scholarly journals Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

2020 ◽  
Vol 117 (12) ◽  
pp. 6771-6776 ◽  
Author(s):  
Emmie de Wit ◽  
Friederike Feldmann ◽  
Jacqueline Cronin ◽  
Robert Jordan ◽  
Atsushi Okumura ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Clinical Signs ◽  
Case Fatality ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Lung Lesions ◽  
Macaque Model ◽  
Novel Coronavirus ◽  
Clear Clinical Benefit

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

scholarly journals Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Kun-Chao Wu ◽  
Ji-Neng Lv ◽  
Hui Yang ◽  
Feng-Mei Yang ◽  
Rui Lin ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Clinical Characteristics ◽  
Rhesus Macaques ◽  
Oculocutaneous Albinism ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Melanin Biosynthesis ◽  
Preclinical Trials ◽  
Animal Resources

Human visual acuity is anatomically determined by the retinal fovea. The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism (OCA), which is characterized by a disorder of melanin synthesis. Although people of all ethnic backgrounds can be affected, no efficient treatments for OCA have been developed thus far, due partly to the lack of effective animal models. Rhesus macaques are genetically homologous to humans and, most importantly, exhibit structures of the macula and fovea that are similar to those of humans; thus, rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases. In this study, we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior, fundus examination, and optical coherence tomography. Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2, both of which were further confirmed to affect melanin biosynthesis via in vitro assays. These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA.

scholarly journals Proteomic Insights into Senescence of Testicular Peritubular Cells from a Nonhuman Primate Model

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2498
Author(s):  
Jan B. Stöckl ◽  
Nina Schmid ◽  
Florian Flenkenthaler ◽  
Charis Drummer ◽  
Rüdiger Behr ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Human Testis ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Morphological Alterations ◽  
Age Related ◽  
Cell Niche ◽  
Peritubular Cells

Age-related changes in the human testis may include morphological alterations, disturbed steroidogenesis, and impaired spermatogenesis. However, the specific impact of cell age remains poorly understood and difficult to assess. Testicular peritubular cells fulfill essential functions, including sperm transport, contributions to the spermatogonial stem cell niche, and paracrine interactions within the testis. To study their role in age-associated decline of testicular functions, we performed comprehensive proteome and secretome analyses of repeatedly passaged peritubular cells from Callithrix jacchus. This nonhuman primate model better reflects the human testicular biology than rodents and further gives access to young donors unavailable from humans. Among 5095 identified proteins, 583 were differentially abundant between samples with low and high passage numbers. The alterations indicate a reduced ability of senescent peritubular cells to contract and secrete proteins, as well as disturbances in nuclear factor (NF)-κB signaling and a reduced capacity to handle reactive oxygen species. Since this in vitro model may not exactly mirror all molecular aspects of in vivo aging, we investigated the proteomes and secretomes of testicular peritubular cells from young and old donors. Even though the age-related alterations at the protein level were less pronounced, we found evidence for impaired protein secretion, altered NF-κB signaling, and reduced contractility of these in vivo aged peritubular cells.

Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1261-1269 ◽  
Author(s):  
Carolina Berger ◽  
C. Anthony Blau ◽  
Meei-Li Huang ◽  
John D. Iuliucci ◽  
David C. Dalgarno ◽  
...  
Keyword(s):  
T Cells ◽  
Transgene Expression ◽  
Macaca Nemestrina ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Enhanced Sensitivity ◽  
Chemically Induced ◽  
Chemically Induced Dimerization

Abstract Conditional suicide genes derived from pathogens have been developed to confer drug sensitivity and enhance safety of cell therapy, but this approach is limited by immune responses to the transgene product. We examined a strategy to regulate survival of transferred cells based on induction of apoptosis through oligomerization of a modified human Fas receptor by a bivalent drug (AP1903). Three macaques (Macaca nemestrina) received autologous T cells retrovirally engineered to express a Fas suicide-construct (LV'VFas). High levels of transduced cells were present in blood following cell transfer, but LV'VFas+ cells declined rapidly after AP1903 administration. A small fraction of LV'VFas+ cells resisted elimination by AP1903, in part due to insufficient levels of transgene expression in resting T cells, because reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response to the transgene product was observed, but epitope mapping indicated the response was directed to discrete components of human LV'VFas that were variant with the corresponding macaque sequences. These data demonstrate that chemically induced dimerization can be used to regulate survival of adoptively transferred T cells in vivo.

scholarly journals Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

2020 ◽  
Author(s):  
Brandi N. Williamson ◽  
Friederike Feldmann ◽  
Benjamin Schwarz ◽  
Kimberly Meade-White ◽  
Danielle P. Porter ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Clinical Benefit ◽  
Rhesus Macaques ◽  
Severe Pneumonia ◽  
Viral Loads ◽  
Macaque Model ◽  
Lower Respiratory Tract Disease ◽  
Tract Disease

AbstractBackgroundEffective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection.MethodsTo evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy.ResultsIn contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue.ConclusionsTherapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

scholarly journals Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

2020 ◽  
Author(s):  
Vincent J. Munster ◽  
Friederike Feldmann ◽  
Brandi N. Williamson ◽  
Neeltje van Doremalen ◽  
Lizzette Pérez-Pérez ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Respiratory Disease ◽  
Rhesus Macaques ◽  
Case Fatality ◽  
World Health ◽  
Virus Shedding ◽  
Viral Loads ◽  
Repeated Sampling ◽  
Novel Coronavirus ◽  
Health Organization

An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a ∼2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.

scholarly journals A Nonhuman Primate Model of Lung Regeneration: Detergent-Mediated Decellularization and Initial In Vitro Recellularization with Mesenchymal Stem Cells

2012 ◽  
Vol 18 (23-24) ◽  
pp. 2437-2452 ◽  
Author(s):  
Ryan W. Bonvillain ◽  
Svitlana Danchuk ◽  
Deborah E. Sullivan ◽  
Aline M. Betancourt ◽  
Julie A. Semon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nonhuman Primate ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Lung Regeneration

scholarly journals I267L Is Neither the Virulence- Nor the Replication-Related Gene of African Swine Fever Virus and Its Deletant Is an Ideal Fluorescent-Tagged Virulence Strain

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 53
Author(s):  
Yanyan Zhang ◽  
Junnan Ke ◽  
Jingyuan Zhang ◽  
Huixian Yue ◽  
Teng Chen ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
African Swine Fever Virus ◽  
Clinical Signs ◽  
Case Fatality ◽  
African Swine Fever ◽  
Fever Virus ◽  
Economic Losses ◽  
Effective Vaccine ◽  
Domestic Pigs

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF) which reaches up to 100% case fatality in domestic pigs and wild boar and causes significant economic losses in the swine industry. Lack of knowledge of the function of ASFV genes is a serious impediment to the development of the safe and effective vaccine. Herein, I267L was identified as a relative conserved gene and an early expressed gene. A recombinant virus (SY18ΔI267L) with I267L gene deletion was produced by replacing I267L of the virulent ASFV SY18 with enhanced green fluorescent protein (EGFP) cassette. The replication kinetics of SY18ΔI267L is similar to that of the parental isolate in vitro. Moreover, the doses of 102.0 TCID50 (n = 5) and 105.0 TCID50 (n = 5) SY18ΔI267L caused virulent phenotype, severe clinical signs, viremia, high viral load, and mortality in domestic pigs inoculated intramuscularly as the virulent parental virus strain. Therefore, the deletion of I267L does not affect the replication or the virulence of ASFV. Utilizing the fluorescent-tagged virulence deletant can be easy to gain a visual result in related research such as the inactivation effect of some drugs, disinfectants, extracts, etc. on ASFV.

scholarly journals In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis

2017 ◽  
Vol 115 (1) ◽  
pp. E62-E71 ◽  
Author(s):  
Uma S. Gautam ◽  
Taylor W. Foreman ◽  
Allison N. Bucsan ◽  
Ashley V. Veatch ◽  
Xavier Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Clinical Signs ◽  
Bacterial Killing ◽  
Checkpoint Signaling ◽  
Macaque Model ◽  
Immune Mediated ◽  
Tryptophan Catabolism

Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4+ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4+ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.

scholarly journals Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing and in Human Immunodeficiency Virus-Infected Children after Intravenous and Oral Dosing

1998 ◽  
Vol 42 (7) ◽  
pp. 1815-1818 ◽  
Author(s):  
Brigitta U. Mueller ◽  
Barry D. Anderson ◽  
Maureen Q. Farley ◽  
Robert Murphy ◽  
Judy Zuckerman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cerebrospinal Fluid ◽  
Nonhuman Primates ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Terminal Half Life ◽  
Elimination Clearance

ABSTRACT KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug’s efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.

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