Michael K. Axthelm

Oregon National Primate Research Center

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Louis J. Picker

Children's Cancer Therapy Development Institute

Alfred W. Legasse

Oregon National Primate Research Center

Scott G. Hansen

Oregon Health & Science University

Jonah B. Sacha

Oregon Health & Science University

Jeffrey D. Lifson

Frederick National Laboratory for Cancer Research

Klaus Früh

Oregon Health & Science University

Andrew Sylwester

Oregon Health & Science University

Scott W. Wong

Oregon National Primate Research Center

Jeremy Smedley

Oregon National Primate Research Center

Haesun Park

Georgia Institute of Technology

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Oregon Health & Science University

378

Oregon National Primate Research Center

333

Children's Cancer Therapy Development Institute

124

Harvard University

University of Washington

National Institutes of Health

Vaccine and Gene Therapy Institute

Stanford University

National Institute of Allergy and Infectious Diseases

National Cancer Institute

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Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model

PLoS neglected tropical diseases (2014)

Flora Engelmann Laurence Josset Thomas Girke Byung Park Alex Barron

Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.

Yellow fever vaccine

Rhesus macaque

10.1371/journal.pntd.0003295

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Citations (70)

Changes in Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Responsible for the Pathogenicity of a Multiply Passaged Simian-Human Immunodeficiency Virus (SHIV-HXBc2)

Journal of Virology (1999)

Mark J. Cayabyab Gunilla B. Karlsson Bijan Etemad-Moghadam Wolfgang Hofmann Tavis D. Steenbeke

In vivo passage of a poorly replicating, nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) generated an efficiently replicating virus, KU-1, that caused rapid CD4(+) T-lymphocyte depletion and AIDS-like illness in monkeys (S. V. Joag, Z. Li, L. Foresman, E. B. Stephens, L.-J. Zhao, I. Adany, D. M. Pinson, H. M. McClure, and O. Narayan, J. Virol. 70:3189-3197, 1996). The env gene of the KU-1 virus was used to create a molecularly cloned virus, SHIV-HXBc2P 3.2, that differed from a nonpathogenic SHIV-HXBc2 virus in only 12 envelope glycoprotein residues. SHIV-HXBc2P 3.2 replicated efficiently and caused rapid and persistent CD4(+) T-lymphocyte depletion in inoculated rhesus macaques. Compared with the envelope glycoproteins of the parental SHIV-HXBc2, the SHIV-HXBc2P 3.2 envelope glycoproteins supported more efficient infection of rhesus monkey peripheral blood mononuclear cells. Both the parental SHIV-HXBc2 and the pathogenic SHIV-HXBc2P 3.2 used CXCR4 but none of the other seven transmembrane segment receptors tested as a second receptor. Compared with the parental virus, viruses with the SHIV-HXBc2P 3.2 envelope glycoproteins were more resistant to neutralization by soluble CD4 and antibodies. Thus, changes in the envelope glycoproteins account for the ability of the passaged virus to deplete CD4(+) T lymphocytes rapidly and specify increased replicative capacity and resistance to neutralization.

Simian immunodeficiency virus

10.1128/jvi.73.2.976-984.1999

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Citations (88)

Figure S4 from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein

Michael D. Oberst Catherine Augé Chad D. Morris Stacy Kentner Kathy Mulgrew

<p>Expression of cell surface Fc gamma receptors on human cells</p>

Immune Modulation

Modulation (music)

10.1158/1535-7163.22505539.v1

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Data from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein

Michael D. Oberst Catherine Augé Chad D. Morris Stacy Kentner Kathy Mulgrew

<div>Abstract<p>Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. <i>Mol Cancer Ther; 17(5); 1024–38. ©2018 AACR</i>.</p></div>

Memory T cell

10.1158/1535-7163.c.6538102.v1

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Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer

Proceedings of the National Academy of Sciences (2013)

Nathan J. Weyand Anne M. Wertheimer Theodore R. Hobbs Jennifer L. Sisko Nyiawung A. Taku

The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbe–host interactions. We developed a rhesus macaque model for studying Neisseria –host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria , as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates.

Neisseria

Neisseria gonorrhoeae

Rhesus macaque

Horizontal Gene Transfer

Tissue tropism

10.1073/pnas.1217420110

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Citations (31)

Optimization and use of near infrared imaging to guide lymph node collection in rhesus macaques (Macaca mulatta)

Journal of Medical Primatology (2022)

Jeremy Smedley Rachele M. Bochart Miranda Fischer Heidi Funderburgh Vanessa J. Kelly

Abstract Background Identification of lymph nodes (LNs) draining a specific site or in obese macaques can be challenging. Methods Indocyanine Green (ICG) was administered intradermal (ID), intramuscular, in the oral mucosa, or subserosal in the colon followed by Near Infrared (NIR) imaging. Results After optimization to maximize LN identification, intradermal ICG was successful in identifying 50–100% of the axillary/inguinal LN at a site. Using NIR, collection of peripheral and mesenteric LNs in obese macaques was 100% successful after traditional methods failed. Additionally, guided collection of LNs draining the site of intraepithelial or intramuscular immunization demonstrated significantly increased numbers of T follicular helper (Tfh) cells in germinal centers of draining compared to nondraining LNs. Conclusion These imaging techniques optimize our ability to evaluate immune changes within LNs over time, even in obese macaques. This approach allows for targeted serial biopsies that permit confidence that draining LNs are being harvested throughout the study.

Indocyanine Green

Intradermal injection

10.1111/jmp.12605

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Citations (3)

Correction: Corrigendum: Immune clearance of highly pathogenic SIV infection

Nature (2014)

Scott G. Hansen Michael Piatak Abigail B. Ventura Colette M. Hughes Roxanne M. Gilbride

10.1038/nature13840

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Citations (1)

Increased CD4+ T Cell Levels during IL-7 Administration of Antiretroviral Therapy-Treated Simian Immunodeficiency Virus-Positive Macaques Are Not Dependent on Strong Proliferative Responses

The Journal of Immunology (2010)

Amanda Leone Mukta Rohankhedkar Afam A. Okoye Alfred W. Legasse Michael K. Axthelm

CD4(+) T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4(+) T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4(+) and CD8(+) subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4(+) T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4(+) T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4(+) T cell proliferation initially and provide increased CD4(+) T cell survival.

Simian immunodeficiency virus

Rhesus macaque

10.4049/jimmunol.0902626

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Citations (33)

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy

Journal of Clinical Investigation (2022)

Benjamin Varco-Merth William Brantley Alejandra Marenco Derick D. Duell Devin N. Fachko

Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA–treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.

Simian immunodeficiency virus

Simian

10.1172/jci156063

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Citations (12)

Mayaro virus pathogenesis and immunity in rhesus macaques

PLoS neglected tropical diseases (2023)

Whitney C. Weber Caralyn Labriola Craig N. Kreklywich Karina Ray Nicole N. Haese

Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 10 5 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.

Viremia

Rhesus macaque

Pathogenesis

10.1371/journal.pntd.0011742

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Citations (5)