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1.  Specific Pathogen-Free Status Alters Immunophenotype in Rhesus Macaques: Implications for the Study of Simian Immunodeficiency Virus 
AIDS Research and Human Retroviruses  2011;27(10):1033-1042.
The repertoire of viruses to which research primates are exposed, even in the absence of clinical disease, may contribute to experimental confounding. In this study we examined whether standard specific pathogen-free (SPF) rhesus macaques exposed to a wider spectrum of enzootic viruses and expanded SPF macaques derived to exclude a greater number of viral agents would display alterations in immune activation or immune cell populations. Given the impact of immunophenotype on human immunodeficiency virus (HIV) progression and the importance of the simian immunodeficiency virus (SIV) model for the study of HIV pathogenesis, we elected to additionally examine the impact of SPF status on the capacity of peripheral blood mononuclear cells (PBMCs) to support SIV replication. The expanded SPF group displayed significant immune alterations including increased serum interleukin (IL)-15 and a greater in vitro elaboration of GM-CSF, IL1ra, VEGF, IL-10, IL12/23, and MIP-1b. Consistent with reduced viral antigenic exposure in expanded SPF macaques, decreased CD4+ and CD8+ transitional and effector memory (TEM) cell populations were observed. Expanded SPF PBMC cultures also demonstrated an increased peak (192.61 ng/ml p27) and area under the curve in in vitro SIV production (1968.64 ng/ml p27) when compared to standard SPF macaques (99.32 ng/ml p27; p=0.03 and 915.17 ng/ml p27; p=0.03, respectively). In vitro SIV replication did not correlate with CD4+ TEM cell counts but was highly correlated with serum IL-15 in the subset of animals examined. Findings suggest that an altered immunophenotype associated with the maintenance of primates under differing levels of bioexclusion has the potential to impact the outcome of SIV studies and models for which the measurement of immunologic endpoints is critical.
PMCID: PMC3186704  PMID: 21391843
2.  Characterization of plasma thiol redox potential in a common marmoset model of aging☆ 
Redox Biology  2013;1(1):387-393.
Due to its short lifespan, ease of use and age-related pathologies that mirror those observed in humans, the common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate model of aging. Blood and extracellular fluid possess two major thiol-dependent redox nodes involving cysteine (Cys), cystine (CySS), glutathione (GSH) and glutathione disulfide (GSSG). Alteration in these plasma redox nodes significantly affects cellular physiology, and oxidation of the plasma Cys/CySS redox potential (EhCySS) is associated with aging and disease risk in humans. The purpose of this study was to determine age-related changes in plasma redox metabolites and corresponding redox potentials (Eh) to further validate the marmoset as a nonhuman primate model of aging. We measured plasma thiol redox states in marmosets and used existing human data with multivariate adaptive regression splines (MARS) to model the relationships between age and redox metabolites. A classification accuracy of 70.2% and an AUC of 0.703 were achieved using the MARS model built from the marmoset redox data to classify the human samples as young or old. These results show that common marmosets provide a useful model for thiol redox biology of aging.
Graphical abstract
•Characterization of the Common Marmoset as a model for aging research.•Plasma thiol redox measurements in marmosets ranging in age from 2–16 years.•Similar to humans, marmosets exhibit age-related alterations in plasma thiol redox metabolites.•Marmoset redox data can be used to classify humans as young or old.
PMCID: PMC3757708  PMID: 24024176
Cysteine; Cystine; Glutathione; Marmoset; Plasma
3.  High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring 
Toxicology  2012;295(1-3):47-55.
High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: 1) whether more chemicals are detected in humans living in a less controlled environment than captive species, and 2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537 to 3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.
PMCID: PMC3332037  PMID: 22387982
metabolomics; plasma; mass spectrometry; probability-based modularity clustering; exposome
4.  Differential contribution of dietary fat and monosaccharide to metabolic syndrome in the common marmoset (Callithrix jacchus) 
Obesity (Silver Spring, Md.)  2010;19(6):1145-1156.
There is a critical need for animal models to study aspects type 2 diabetes mellitus pathogenesis and prevention. While the rhesus macaque is such an established model, the common marmoset has added benefits including reduced zoonotic risks, shorter life span, and a predisposition to birth twins demonstrating chimerism. The marmoset as a model organism for the study of metabolic syndrome has not been fully evaluated. Marmosets fed high-fat or glucose-enriched diets were followed longitudinally to observe effects on morphometric and metabolic measures. Effects on pancreatic histomorphometry and vascular pathology were examined terminally. The glucose–enriched diet group developed an obese phenotype and a prolonged hyperglycemic state evidenced by a rapid and persistent increase in mean glycosylated hemoglobin (HgbA1c) observed as early as week 16. In contrast, marmosets fed a high-fat diet did not maintain an obese phenotype and demonstrated a delayed increase in HgbA1c that did not reach statistical significance until week 40. Consumption of either diet resulted in profound pancreatic islet hyperplasia suggesting a compensation for increased insulin requirements. Although the high fat diet group developed atherosclerosis of increased severity, the presence of lesions correlated with glucose intolerance only in the glucose-enriched diet group. The altered timing of glucose dysregulation, differential contribution to obesity, and variation in vascular pathology suggests mechanisms of effect specific to dietary nutrient content. Feeding nutritionally modified diets to common marmosets recapitulates aspects of metabolic disease and represents a model that may prove instrumental to elucidating the contribution of nutrient excess to disease development.
PMCID: PMC3099141  PMID: 21164504
5.  Non-Human Primate Model of Kaposi's Sarcoma-Associated Herpesvirus Infection 
PLoS Pathogens  2009;5(10):e1000606.
Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.
Author Summary
Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8), the most recently identified human tumor-inducing virus, has been linked to Kaposi's sarcoma, pleural effusion lymphomas and multicentric Castleman's disease. In fact, KSHV accounts for a large proportion of the cancer deaths in Africa. Further, the incidence of KSHV in the US and Europe has greatly increased due to the AIDS pandemic. Despite these pressing human health problems, studies of KSHV infection are greatly hampered by the lack of cell culture and animal models. To address this serious need, we set out to develop an animal model for KSHV infection. In this manuscript, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Our study demonstrates that experimental KSHV infection of the common marmoset is highly analogous to its infection of humans, including the means of infection, sustained serological responses, latent infection of PBMCs, virus persistence, and KS-like skin lesion development, although the latter was infrequent in experimental KSHV infections. This model thus provides a unique opportunity to dissect the molecular mechanisms of KSHV infection, persistence, and pathogenesis directly in primates.
PMCID: PMC2745662  PMID: 19798430

Results 1-5 (5)