scholarly journals The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

2021 ◽  
Vol 17 (12) ◽  
pp. e1010162
Author(s):  
Alexandra Melton ◽  
Lara A. Doyle-Meyers ◽  
Robert V. Blair ◽  
Cecily Midkiff ◽  
Hunter J. Melton ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Macaca Nemestrina ◽  
The Novel ◽  
Pigtail Macaque ◽  
Immunodeficiency Virus ◽  
Cytotoxic Molecules ◽  
Pathologic Lesions ◽  
Novel Coronavirus

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

scholarly journals The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

2021 ◽  
Author(s):  
Alexandra Melton ◽  
Lara A Doyle-Meyers ◽  
Robert V Blair ◽  
Cecily Midkiff ◽  
Hunter J Melton ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Macaca Nemestrina ◽  
The Novel ◽  
Pigtail Macaque ◽  
Immunodeficiency Virus ◽  
Cytotoxic Molecules ◽  
Pathologic Lesions ◽  
Novel Coronavirus

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over four million people worldwide as of July 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

scholarly journals Consistent Patterns of Change during the Divergence of Human Immunodeficiency Virus Type 1 Envelope from That of the Inoculated Virus in Simian/Human Immunodeficiency Virus-Infected Macaques

2006 ◽  
Vol 80 (2) ◽  
pp. 999-1014 ◽  
Author(s):  
W.M. Blay ◽  
S. Gnanakaran ◽  
B. Foley ◽  
N. A. Doria-Rose ◽  
B. T. Korber ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disulfide Bonds ◽  
Neutralizing Antibodies ◽  
Outer Region ◽  
Synonymous Substitution ◽  
Cross Sectional Study ◽  
Macaca Nemestrina ◽  
Cross Sectional ◽  
Immunodeficiency Virus ◽  
And Shifts

ABSTRACT We have analyzed changes to proviral Env gp120 sequences and the development of neutralizing antibodies (NAbs) during 1 year of simian/human immunodeficiency virus SHIV-89.6P infection in 11 Macaca nemestrina macaques. Seven macaques had significant env divergence from that of the inoculum, and macaques with greater divergence had higher titers of homologous NAbs. Substitutions in sequons encoding potential N-linked glycosylation sites (PNGs) were among the first to be established, although overall the total number of sequons did not increase significantly. The majority (19 of 23) of PNGs present in the inoculum were conserved in the sequences from all macaques. Statistically significant variations in PNGs occurred in multiple macaques within constrained regions we term “hot spots,” resulting in the selection of sequences more similar to the B consensus. These included additions on V1, the N-terminal side of V4, and the outer region of C2. Complex mutational patterns resulted in convergent PNG shifts in V2 and V5. Charge changes in Env V1V2, resulting in a net acidic charge, and a proline addition in V5 occurred in several macaques. Molecular modeling of the 89.6P sequence showed that the conserved glycans lie on the silent face of Env and that many are proximal to disulfide bonds, while PNG additions and shifts are proximal to the CD4 binding site. Nonsynonymous-to-synonymous substitution ratios suggest that these changes result from selective pressure. This longitudinal and cross-sectional study of mutations in human immunodeficiency virus (HIV) env in the SHIV background provides evidence that there are more constraints on the configuration of the glycan shield than were previously appreciated.

scholarly journals Comparison of Four SARS-CoV-2 Neutralization Assays

Vaccines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 13
Author(s):  
Lydia Riepler ◽  
Annika Rössler ◽  
Albert Falch ◽  
André Volland ◽  
Wegene Borena ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
The Other ◽  
In Vitro Assays ◽  
The Novel ◽  
Effective Protection ◽  
Vaccine Candidates ◽  
Vesicular Stomatitis ◽  
Novel Coronavirus

Neutralizing antibodies are a major correlate of protection for many viruses including the novel coronavirus SARS-CoV-2. Thus, vaccine candidates should potently induce neutralizing antibodies to render effective protection from infection. A variety of in vitro assays for the detection of SARS-CoV-2 neutralizing antibodies has been described. However, validation of the different assays against each other is important to allow comparison of different studies. Here, we compared four different SARS-CoV-2 neutralization assays using the same set of patient samples. Two assays used replication competent SARS-CoV-2, a focus forming assay and a TCID50-based assay, while the other two assays used replication defective lentiviral or vesicular stomatitis virus (VSV)-based particles pseudotyped with SARS-CoV-2 spike. All assays were robust and produced highly reproducible neutralization titers. Titers of neutralizing antibodies correlated well between the different assays and with the titers of SARS-CoV-2 S-protein binding antibodies detected in an ELISA. Our study showed that commonly used SARS-CoV-2 neutralization assays are robust and that results obtained with different assays are comparable.

scholarly journals Can common coronavirus compete with novel coronavirus？

2020 ◽  
Author(s):  
ZHONGNENG XU
Keyword(s):  
Resource Competition ◽  
Respiratory Infections ◽  
Medical Application ◽  
Theoretical Implication ◽  
Research Area ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
The Common ◽  
Novel Coronavirus ◽  
Virus Interactions

The novel coronavirus, SARS-CoV-2, caused lethal human respiratory infections, and there is a big problem to control the disease. The application of other viruses to compete with the novel coronavirus was proposed in this paper. On the viewpoint of receptor competition, resource competition, and cross immunity, an attempt should be made to select a natural virus, such as the common coronavirus causing the common cold in human, or transform a virus with biotechnology in order to resist the novel coronavirus. Similar scenarios were suggested to deal with other viruses like human immunodeficiency virus. Microecological communities of viruses could form an independent research area to dig the deeper biological and medical significance. The present study provided the information to further the theoretical implication and medical application of the study of virus interactions.

scholarly journals Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Mauricio A. Martins ◽  
Lucas Gonzalez-Nieto ◽  
Michael J. Ricciardi ◽  
Varian K. Bailey ◽  
Christine M. Dang ◽  
...  
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Vaccine Efficacy ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Hiv Vaccine ◽  
Partial Control ◽  
Immunodeficiency Virus

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

scholarly journals Outpatient management of heart valve disease following the COVID-19 pandemic: implications for present and future care

Heart ◽  
2020 ◽  
Vol 106 (20) ◽  
pp. 1549-1554 ◽  
Author(s):  
Benoy Nalin Shah ◽  
Dominik Schlosshan ◽  
Hannah Zelie Ruth McConkey ◽  
Mamta Heena Buch ◽  
Andrew John Marshall ◽  
...  
Keyword(s):  
Heart Valve ◽  
Waiting Times ◽  
Severe Disease ◽  
Valve Disease ◽  
Heart Valve Disease ◽  
The Novel ◽  
Future Care ◽  
Novel Coronavirus

The established processes for ensuring safe outpatient surveillance of patients with known heart valve disease (HVD), echocardiography for patients referred with new murmurs and timely delivery of surgical or transcatheter treatment for patients with severe disease have all been significantly impacted by the novel coronavirus pandemic. This has created a large backlog of work and upstaging of disease with consequent increases in risk and cost of treatment and potential for worse long-term outcomes. As countries emerge from lockdown but with COVID-19 endemic in society, precautions remain that restrict ‘normal’ practice. In this article, we propose a methodology for restructuring services for patients with HVD and provide recommendations pertaining to frequency of follow-up and use of echocardiography at present. It will be almost impossible to practice exactly as we did prior to the pandemic; thus, it is essential to prioritise patients with the greatest clinical need, such as those with symptomatic severe HVD. Local procedural waiting times will need to be considered, in addition to usual clinical characteristics in determining whether patients requiring intervention would be better suited having surgical or transcatheter treatment. We present guidance on the identification of stable patients with HVD that could have follow-up deferred safely and suggest certain patients that could be discharged from follow-up if waiting lists are triaged with appropriate clinical input. Finally, we propose that novel models of working enforced by the pandemic—such as increased use of virtual clinics—should be further developed and evaluated.

scholarly journals Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Guillaume Carissimo ◽  
Weili Xu ◽  
Immanuel Kwok ◽  
Mohammad Yazid Abdad ◽  
Yi-Hao Chan ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Whole Blood ◽  
Roc Analysis ◽  
Γδ T Cells ◽  
High Sensitivity ◽  
The Novel ◽  
Cellular Mechanisms ◽  
Cell Counts ◽  
Novel Coronavirus

Abstract SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.

scholarly journals Infection Control in Dental Anesthesiology: A Time for Preliminary Reconsideration of Current Practices

2020 ◽  
Vol 67 (2) ◽  
pp. 109-120
Author(s):  
James Tom
Keyword(s):  
Infection Control ◽  
Rapid Evolution ◽  
Protective Equipment ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
Protective Eyewear ◽  
Risk Of Exposure ◽  
Novel Coronavirus ◽  
Care History ◽  
Current Practices

Relegated to clinical afterthought, the topic of infection control has never taken center stage in our modern dental sedation and anesthesiology practices. Surgical and procedural masks, gloves, gowns, protective eyewear, and appropriate surgical attire have remained de rigueur in both fashion and custom for decades. However, the emergence of certain seminal events throughout health care history has driven mandated changes when practitioners, staff, patients, and the surrounding communities were exposed or put at risk of exposure to infectious disease. Hepatitis, human immunodeficiency virus, and now the global COVID-19 pandemic involving the novel coronavirus SARS-CoV-2, have forced us into rethinking our current practices. This review article will contextualize previous epidemics and their influence on infection control in dental settings, and it will explore the rapid evolution of current modifications to personal protective equipment and infection mitigation practices specific to sedation and anesthesia in dentistry.

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