A SIV molecular clone that targets the CNS and induces neuroAIDS in rhesus macaques

Matsuda, Kenta; Riddick, Nadeene E.; Lee, Cheri A; Puryear, Sarah; Wu, Fan; Lafont, Bernard A. P.; Whitted, Sonya; Hirsch, Vanessa M.

doi:10.1371/journal.ppat.1006538

Cited by 25 publications

(44 citation statements)

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“…Direct infection of microglia/macrophages is thus perhaps responsible for the apoptotic changes and dysfunction/lack of activation in the presence of overwhelmingly high CSF VLs. This is further confirmed by the presence of SIV RNA in the brain tissues of our animals and by its colocalization with microglial nodules (11,24,25). Interestingly, in one of the animals that died in the early stages of the disease (SIV#2), SIV RNA staining seemed similar in shape to microglial cells (Fig.…”

Section: Discussionsupporting

confidence: 83%

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Hammoud

Sinharay

Shah

et al. 2019

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The exact cause of neurocognitive dysfunction in HIV-positive patients despite successful control of the infection in the periphery is not completely understood. One suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that eventually leads to neuronal loss and dysfunction. However, the exact role of microglial activation in the earliest stages of the infection with high cerebrospinal fluid (CSF) viral loads (VL) is unclear. In this study, we imaged the translocator protein (TSPO), a mitochondrial membrane receptor known to be upregulated in activated microglia and macrophages, in rhesus macaques before and multiple times after inoculation with a neurotropic simian immunodeficiency virus (SIV) strain (SIVsm804E), using 18F-DPA714 positron emission tomography (PET). The whole-brain standardized uptake values of TSPO at equilibrium reflecting total binding (SUVT) and binding potentials (BPND) were calculated and correlated with CSF and serum markers of disease, and a corresponding postmortem immunostaining analysis was also performed. SUVT was found to be inversely correlated with both CSF VL and monocyte chemoattractant protein 1 (MCP-1) levels. In SIV-infected macaques with very high CSF VL at necropsy (>106 copies/ml), we found decreased TSPO binding by PET, and this was supported by immunostaining which showed glial and neuronal apoptosis rather than microglial activation. On the other hand, with only moderately elevated CSF VL (∼104 copies/ml), we found increased TSPO binding as well as focal and diffuse microglial activation on immunostaining. Our results in the SIV-infected macaque model provide insights into the relationship between HIV neuropathology and CSF VL at various stages of the disease. IMPORTANCE Neurological and cognitive problems are a common complication of HIV infection and are prevalent even in treated individuals. Although the molecular processes underlying brain involvement with HIV are not completely understood, inflammation is suspected to play a significant role. Our work presents an in vivo assessment of neuroinflammation in an animal model of HIV, the simian immunodeficiency virus (SIV)-infected rhesus macaque. Using positron emission tomography (PET) imaging, we identified changes in brain inflammation after inoculation with SIV over time. Interestingly, we found decreased binding of the PET ligand in the presence of very high cerebrospinal fluid (CSF) viral loads. These findings were supported by immunostaining which showed marked glial loss instead of inflammation. This study provides insight into glial and neuronal changes associated with very high CSF viral load and could reflect similar changes occurring in HIV-infected patients.

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Section: Discussionsupporting

confidence: 83%

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Hammoud

Sinharay

Shah

et al. 2019

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“…Using an immunofluorescence assay (IFA) coupled with both DNA and RNAscope, we see that RMs with SIVE harbor SIV DNA that is transcriptionally active in Br-M⌽s within lymphoid-rich lesions. We have previously shown that CL757 is highly adapted to replicate in the CNS compared to its parental clone, SIVsmmE543-3 (E543-3), which is generally excluded from replicating in the CNS (22). Our study shows that while trafficking does occur between the CNS and the periphery, Br-mCD4s appear to harbor replication-competent virus in the CNS in the absence of SIVE.…”

Section: Discussionmentioning

confidence: 55%

“…The animals used in this study were taken from a variety of different studies as they became available. This included a subset of the animals inoculated with the neurotropic clone CL757, described previously (22). In a study by Matsuda et al 22, 8 animals were inoculated with CL757, and only 4 animals developed neuroAIDS.…”

Section: Resultsmentioning

confidence: 99%

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Simian Immunodeficiency Virus-Infected Memory CD4⁺T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

Lee

Beasley

Sundar

et al. 2020

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Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

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“…We also evaluated whole-brain cell suspensions obtained from a separate group of SIV-infected monkeys (group B, n = 13), of which only six animals showed neurological symptoms and were found to have neuropathology consistent with SIVE, as described earlier (16).…”

Section: Methodsmentioning

confidence: 99%

Potential Mechanism for HIV-Associated Depression: Upregulation of Serotonin Transporters in SIV-Infected Macaques Detected by 11C-DASB PET

et al. 2019

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Purpose: Increased incidence of depression in HIV+ patients is associated with lower adherence to treatment and increased morbidity/mortality. One possible underlying pathophysiology is serotonergic dysfunction. In this study, we used an animal model of HIV, the SIV-infected macaque, to longitudinally image serotonin transporter (SERT) expression before and after inoculation, using 11C-DASB (SERT ligand) PET imaging. Methods: We infected seven rhesus macaques with a neurovirulent SIV strain and imaged them at baseline and multiple time points after inoculation (group A). Pyrosequencing methylation analysis of the SERT promoter region was performed. We also measured SERT mRNA/protein in brain single-cell suspensions from another group (group B) of SIV-infected animals (n = 13). Results: Despite some animals showing early fluctuations, 86% of our group A animals eventually showed a net increase in midbrain/thalamus binding potential (BP ND ) over the course of their disease (mean increased binding between last time point and baseline = 30.2% and 32.2%, respectively). Repeated-measures mixed-model analysis showed infection duration to be predictive of midbrain BP ND (p = 0.039). Thalamic BP ND was statistically significantly associated with multiple CSF cytokines (P < 0.05). There was higher SERT protein levels in the second group (group B) of SIV-infected animals with SIV encephalitis (SIVE) compared to those without SIVE (p = 0.014). There were no longitudinal changes in SERT gene promoter region percentage methylation between baselines and last time points in group A animals. Conclusion: Upregulated SERT leading to lower synaptic levels of serotonin is a possible mechanism of depression in HIV+ patients, and extrapolating our conclusions from SIV to HIV should be sought using translational human studies.

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A SIV molecular clone that targets the CNS and induces neuroAIDS in rhesus macaques

Cited by 25 publications

References 50 publications

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Simian Immunodeficiency Virus-Infected Memory CD4⁺T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

Potential Mechanism for HIV-Associated Depression: Upregulation of Serotonin Transporters in SIV-Infected Macaques Detected by 11C-DASB PET

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A SIV molecular clone that targets the CNS and induces neuroAIDS in rhesus macaques

Cited by 25 publications

References 50 publications

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

Simian Immunodeficiency Virus-Infected Memory CD4+T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

Potential Mechanism for HIV-Associated Depression: Upregulation of Serotonin Transporters in SIV-Infected Macaques Detected by 11C-DASB PET

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Simian Immunodeficiency Virus-Infected Memory CD4⁺T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS