Monoclonal antibodies protect aged rhesus macaques from SARS-CoV-2-induced immune activation and neuroinflammation

Hawes, Chase E.; Lakshmanappa, Yashavanth Shaan; Roh, Jamin W.; Schmidt, Brian; Dutra, Joseph; Louie, William; Liu, Hongwei; Ma, Zhien; Watanabe, Jennifer; Usachenko, Jodie; Immareddy, Ramya; Sammak, Rebecca L.; Pollard, Rachel E.; Olstad, Katherine J.; Coffey, Lark L.; Kozlowski, Pamela A.; Hartigan-O’Connor, Dennis J.; Nussenzweig, Michel C.; Rompay, Koen K. A. Van; Morrison, John H.; Iyer, Smita S.

doi:10.1016/j.celrep.2021.109942

Cited by 14 publications

(18 citation statements)

References 40 publications

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“…Consistent with and based on their high neutralizing in vitro potency, all antibodies selected for advanced clinical development target the RBD of SARS-CoV-2. Experiments in animal models conclusively demonstrated their in vivo potential, as pre-or post-exposure administration of neutralizing antibodies prevented or dampened infection, manifesting in reduced viral titers and/or pulmonary inflammation (Baum et al, 2020a;Bertoglio et al, 2021;Cao et al, 2020; Kim et al, 2021a;Loo et al, 2022;Martinez et al, 2021;Sch€ afer et al, 2021;Shi et al, 2020;Verma et al, 2021;Wang et al, 2020b;Zost et al, 2020a).…”

Section: Development Of Therapeutic Antibodiesmentioning

confidence: 94%

Antibody-mediated neutralization of SARS-CoV-2

et al. 2022

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Section: Development Of Therapeutic Antibodiesmentioning

confidence: 94%

Antibody-mediated neutralization of SARS-CoV-2

et al. 2022

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“…Brackets indicate cytokine families. G Quantification of interleukin, CXCL-chemokines, and CCL-chemokines levels (expressed in Log 2 Normalized Protein Expression [Log 2 NPX]) in the CSF of a cohort of uninfected animals (age 21–22 years; 8 females) [ 32 ]. A , F Data points indicate samples derived from brain region (indicated by color) and animal.…”

Section: Resultsmentioning

confidence: 99%

“…To substantiate homeostatic cytokine and chemokine RNA-seq data, we performed protein-based analysis of the CSF from 8 uninfected rhesus macaques utilizing the O-link platform [ 32 ] (Fig. 2 G).…”

Section: Resultsmentioning

confidence: 99%

Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection

Hawes

Elizaldi

Beckman

et al. 2022

J Neuroinflammation

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Background Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). Methods We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. Results RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. Conclusions Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.

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“…Frozen lung sample was directly immersed in 0.5 ml DMEM (GIBCO) in a 2 ml centrifuge tube with a 5 mm glass bead and homogenized in a TissueLyser II (Qiagen) at 30 hertz for 4 minutes followed by centrifugation at 16,000 g for 4 minutes. Titers of the released progeny virus from the lung homogenate and BAL supernatant samples were determined by plaque assay using Vero E6 cells as described previously [ 54 ]. Briefly, virus was serial diluted and inoculated onto confluent monolayers of Vero E6 cells, followed by agarose overlay.…”

Section: Methodsmentioning

confidence: 99%

Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity had no antiviral effects but moderately reduced lung inflammation

et al. 2022

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Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

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Monoclonal antibodies protect aged rhesus macaques from SARS-CoV-2-induced immune activation and neuroinflammation

Cited by 14 publications

References 40 publications

Antibody-mediated neutralization of SARS-CoV-2

Antibody-mediated neutralization of SARS-CoV-2

Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection

Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity had no antiviral effects but moderately reduced lung inflammation

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