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This paper presents a detailed gross description of all anatomical elements of the humerus in the African green monkey and provides comparative and differential elements on monkey osteology. The osteometric investigation adds value to the gross morphological investigation, adjoining metric data to the gross descriptive data set. An in-depth investigation of the microstructural aspects of the humeral bone tissue is provided, with qualitative and quantitative details and potential for diagnostic applications. Of the gross morphological elements described, several unique features specific to this species include the humeral head shape that presents with distinctive low convexity and caudal placement, the shape of the intertubercular groove, the less developed greater tubercle, and the disposition of the rotator cuff muscle insertion. Furthermore, the overall cranio-lateral curvature of the bone shaft was found to have a distinctive 154–155 degree of angulation of the diaphysis, and the well-developed medial epicondyle was observed with its distinctive medio-caudal retroflexion. The histological investigation was more indicative of a typical non-primate organization of the bone tissue, with laminar vascular and avascular structures combined with the presence of the secondary Haversian system involving a mixture of scattered and dense unorganized secondary osteonal structures. The histomorphometric investigation yielded metrical data for the secondary osteonal structures in terms of area (20,331 ± 5105 µm2), perimeter, and vascular canal area (64,769 ± 257 µm2). [ABSTRACT FROM AUTHOR]

Objective: To document ocular lesions and establish ophthalmic diagnostic test reference values in a colony of African green monkeys (Chlorocebus aethiops sabaeus). Animals Studied: Fifty one geriatric (GAGM, 19–30 years old), 10 adult (AAGM, 5–9 years old) and 10 juvenile (JAGM, <2 years old) African green monkeys housed in a single Caribbean research colony. Procedures: Ocular biomicroscopy, indirect fundoscopy, Schirmer tear test (STT), rebound tonometry (TonoVet®) and corneal fluorescein staining were performed. Mixed ANCOVA tests were performed to compare STT and IOP between groups. Results: Common ocular lesions in GAGM included vitreal degeneration (27/51, 51/102 eyes) and cataracts (21/51, 32/102 eyes). Vitreal degeneration was also common in AAGM (8/10, 16/20 eyes) and infrequent in JAGM (3/10, 6/20 eyes). Cataracts were not present in any JAGM or AAGM. All eyes in all three groups had perilimbal corneal pigmentation and faint lace‐like anterior corneal stromal opacification. Median (range) STT values were 16.0 (18) mm/min in GAGM. Mean (SD) STT values were 14.2 (4.6) mm/min in AAGM, and 8.9 (3.4) mm/min in JAGM. Median (range) IOP values were 16.5 (27) mmHg in GAGM. Mean (SD) IOP values were 18.0 (2.8) mmHg in AAGM, and 14.1 (2.2) mmHg in JAGM. JAGM had significantly lower STT and IOP values compared to AAGM (p =.0449,.0057, respectively) and GAGM (p =.0002,.0130, respectively). Conclusions: Spontaneous ocular lesions were common in geriatric monkeys in this research colony. IOP and STT values were lower in juvenile African green monkeys relative to adult or geriatric animals. [ABSTRACT FROM AUTHOR]

This paper presents a detailed gross description of all anatomical elements of the humerus in the African green monkey and provides comparative and differential elements on monkey osteology. The osteometric investigation adds value to the gross morphological investigation, adjoining metric data to the gross descriptive data set. An in-depth investigation of the microstructural aspects of the humeral bone tissue is provided, with qualitative and quantitative details and potential for diagnostic applications. Of the gross morphological elements described, several unique features specific to this species include the humeral head shape that presents with distinctive low convexity and caudal placement, the shape of the intertubercular groove, the less developed greater tubercle, and the disposition of the rotator cuff muscle insertion. Furthermore, the overall cranio-lateral curvature of the bone shaft was found to have a distinctive 154–155 degree of angulation of the diaphysis, and the well-developed medial epicondyle was observed with its distinctive medio-caudal retroflexion. The histological investigation was more indicative of a typical non-primate organization of the bone tissue, with laminar vascular and avascular structures combined with the presence of the secondary Haversian system involving a mixture of scattered and dense unorganized secondary osteonal structures. The histomorphometric investigation yielded metrical data for the secondary osteonal structures in terms of area (20,331 ± 5105 µm2), perimeter, and vascular canal area (64,769 ± 257 µm2).

Nonhuman primates (NHPs) are valuable models for studying healthspan, including frailty development. Frailty metrics in people centers on functional measures, including usual gait speed which can be predictive of all‐cause mortality. This concept that physical competencies are able to prognosticate an individual's health trajectory over chronologic aging is well‐accepted and has led to refinements in how physical function is evaluated, and include measures of strength and power along with walking speed. NHP studies of aging require evaluation of physical function, which can be difficult in field and research settings. We compared stair climb velocity to usual walking speed in 28 peri‐geriatric to geriatric NHPs, as incorporating a climbing obstacle integrates multiple components of physical function: isolated leg and back strength, proprioception, balance, and range of motion. We find that stair climbing speed was reliable between observers, and whether timing was in‐person take from video capture. The stair climb rates were 50% more associated with chronological age than walking speed (R = −0.68 vs. −0.45) and only stair climbing speeds were retained as predictive of age when walking speed and bodyweight were included in multivariate models (overall R2 = 0.44; p < 0.0001). When comparing young (10−16 years) versus geriatric (16−29 years) stair climbing speed was significantly different (p < 0.001), while walking speeds only tended to be slower (p = 0.12) suggesting that the additional challenge of a stair climb better unmasks subclinical frailty development that usual walking speed. Research highlights: We evaluated the utility of measuring natural climbing as a measure of physical function for aging nonhuman primates. We found that this simple new measurement technique is reliable as live or video capture and more sensitive to age‐related decline than traditionally measured gait speed. [ABSTRACT FROM AUTHOR]

Nonhuman primates (NHPs) are important to study the pathophysiology of neurodegenerative disease and evaluate therapies targeting the central nervous system (CNS). Understanding the age‐associated incidence of natural CNS pathology in a given NHP species is critical to assess the safety of potential treatments for neurodegenerative disorders like Alzheimer's disease (AD). We describe background and age‐related neuropathology in the St. Kitts African green monkey (AGM), a recognized translational model for neurodegenerative research, additionally defining the age progression of AD‐associated neuropathology in this species. Seventy‐one AGM brains were examined, representing age groups of 3–6 years (n = 20), 7–9 years (n = 20), 10–15 years (n = 20), and >15 years (n = 11). A subset of brains (n = 31) was assessed immunohistochemically for AD‐related pathology, including expressions of Aβ, tau, and GFAP. Age‐related microscopic findings included hemosiderosis, spheroid formation, neuronal lipofuscinosis and neuromelanosis, white matter and neuropil vacuolation, astrocytosis, and focal microgliosis. Non‐age‐related findings included perivascular ceroid‐laden macrophages, meningeal melanosis, and vascular mineralization. Immunohistochemistry revealed 4G8‐immunopositive Aβ plaques and vascular deposits in the prefrontal, frontal, cingulate, and temporal cortices of nine animals over 15 years of age, with associated increase in GFAP expression. In 12 animals, 11 over the age of 10 years, phosphorylated tau CP13‐immunoreactive neurons, neuropil, and oligodendrocyte‐like cells were seen in the prefrontal, frontal, cingulate, orbital, temporal, and entorhinal cortices as well as the hippocampus; no neurofibrillary tangles were observed. AD‐related pathology showed an age‐related development in cognitive‐associated areas in the AGM, highlighting the value of the AGM as a natural model for these neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused many deaths and contributed to a tremendous public health concern worldwide since 2020. Angiotensin-converting enzyme 2 (ACE2) binds to the SARS-CoV-2 virus as a receptor. The challenge of different nonhuman primate (NHP) species by SARS-CoV-2 virus demonstrated different effects on virus replication and disease pathology. This study characterizes differences between host ACE2 sequences of three NHP species: Macaca mulatta, Macaca fascicularis, and Chlorocebus sabaeus. In addition, the binding affinity between the ACE2 ectodomain and the SARS-CoV-2 S receptor-binding domain (RBD) was analyzed. Variation of ACE2 sequence among NHP species and the binding affinity may account for different susceptibility and responses to SARS-CoV-2 infection.

Increases of soluble urokinase plasminogen activator receptor (suPAR) were measured in both urine and plasma of a Chlorocebus aethiops (African green monkey; AGM) mucosal infected with SARS‐CoV‐2. The data indicate that elevated suPAR may be associated with renal dysfunction and pathology in the context of COVID‐19. [ABSTRACT FROM AUTHOR]

Hymenolepis diminuta is a tapeworm commonly found worldwide in small rodents such as rats with occasional reports in other definitive hosts such as primates including chimpanzees and humans. It has not been reported in African green monkey (AGM, Chlorocebus sabaeus), and the parasite's molecular phenotype and phylogeny remain primitively sketchy. The aims of the current study were to determine if H. diminuta infected AGMs, to molecularly characterize H. diminuta and to review its infection in non-human primates. Feces of AGMs were examined visually for adult helminths and microscopically for eggs using centrifugation flotation. Total DNA extracted from eggs was amplified by PCR followed by DNA sequencing of targeted sequences of nuclear rRNA + internal transcribed spacers (ITS) and mitochondrial cox1. Phylogenetic analyses were performed. The DNA sequences of both nuclear rRNA + ITS and mitochondrial cox1 showed more than 98% and 99% identity to the known sequences respectively. Hymenolepis diminuta has been reported in various non-human primates with the highest prevalence of 38.5% in the white-headed capuchin monkey. The study presented here confirms that this tapeworm is capable of infecting various species of non-human primates with the first report of infections in AGM. Phylogenetic analyses of rRNA + ITS and mitochondrial cox1 demonstrated three separated clades I, II and III with the newly described AGM1 isolate belonging to the clade I. Whether these differences are at species level remains to be confirmed. [ABSTRACT FROM AUTHOR]

Summary: Background: Nipah virus (NiV) causes recurrent outbreaks of lethal respiratory and neurological disease in Southeast Asia. The World Health Organization considers the development of an effective vaccine against NiV a priority. Methods: We produced two NiV vaccine candidates using the licensed VSV-EBOV vaccine as a backbone and tested its efficacy against lethal homologous and heterologous NiV challenge with Nipah virus Bangladesh and Nipah virus Malaysia, respectively, in the African green monkey model. Findings: The VSV-EBOV vaccine expressing NiV glycoprotein G (VSV-NiVG) induced high neutralising antibody titers and afforded complete protection from homologous and heterologous challenge. The VSV-EBOV vaccine expressing NiV fusion protein F (VSV-NiVF) induced a lower humoral response and afforded complete homologous protection, but only partial heterologous protection. Both vaccines reduced virus shedding from the upper respiratory tract, and virus replication in the lungs and central nervous system. None of the protected animals vaccinated with VSV-NiVG or VSV-NiVF showed histological lesions in the CNS, but one VSV-NiVF-vaccinated animal that was not protected developed severe meningoencephalitis. Interpretation: The VSV-NiVG vaccine offers broad protection against NiV disease. Funding: This study was supported by the Intramural Research Program, NIAID, NIH.

Prolonged seizures are a hallmark feature of intoxication with anticholinesterase nerve agents such as soman. While benzodiazepine drugs are typically used to control these seizures, studies in both rats and guinea pigs have shown that potent, centrally acting anticholinergic drugs such as scopolamine can also terminate such seizures. The present study was performed to determine if scopolamine could produce similar anticonvulsant effects in a nonhuman primate model of soman intoxication. Adult male African green monkeys, implanted with telemetry devices to record cortical electroencephalographic activity, were pretreated with pyridostigmine (0.02 mg/kg, intramuscularly [im]) and 40 min later challenged with 15 µg/kg (im) of the nerve agent soman. One min after soman exposure the animals were treated with atropine (0.4 mg/kg, im) and the oxime 2-PAM (25.7 mg/kg, im). One min after the start of seizure activity the animals were administered scopolamine (0.01–0.1 mg/kg, im), using an up-down dosing design over successive animals. Scopolamine was highly effective in stopping soman-induced seizures with an ED50 = 0.0312 mg/kg (0.021–0.047 mg/kg = 95% confidence limits). Seizure control was rapid, with all epileptiform activity stopping on average 21.7 min after scopolamine treatment. A separate pK study showed that scopolamine absorption peaked approximately 10 min after im administration and a dose of 0.032 mg/kg produced maximum plasma levels of 17.62 ng/ml. The results show that scopolamine exerts potent and rapid anticonvulsant action against soman-induced seizures and that it may serve as a valuable adjunct to current antidote treatments for nerve agent intoxication. [ABSTRACT FROM AUTHOR]

Aims: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid‐beta oligomers (AβOs), a key upstream initiator of AD pathology. Methods: AβOs or vehicle were repeatedly delivered over 4 weeks to age‐matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD‐like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. Results: IT administration of AβOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AβO injections. Conclusions: Repeated IT delivery of AβOs in young adult AGMs led to an accelerated AD‐like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de‐risk the clinical trial of diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Wicked problems in One Health are associated with dynamicity and uncertainty that require experts, authorities and community members to reach for innovative means of collective inquiry, and collaborative interventions to address the deep social issues at the root of interspecies problems. In this study we explore the value of harm reduction concepts to understand a hundreds of year old issue, the St. Kitts’ “monkey problem,” which involves the invasive African green monkey (Chlorocebus sabaeus) as the cause of deleterious effects on agriculture, but concurrent positive effects on tourism and biomedical research. The harm reduction approach, a systems and settings-based approach with decades of success in public health, can serve as a framework to produce action on persistent societal problems. Harm reduction concepts and methods and participatory epidemiology were used to uncover local perceptions about human-monkey interactions and “meet people where they are” by asking the research question: Are there commonalities in perceptions and values linked to the St. Kitts’ “monkey problem” that are shared across diverse representatives of society that can act as a common starting place to launch collaborative responses to this invasive species? Through a series of focus group activities and interviews we found that the Kittitian “monkey problem” is a contentious and dichotomous problem pervasive in most of society that has no single stakeholders nor one solution. Harm reduction helped to map the island’s human-monkey system and elucidated an entry point toward tackling this problem through the identification of shared values, and also provided a model for incremental gains that may be achieved. Likening the St. Kitts “monkey problem” to a wicked problem enabled stakeholders to seek more options to manage the problem rather than to conclusively solve it. Frequently mentioned shared values including the protection of farmer crops and backyard harvests likely represent strong entry points to this problem and a jumping-off point to begin collective action toward future improvements.

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, we compared African green monkeys infected intranasally with either the UK B.1.1.7 (Alpha) variant or its contemporary D614G progenitor. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.

CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered. [ABSTRACT FROM AUTHOR]

Abstract Introduction Previous studies in humans support the dual‐allergen exposure hypothesis, and several studies in mouse models have demonstrated that cutaneous exposure to disrupted or intact skin can lead to sensitization to peanut. However, the field lacks definitive evidence that cutaneous exposure leads to peanut allergy in humans or other primates. Methods Peanut extract was applied to the shaved back of the neck of four male and four female African green monkeys three times per week for 4 weeks. An oral food challenge (OFC) was performed the following week by gavage of 200 mg of peanut protein, and vital signs were monitored for 30 minutes post‐OFC. Blood was collected at baseline, day 11, day 32, and 30 minutes post‐OFC. Total IgE, and peanut‐specific immunoglobulin E (IgE) and immunoglobulin G (IgG) were quantified in serum collected throughout the 4 weeks. Histamine was measured in serum collected 30 minutes post‐OFC. Results Peanut‐specific IgE was undetectable at any time points in any of the monkeys, and there was no consistent increase in total IgE. During the oral challenge, none of the monkeys experienced allergic symptoms and histamine levels did not change. However, seven of the eight monkeys produced increasing peanut‐specific IgG by day 32, indicating that repeated skin exposure to peanut is immunogenic. Conclusions Skin exposure to peanut did not lead to sensitization in this study, and monkeys did not experience anaphylaxis upon peanut challenge. However, monkeys produced increased peanut‐specific IgG throughout peanut exposure, indicating that repeated skin exposure to peanut is immunogenic.

Background: Nipah virus is an emerging zoonotic virus that causes severe respiratory disease and meningoencephalitis. The pathophysiology of Nipah virus meningoencephalitis is poorly understood., Methods: We have collected the brains of African green monkeys during multiple Nipah virus, Bangladesh studies, resulting in 14 brains with Nipah virus-associated lesions., Results: The lesions seen in the brain of African green monkeys infected with Nipah virus, Bangladesh were very similar to those observed in humans with Nipah virus, Malaysia infection. We observed viral RNA and antigen within neurons and endothelial cells, within encephalitis foci and in uninflamed portions of the CNS. CD8+ T cells had a consistently high prevalence in CNS lesions. We developed a UNet model for quantifying and visualizing inflammation in the brain in a high-throughput and unbiased manner. While CD8+ T cells had a consistently high prevalence in CNS lesions, the model revealed that CD68+ cells were numerically the immune cell with the highest prevalence in the CNS of NiV-infected animals., Conclusion: Our study provides an in-depth analysis on Nipah virus infection in the brains of primates, and similarities between lesions in patients and the animals in our study validate this model., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Age‐related neurodegeneration characteristic of late‐onset Alzheimer's disease (LOAD) begins in middle age, well before symptoms. Translational models to identify modifiable risk factors are needed to understand etiology and identify therapeutic targets. Here, we outline the evidence supporting the vervet monkey (Chlorocebus aethiops sabaeus) as a model of aging‐related AD‐like neuropathology and associated phenotypes including cognitive function, physical function, glucose handling, intestinal physiology, and CSF, blood, and neuroimaging biomarkers. This review provides the most comprehensive multisystem description of aging in vervets to date. This review synthesizes a large body of evidence that suggests that aging vervets exhibit a coordinated suite of traits consistent with early AD and provide a powerful, naturally occurring model for LOAD. Notably, relationships are identified between AD‐like neuropathology and modifiable risk factors. Gaps in knowledge and key limitations are provided to shape future studies to illuminate mechanisms underlying divergent neurocognitive aging trajectories and to develop interventions that increase resilience to aging‐associated chronic disease, particularly, LOAD. Research Highlights: Aging vervets exhibit a suite of traits consistent with early Alzheimer's disease (AD) and provide a powerful, naturally occurring model for AD.This comprehensive characterization of vervet monkeys provides the foundation for future studies of modifiable factors that increase risk or resilience to AD. [ABSTRACT FROM AUTHOR]

Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome. [ABSTRACT FROM AUTHOR]

Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome.

Chlorocebus aethiops sabaeus, the African Green monkey (AGM), has been proved to exhibit renal vascular remodeling and spontaneous hypertension. However, little is known about the roles of microRNAs (miRNAs) in this process.Using small RNA deep sequencing, we compared the plasma miRNA expression patterns between hypertensive (HT) AGMs and normotensive (NT) AGMs. Expression of miRNAs (miR-122, miR-339, miR-296-5p) was validated independently in plasma samples from 10 HT AGMs and 10 NT AGMs (fold changes are 2.0, 1.6, 2.7 respectively; all P< 0.001). Potential BP (blood pressure)-regulating mRNA targets were predicted by TargetScan and confirmed in the Vero cells. We report for the first time a circulating miRNA profile for AGM. miRNAs, such as miR-122, miR-339, miR-296-5p, may be involved in renal pathologies and spontaneous hypertension of AGM.

Abstract Background Non-human primates (NHPs) are important models of medical research on obesity and cardiovascular diseases. As two of the most commonly used NHPs, cynomolgus macaque (CM) and African green monkey (AGM) own different capacities in lipid metabolism of which the mechanism is unknown. This study investigated the expression profiles of lipid metabolism-related microRNAs (miRNAs) in CM and AGM and their possible roles in controlling lipid metabolism-related gene expression. Methods By small RNA deep sequencing, the plasma miRNA expression patterns of CM and AGM were compared. The lipid metabolism-related miRNAs were validated through quantitative reverse-transcription (RT) polymerase chain reaction (PCR). Related-target genes were predicted by TargetScan and validated in Vero cells. Results Compared to CM, 85 miRNAs were upregulated with over 1.5-fold change in AGM of which 12 miRNAs were related to lipid metabolism. miR-122, miR-9, miR-185, miR-182 exhibited the greatest fold changes(fold changes are 51.2, 3.8, 3.7, 3.3 respectively; all P

Abstract Background The characterization of genomic or epigenomic variation in human and animal models could provide important insight into pathophysiological mechanisms of various diseases, and lead to new developments in disease diagnosis and clinical intervention. The African green monkey (AGM; Chlorocebus aethiops) and cynomolgus monkey (CM; Macaca fascicularis) have long been considered important animal models in biomedical research. However, non-human primate-specific methods applicable to epigenomic analyses in AGM and CM are lacking. The recent development of methyl-capture sequencing (MC-seq) has an unprecedented advantage of cost-effectiveness, and further allows for extending the methylome coverage compared to conventional sequencing approaches. Results Here, we used a human probe-designed MC-seq method to assay DNA methylation in DNA obtained from 13 CM and three AGM blood samples. To effectively adapt the human probe-designed target region for methylome analysis in non-human primates, we redefined the target regions, focusing on regulatory regions and intragenic regions with consideration of interspecific sequence homology and promoter region variation. Methyl-capture efficiency was controlled by the sequence identity between the captured probes based on the human reference genome and the AGM and CM genome sequences, respectively. Using reasonable guidelines, 56 and 62% of the human-based capture probes could be effectively mapped for DNA methylome profiling in the AGM and CM genome, respectively, according to numeric global statistics. In particular, our method could cover up to 89 and 87% of the regulatory regions of the AGM and CM genome, respectively. Conclusions Use of human-based MC-seq methods provides an attractive, cost-effective approach for the methylome profiling of non-human primates at the single-base resolution level.

Abstract Background The initial envelope (Env)-specific antibody response in acutely HIV-1-infected individuals and simian immunodeficiency virus (SIV)-infected rhesus monkeys (RMs) is dominated by non-neutralizing antibodies targeting Env gp41. In contrast, natural primate SIV hosts, such as African green monkeys (AGMs), develop a predominant Env gp120-specific antibody response to SIV infection. However, the fine-epitope specificity and function of SIV Env-specific plasma IgG, and their potential role on autologous virus co-evolution in SIV-infected AGMs and RMs remain unclear. Results Unlike the dominant linear gp41-specific IgG responses in RMs, SIV-infected AGMs demonstrated a unique linear variable loop 2 (V2)-specific plasma IgG response that arose concurrently with high gp120-directed antibody-dependent cellular cytotoxicity (ADCC) activity, and SIVsab-infected cell binding responses during acute infection. Moreover, SIV variants isolated from SIV-infected AGMs exhibited high amino acid mutation frequencies within the Env V1V2 loop compared to those of RMs. Notably, the linear V2-specific IgG epitope in AGMs overlaps with an analogous region of the HIV V2 loop containing the K169 mutation epitope identified in breakthrough viruses from RV144 vaccinees. Conclusion Vaccine-elicited Env V2-specific IgG responses have been proposed as an immune correlate of reduced risk in HIV-1/SIV acquisition in humans and RMs. Yet the pathways to elicit these potentially-protective V2-specific IgG responses remain unclear. In this study, we demonstrate that SIV-infected AGMs, which are the natural hosts of SIV, exhibited high plasma linear V2-specific IgG binding responses that arose concurrently with SIV Env gp120-directed ADCC-mediating, and SIV-infected cell plasma IgG binding responses during acute SIV infection, which were not present in acutely SIV-infected RMs. The linear V2-specific antibody response in AGMs targets an overlapping epitope of the proposed site of vaccine-induced immune pressure defined in the moderately protective RV144 HIV-1 vaccine trial. Identifying host factors that control the early elicitation of Env V2-specific IgG and ADCC antibody responses in these natural SIV hosts could inform vaccination strategies aimed at rapidly inducing potentially-protective HIV-1 Env-specific responses in humans.

Despite its important biological role, the evolution of recombination rates remains relatively poorly characterized. This owes, in part, to the lack of high-quality genomic resources to address this question across diverse species. Humans and our closest evolutionary relatives, anthropoid apes, have remained a major focus of large-scale sequencing efforts, and thus recombination rate variation has been comparatively well studied in this group—with earlier work revealing a conservation at the broad- but not the fine-scale. However, in order to better understand the nature of this variation, and the time scales on which substantial modifications occur, it is necessary to take a broader phylogenetic perspective. I here present the first fine-scale genetic map for vervet monkeys based on whole-genome population genetic data from ten individuals and perform a series of comparative analyses with the great apes. The results reveal a number of striking features. First, owing to strong positive correlations with diversity and weak negative correlations with divergence, analyses suggest a dominant role for purifying and background selection in shaping patterns of variation in this species. Second, results support a generally reduced broad-scale recombination rate compared with the great apes, as well as a narrower fraction of the genome in which the majority of recombination events are observed to occur. Taken together, this data set highlights the great necessity of future research to identify genomic features and quantify evolutionary processes that are driving these rate changes across primates. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies in humans support the dual‐allergen exposure hypothesis, and several studies in mouse models have demonstrated that cutaneous exposure to disrupted or intact skin can lead to sensitization to peanut. However, the field lacks definitive evidence that cutaneous exposure leads to peanut allergy in humans or other primates. Methods: Peanut extract was applied to the shaved back of the neck of four male and four female African green monkeys three times per week for 4 weeks. An oral food challenge (OFC) was performed the following week by gavage of 200 mg of peanut protein, and vital signs were monitored for 30 minutes post‐OFC. Blood was collected at baseline, day 11, day 32, and 30 minutes post‐OFC. Total IgE, and peanut‐specific immunoglobulin E (IgE) and immunoglobulin G (IgG) were quantified in serum collected throughout the 4 weeks. Histamine was measured in serum collected 30 minutes post‐OFC. Results: Peanut‐specific IgE was undetectable at any time points in any of the monkeys, and there was no consistent increase in total IgE. During the oral challenge, none of the monkeys experienced allergic symptoms and histamine levels did not change. However, seven of the eight monkeys produced increasing peanut‐specific IgG by day 32, indicating that repeated skin exposure to peanut is immunogenic. Conclusions: Skin exposure to peanut did not lead to sensitization in this study, and monkeys did not experience anaphylaxis upon peanut challenge. However, monkeys produced increased peanut‐specific IgG throughout peanut exposure, indicating that repeated skin exposure to peanut is immunogenic. [ABSTRACT FROM AUTHOR]

Viruses in the genus Henipavirus encompass 2 highly pathogenic emerging zoonotic pathogens, Hendra virus (HeV) and Nipah virus (NiV). Despite the impact on human health, there is currently limited full-genome sequence information available for henipaviruses. This lack of full-length genomes hampers our ability to understand the molecular drivers of henipavirus emergence. Furthermore, rapidly deployable viral genome sequencing can be an integral part of outbreak response and epidemiological investigations to study transmission chains. In this study, we describe the development of a reverse-transcription, long-range polymerase chain reaction (LRPCR) assay for efficient genome amplification of NiV, HeV, and a related non-pathogenic henipavirus, Cedar virus (CedPV). We then demonstrated the utility of our method by amplifying partial viral genomes from 6 HeV-infected tissue samples from Syrian hamsters and 4 tissue samples from a NiV-infected African green monkey with viral loads as low as 52 genome copies/mg. We subsequently sequenced the amplified genomes on the portable Oxford Nanopore MinION platform and analyzed the data using a newly developed field-deployable bioinformatic pipeline. Our LRPCR assay allows amplification and sequencing of 2 or 4 amplicons in semi-nested reactions. Coupled with an easy-to-use bioinformatics pipeline, this method is particularly useful in the field during outbreaks in resource-poor environments. [ABSTRACT FROM AUTHOR]

African monkeys are resistant to HIV-1 infection due to intrinsic restriction mechanisms found in their cells. However, although they can be infected by monkey-adapted modified HIV-1 particles that are designed to overcome known restriction factors, virus numbers drop to undetectable levels in immunocompetent animals. These results indicate the possibility of the presence of yet unidentified factor(s) that restrict HIV-1 in old-world monkey (OWM) cells after integration of the viral genome into the host cell chromosome. In the light of these findings, we hypothesized that OWMs might have evolved resistance mechanism(s) against HIV-1 by switching specific gene(s) on in response to the synthesis of viral proteins in infected cells. In an attempt to mimic post-infection status, we expressed HIV-1 Tat gene in African green monkey cells and compared the whole proteome with normal cells and identified secretory leukocyte protease inhibitor (SLPI), a protein with known extracellular anti-HIV-1 activity, as an over-expressed protein in the presence of HIV-1 Tat protein by 2D-PAGE and mass spectrometry analysis. We also showed that overexpression of SLPI in the presence of HIV-1 Tat was specific to monkey cells. Our results also suggest that SLPI had a previously undiscovered intracellular anti-HIV activity in addition to its extracellular activity. [ABSTRACT FROM AUTHOR]

Chlorocebus aethiops sabaeus, the African Green monkey (AGM), has been proved to exhibit renal vascular remodeling and spontaneous hypertension. However, little is known about the roles of microRNAs (miRNAs) in this process.Using small RNA deep sequencing, we compared the plasma miRNA expression patterns between hypertensive (HT) AGMs and normotensive (NT) AGMs. Expression of miRNAs (miR-122, miR-339, miR-296-5p) was validated independently in plasma samples from 10 HT AGMs and 10 NT AGMs (fold changes are 2.0, 1.6, 2.7 respectively; all P< 0.001). Potential BP (blood pressure)-regulating mRNA targets were predicted by TargetScan and confirmed in the Vero cells. We report for the first time a circulating miRNA profile for AGM. miRNAs, such as miR-122, miR-339, miR-296-5p, may be involved in renal pathologies and spontaneous hypertension of AGM. [ABSTRACT FROM AUTHOR]

Abstract Generating human organs inside interspecies chimeras might one day produce patient-specific organs for clinical applications, but further advances in identifying human chimera-competent pluripotent stem (PS) cells are needed. Moreover, the potential for human PS cells to contribute to the brains in human-animal chimeras raises ethical questions. The use of non-human primate (NHP) chimera-competent PS cells would allow one to test interspecies organogenesis strategies while also bypassing such ethical concerns. Here, we provide the first evidence for a putative chimera-competent pluripotent state in NHPs. Using histone deacetylase (HDAC) and selective kinase inhibition, we converted the PS cells of an Old World monkey, the African Green monkey (aGM), to an ERK-independent cellular state that can be propagated in culture conditions similar to those that sustain chimera-competency in rodent cells. The obtained stem cell lines indefinitely self-renew in MEK inhibitor-containing culture media lacking serum replacement and FGF. Compared to conventional PS cells, the novel stem cells express elevated levels of KLF4, exhibit more intense nuclear staining for TFE3, and manifest increased mitochondrial membrane depolarization. These data are preliminary but indicate that the key to deriving primate chimera-competent PS cells is to shield cells from the activation of ERK, PKC, and WNT signaling. Because of the similarity of aGMs to humans, the more ethically palatable use of NHP cells, and the more similar gestation length between aGMs and large animals such as sheep, the aGM cell lines described herein will serve as a useful tool for evaluating the efficacy and safety of interspecies organogenesis strategies. Future studies will examine chimera-competency and generalizability to human cells. Highlights • Conversion of African green monkey pluripotent stem cells to an ERK-independence using HDAC inhibitor and kinase inhibitors. • Maintenance of African green monkey PS cells in serum-free conditions with MEK, PKC, GSK3, and Tankyrase inhibitors and LIF. • African green monkey ERK-independent pluripotent stem cells possess features associated with a more naïve pluripotent state. • Conversion of African green monkey putative pluripotent stem cells back to a conventional ES cell state. [ABSTRACT FROM AUTHOR]

Background: Management of diabetes remains a major health and economic challenge, demanding test systems in which to develop new therapies. These studies assessed different methodologies for determining glucose tolerance in green monkeys. Methods: Twenty‐eight African green monkeys between 4 and 24 years old underwent single or repeat intravenous glucose tolerance testing (IVGTT), oral glucose tolerance testing (OGTT), and/or graded glucose infusion testing. Results: Geriatric monkeys exhibited glucose intolerance with impaired glucose‐stimulated insulin secretion following IVGTT. Repeat IVGTT and OGTT assessments were inconsistent. Monkeys with low glucose‐stimulated insulin secretion after graded glucose infusion exhibited elevated blood glucose levels. Conclusion: IVGTT and graded glucose infusion protocols revealed differences in glucose tolerance among green monkeys at single time points, including age‐dependent differences suggestive of shifts in pancreatic beta‐cell functional capacity, but care should be applied to study design and the interpretation of data in the setting of longitudinal studies. [ABSTRACT FROM AUTHOR]

For nearly three decades, more than 80 embryonic stem cell lines and more than 100 induced pluripotent stem cell lines have been derived from New World monkeys, Old World monkeys, and great apes. In this comprehensive review, we examine these cell lines originating from marmoset, cynomolgus macaque, rhesus macaque, pig-tailed macaque, Japanese macaque, African green monkey, baboon, chimpanzee, bonobo, gorilla, and orangutan. We outline the methodologies implemented for their establishment, the culture protocols for their long-term maintenance, and their basic molecular characterization. Further, we spotlight any cell lines that express fluorescent reporters. Additionally, we compare these cell lines with human pluripotent stem cell lines, and we discuss cell lines reprogrammed into a pluripotent naive state, detailing the processes used to attain this. Last, we present the findings from the application of these cell lines in two emerging fields: intra- and interspecies embryonic chimeras and blastoids., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Highlights • The paper examines four possible mathematical models for the effect of fusion inhibitor treatment of respiratory syncytial virus infections. • The models are fit to data from a treatment study of RSV in African green monkeys. • We find that the data are insufficient to discriminate between the different drug models. • We find dose and treatment delay combinations that could discriminate between the different models. Abstract Respiratory syncytial virus (RSV) is a respiratory infection that can cause serious illness, particularly in infants. In this study, we test four different model implementations for the effect of a fusion inhibitor, including one model that combines different drug effects, by fitting the models to data from a study of TMC353121 in African green monkeys. We use mathematical modeling to estimate the drug efficacy parameters, ε max , the maximum efficacy of the drug, and EC 50 , the drug concentration needed to achieve half the maximum effect. We find that if TMC353121 is having multiple effects on viral kinetics, more detailed data, using different treatment delays, is needed to detect this effect. [ABSTRACT FROM AUTHOR]

Abstract Experimental results in vitro and in animal models are used to guide researchers in testing vaccines or treatment in humans. However, viral kinetics are different in vitro, in animals, and in humans, so it is sometimes difficult to translate results from one system to another. In this study, we use a mathematical model to fit experimental data from multiple cycle respiratory syncytial virus (RSV) infections in vitro, in african green monkey (AGM), and in humans in order to quantitatively compare viral kinetics in the different systems. We find that there are differences in viral clearance rate, productively infectious cell lifespan, and eclipse phase duration between in vitro and in vivo systems and among different in vivo systems. We show that these differences in viral kinetics lead to different estimates of drug effectiveness of fusion inhibitors in vitro and in AGM than in humans. [ABSTRACT FROM AUTHOR]

Background: The characterization of genomic or epigenomic variation in human and animal models could provide important insight into pathophysiological mechanisms of various diseases, and lead to new developments in disease diagnosis and clinical intervention. The African green monkey (AGM; Chlorocebus aethiops) and cynomolgus monkey (CM; Macaca fascicularis) have long been considered important animal models in biomedical research. However, non-human primate-specific methods applicable to epigenomic analyses in AGM and CM are lacking. The recent development of methyl-capture sequencing (MC-seq) has an unprecedented advantage of cost-effectiveness, and further allows for extending the methylome coverage compared to conventional sequencing approaches. Results: Here, we used a human probe-designed MC-seq method to assay DNA methylation in DNA obtained from 13 CM and three AGM blood samples. To effectively adapt the human probe-designed target region for methylome analysis in non-human primates, we redefined the target regions, focusing on regulatory regions and intragenic regions with consideration of interspecific sequence homology and promoter region variation. Methyl-capture efficiency was controlled by the sequence identity between the captured probes based on the human reference genome and the AGM and CM genome sequences, respectively. Using reasonable guidelines, 56 and 62% of the human-based capture probes could be effectively mapped for DNA methylome profiling in the AGM and CM genome, respectively, according to numeric global statistics. In particular, our method could cover up to 89 and 87% of the regulatory regions of the AGM and CM genome, respectively. Conclusions: Use of human-based MC-seq methods provides an attractive, cost-effective approach for the methylome profiling of non-human primates at the single-base resolution level. [ABSTRACT FROM AUTHOR]

While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD. [ABSTRACT FROM AUTHOR]

Recombinant vesicular stomatitis virus (VSV) is a promising platform for vaccine development. M51R VSV, an attenuated, M protein mutant strain, is an effective inducer of Type I interferon and dendritic cell (DC) maturation, which are desirable properties to exploit for vaccine design. We have previously evaluated M51R VSV (M51R) and M51R VSV that produces flagellin (M51R-F) as vaccine vectors using murine models, and found that flagellin enhanced DC activation and VSV-specific antibody production after low-dose vaccination. In this report, the immunogenicity of M51R vectors and the adjuvant effect of virus-produced flagellin were evaluated in nonhuman primates following high-dose (108 pfu) and low-dose (105 pfu) vaccination. A single intramuscular vaccination of African green monkeys with M51R or M51R-F induced VSV-specific, dose-dependent humoral immune responses. Flagellin induced a significant increase in antibody production (IgM, IgG and neutralizing antibody) at the low vaccination dose. A VSV-specific cellular response was detected at 6 weeks post-vaccination, but was neither dose-dependent nor enhanced by flagellin; similar numbers of VSV-specific, IFN-producing cells were detected in lymph node and spleen of all animals. These results indicate that virus-directed, intracellular flagellin production may improve VSV-based vaccines encoding heterologous antigens by lowering the dose required to achieve humoral immunity. [ABSTRACT FROM AUTHOR]

Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8+ T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4+ and CD8+ T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon [IFN-+ ], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-γ) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model. IMPORTANCE Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen. [ABSTRACT FROM AUTHOR]

Here, I provide the first direct estimate of the spontaneous mutation rate in an Old World monkey, using a seven individual, three-generation pedigree of African green monkeys. Eight de novo mutations were identified within ∼1.5 Gbp of accessible genome, corresponding to an estimated point mutation rate of 0.94 × 10−8 per site per generation, suggesting an effective population size of ∼12000 for the species. This estimation represents a significant improvement in our knowledge of the population genetics of the African green monkey, one of the most important nonhuman primate models in biomedical research. Furthermore, by comparing mutation rates in Old World monkeys with the only other direct estimates in primates to date-humans and chimpanzees-it is possible to uniquely address how mutation rates have evolved over longer time scales. While the estimated spontaneous mutation rate for African green monkeys is slightly lower than the rate of 1.2 × 10−8 per base pair per generation reported in chimpanzees, it is similar to the lower range of rates of 0.96 × 10−8-1.28 × 10−8 per base pair per generation recently estimated from whole genome pedigrees in humans. This result suggests a long-term constraint on mutation rate that is quite different from similar evidence pertaining to recombination rate evolution in primates. [ABSTRACT FROM AUTHOR]