control group.
Figure 7
Figure 7
Biological Functional Annotations in Untreated vs. ART. DEGs in the ART and the untreated groups were analyzed. Differential pro-inflammatory functions were enriched for each group. The activation and inhibition of functions are shown by orange and blue colors, respectively. DEGs were defined by fold change > 2 and p < 0.05.
Figure 8
Figure 8
ART vs. Untreated Pathway Analyses. (A) Canonical pathways enrichment analysis. The red box highlights the discrepant pathway between groups. (B) Expression of genes in the osteoarthritis pathway. (C) Regulator Effects network in the untreated group. It illustrates the relationships between the upstream regulator (OSM) and downstream function and diseases (damage of cartilage tissue). The measured and predicted activation is represented by the red and orange colors, respectively.
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