Publications by authors named "Ivanela Kondova"

56 Publications

Aerosolized Exposure to H5N1 Influenza Virus Causes Less Severe Disease Than Infection via Combined Intrabronchial, Oral, and Nasal Inoculation in Cynomolgus Macaques.

Viruses 2021 02 22;13(2). Epub 2021 Feb 22.

Department of Virology, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands.

Infection with highly pathogenic avian H5N1 influenza virus in humans often leads to severe respiratory disease with high mortality. Experimental infection in non-human primates can provide additional insight into disease pathogenesis. However, such a model should recapitulate the disease symptoms observed in humans, such as pneumonia and inflammatory cytokine response. While previous studies in macaques have demonstrated the occurrence of typical lesions in the lungs early after infection and a high level of immune activation, progression to severe disease and lethality were rarely observed. Here, we evaluated a routinely used combined route of infection via intra-bronchial, oral, and intra-nasal virus inoculation with aerosolized H5N1 exposure, with or without the regular collection of bronchoalveolar lavages early after infection. Both combined route and aerosol exposure resulted in similar levels of virus replication in nose and throat and similar levels of immune activation, cytokine, and chemokine release in the blood. However, while animals exposed to H5N1 by combined-route inoculation developed severe disease with high lethality, aerosolized exposure resulted in less lesions, as measured by consecutive computed tomography and less fever and lethal disease. In conclusion, not virus levels or immune activation, but route of infection determines fatal outcome for highly pathogenic avian H5N1 influenza infection.
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http://dx.doi.org/10.3390/v13020345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926951PMC
February 2021

Recently Evolved Enhancers Emerge with High Interindividual Variability and Less Frequently Associate with Disease.

Cell Rep 2020 06;31(12):107799

Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, the Netherlands; Erasmus University Medical Center, Department of Developmental Biology, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address:

Mutations in non-coding regulatory DNA such as enhancers underlie a wide variety of diseases including developmental disorders and cancer. As enhancers rapidly evolve, understanding their function and configuration in non-human disease models can have important clinical applications. Here, we analyze enhancer configurations in tissues isolated from the common marmoset, a widely used primate model for human disease. Integrating these data with human and mouse data, we find that enhancers containing trait-associated variants are preferentially conserved. In contrast, most human-specific enhancers are highly variable between individuals, with a subset failing to contact promoters. These are located further away from genes and more often reside in inactive B-compartments. Our data show that enhancers typically emerge as instable elements with minimal biological impact prior to their integration in a transcriptional program. Furthermore, our data provide insight into which trait variations in enhancers can be faithfully modeled using the common marmoset.
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http://dx.doi.org/10.1016/j.celrep.2020.107799DOI Listing
June 2020

Immunohistochemical distribution of 10 GABA receptor subunits in the forebrain of the rhesus monkey Macaca mulatta.

J Comp Neurol 2020 10 3;528(15):2551-2568. Epub 2020 Apr 3.

Division of Pathology and Microbiology, Animal Science Department, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

GABA receptors are composed of five subunits arranged around a central chloride channel. Their subunits originate from different genes or gene families. The majority of GABA receptors in the mammalian brain consist of two α-, two β- and one γ- or δ-subunit. This subunit organization crucially determines the physiological and pharmacological properties of the GABA receptors. Using immunohistochemistry, we investigated the distribution of 10 GABA receptor subunits (α1, α2, α3, α4, α5, β1, β2, β3, γ2, and δ) in the fore brain of three female rhesus monkeys (Macaca mulatta). Within the cerebral cortex, subunits α1, α5, β2, β3, and γ2 were found in all layers, α2, α3, and β1 were more concentrated in the inner and outer layers. The caudate/putamen was rich in α1, α2, α5, all three β-subunits, γ2, and δ. Subunits α3 and α5 were more concentrated in the caudate than in the putamen. In contrast, α1, α2, β1, β2, γ2, and δ were highest in the pallidum. Most dorsal thalamic nuclei contained subunits α1, α2, α4, β2, β3, and γ2, whereas α1, α3, β1, and γ2 were most abundant in the reticular nucleus. Within the amygdala, subunits α1, α2, α5, β1, β3, γ2, and δ were concentrated in the cortical nucleus, whereas in the lateral and basolateral amygdala α1, α2, α5, β1, β3, and δ, and in the central amygdala α1, α2, β3, and γ2 were most abundant. Interestingly, subunit α3-IR outlined the intercalated nuclei of the amygdala. In the hippocampus, subunits α1, α2, α5, β2, β3, γ2, and δ were highly expressed in the dentate molecular layer, whereas α1, α2, α3, α5, β1, β2, β3, and γ2 were concentrated in sector CA1 and the subiculum. The distribution of GABA receptor subunits in the rhesus monkey was highly heterogeneous indicating a high number of differently assembled receptors. In most areas investigated, notably in the striatum/pallidum, amygdaloid nuclei and in the hippocampus it was more diverse than in the rat and mouse indicating a more heterogeneous and less defined receptor assembly in the monkey than in rodent brain.
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http://dx.doi.org/10.1002/cne.24910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496627PMC
October 2020

Differential DNA methylation of vocal and facial anatomy genes in modern humans.

Nat Commun 2020 03 4;11(1):1189. Epub 2020 Mar 4.

Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.
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http://dx.doi.org/10.1038/s41467-020-15020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055320PMC
March 2020

Hominin-specific regulatory elements selectively emerged in oligodendrocytes and are disrupted in autism patients.

Nat Commun 2020 01 16;11(1):301. Epub 2020 Jan 16.

Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.

Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes. Determining which changes are relevant and underlie the emergence of the human brain or its unique susceptibility to neural disease has been challenging. Here we annotate changes to gene regulatory elements (GREs) at cell type resolution in the brains of multiple primate species spanning most of primate evolution. We identify a unique set of regulatory elements that emerged in hominins prior to the separation of humans and chimpanzees. We demonstrate that these hominin gains perferentially affect oligodendrocyte function postnatally and are preferentially affected in the brains of autism patients. This preference is also observed for human-specific GREs suggesting this system is under continued selective pressure. Our data provide a roadmap of regulatory rewiring across primate evolution providing insight into the genomic changes that underlie the emergence of the brain and its susceptibility to neural disease.
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http://dx.doi.org/10.1038/s41467-019-14269-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965079PMC
January 2020

Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques.

Nat Med 2019 02 21;25(2):255-262. Epub 2019 Jan 21.

Biomedical Primate Research Centre, Rijswijk, the Netherlands.

Tuberculosis (TB) remains the deadliest infectious disease, and the widely used Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved vaccination strategy could provide a cost-effective intervention to break the transmission cycle and prevent antimicrobial resistance. Limited knowledge of the host responses critically involved in protective immunity hampers the development of improved TB vaccination regimens. Therefore, assessment of new strategies in preclinical models to select the best candidate vaccines before clinical vaccine testing remains indispensable. We have previously established in rhesus macaques (Macaca mulatta) that pulmonary mucosal BCG delivery reduces TB disease where standard intradermal injection fails. Here, we show that pulmonary BCG prevents infection by using a repeated limiting-dose Mycobacterium tuberculosis challenge model and identify polyfunctional T-helper type 17 (T17) cells, interleukin-10 and immunoglobulin A as correlates of local protective immunity. These findings warrant further research into mucosal immunization strategies and their translation to clinical application to more effectively prevent the spread of TB.
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http://dx.doi.org/10.1038/s41591-018-0319-9DOI Listing
February 2019

Gene expression variability across cells and species shapes innate immunity.

Nature 2018 11 24;563(7730):197-202. Epub 2018 Oct 24.

Wellcome Sanger Institute, Cambridge, UK.

As the first line of defence against pathogens, cells mount an innate immune response, which varies widely from cell to cell. The response must be potent but carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here we characterize the innate immune response's transcriptional divergence between species and variability in expression among cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we map the architecture of the innate immune response. Transcriptionally diverging genes, including those that encode cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes that are involved in the regulation of this response, such as those that encode transcription factors and kinases, are conserved between species and display low cell-to-cell variability in expression. We suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective but balanced response.
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http://dx.doi.org/10.1038/s41586-018-0657-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347972PMC
November 2018

Cell Type and Species-specific Patterns in Neuronal and Non-neuronal Methylomes of Human and Chimpanzee Cortices.

Cereb Cortex 2018 10;28(10):3724-3739

Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.

Epigenetic changes have likely contributed to the large size and enhanced cognitive abilities of the human brain which evolved within the last 2 million years after the human-chimpanzee split. Using reduced representation bisulfite sequencing, we have compared the methylomes of neuronal and non-neuronal cells from 3 human and 3 chimpanzee cortices. Differentially methylated regions (DMRs) with genome-wide significance were enriched in specific genomic regions. Intraspecific methylation differences between neuronal and non-neuronal cells were approximately 3 times more abundant than interspecific methylation differences between human and chimpanzee cell types. The vast majority (>90%) of human intraspecific DMRs (including DMRs in retrotransposons) were hypomethylated in neurons, compared with glia. Intraspecific DMRs were enriched in genes associated with different neuropsychiatric disorders. Interspecific DMRs were enriched in genes showing human-specific brain histone modifications. Human-chimpanzee methylation differences were much more frequent in non-neuronal cells (n. DMRs = 666) than in neurons (n. DMRs = 96). More than 95% of interspecific DMRs in glia were hypermethylated in humans. Although without an outgroup we cannot assign whether a change in methylation occurred in the human or chimpanzee lineage, our results are consistent with a wave of methylation affecting several hundred non-neuronal genes during human brain evolution.
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http://dx.doi.org/10.1093/cercor/bhy180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132288PMC
October 2018

The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to .

Front Immunol 2018 12;9:1123. Epub 2018 Jun 12.

Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.

DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important roles in (Mtb) interactions with dendritic cells, its contribution to the Mtb-macrophage interaction remains poorly understood. Since high levels of IL-4 are correlated with tuberculosis (TB) susceptibility and progression, we investigated the role of DC-SIGN in M(IL-4) macrophages in the TB context. First, we demonstrate that DC-SIGN expression is present both in CD68 macrophages found in tuberculous pulmonary lesions of non-human primates, and in the CD14 cell population isolated from pleural effusions obtained from TB patients (TB-PE). Likewise, we show that DC-SIGN expression is accentuated in M(IL-4) macrophages derived from peripheral blood CD14 monocytes isolated from TB patients, or in macrophages stimulated with acellular TB-PE, arguing for the pertinence of DC-SIGN-expressing macrophages in TB. Second, using a siRNA-mediated gene silencing approach, we performed a transcriptomic analysis of DC-SIGN-depleted M(IL-4) macrophages and revealed the upregulation of pro-inflammatory signals in response to challenge with Mtb, as compared to control cells. This pro-inflammatory gene signature was confirmed by RT-qPCR, cytokine/chemokine-based protein array, and ELISA analyses. We also found that inactivation of DC-SIGN renders M(IL-4) macrophages less permissive to Mtb intracellular growth compared to control cells, despite the equal level of bacteria uptake. Last, at the molecular level, we show that DC-SIGN interferes negatively with the pro-inflammatory response and control of Mtb intracellular growth mediated by another CLR, Dectin-1 (CLEC7A). Collectively, this study highlights a dual role for DC-SIGN as, on the one hand, being a host factor granting advantage for Mtb to parasitize macrophages and, on the other hand, representing a molecular switch to turn off the pro-inflammatory response in these cells to prevent potential immunopathology associated to TB.
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http://dx.doi.org/10.3389/fimmu.2018.01123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006465PMC
July 2019

RNA editing independently occurs at three mir-376a-1 sites and may compromise the stability of the microRNA hairpin.

Gene 2017 Sep 12;628:109-116. Epub 2017 Jul 12.

Institute of Evolutionary Biology (IBE) (Universitat Pompeu Fabra-CSIC), Barcelona 08003, Spain; School of Medicine, University of Magallanes, Punta Arenas, Chile. Electronic address:

RNA editing is being recognized as an important post-transcriptional mechanism that may have crucial roles in introducing genetic variation and phenotypic diversity. Despite microRNA editing recurrence, defining its biological relevance is still under extended debate. To better understand microRNA editing function and regulation we performed an exhaustive characterization of the A-to-I site-specific patterns in mir-376a-1, a mammalian microRNA which RNA editing is involved in the regulation of development and in disease. Thorough an integrative approach based on high-throughput small RNA sequencing, Sanger sequencing and computer simulations we explored mir-376a-1 editing in samples from various individuals and primate species including human placenta and macaque, gorilla, chimpanzee and human brain cortex. We observed that mir-376a-1 editing is a common phenomenon in the mature and primary microRNA molecules and it is more frequently detected in brain than in placenta. Primary mir-376a-1 is edited at three positions, -1, +4 and +44. Editing frequency estimations and in silico simulations indicated that editing was not equally recurrent along the three mir-376a-1 sites, nevertheless no epistatic interactions among them were observed. Particularly, the +4 site, located in the seed region of the mature miR-376a-5p, reached the highest editing frequency in all samples. Secondary structure predictions revealed that the +4 position was the one that conferred the highest stability to the mir-376a-1 hairpin. We suggest that molecular stability might partially explain the editing recurrence observed in certain microRNAs and that editing events conferring new functional regulatory roles in particular tissues and species could have been conserved along evolution, as it might be the case of mir-376a-1 in primate brain cortex.
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http://dx.doi.org/10.1016/j.gene.2017.07.032DOI Listing
September 2017

Spontaneous endometriosis in rhesus macaques: evidence for a genetic association with specific alleles.

Primate Biol 2017 22;4(1):117-125. Epub 2017 Jun 22.

Department of Comparative Genetics, Biomedical Primate Research Centre, 2288 GJ Rijswijk, the Netherlands.

Endometriosis is a poorly understood common debilitating women's reproductive disorder resulting from proliferative and ectopic endometrial tissue associated with variable clinical symptoms including dysmenorrhea (painful menstrual periods), dyspareunia (pain on intercourse), female infertility, and an increased risk of malignant transformation. The rhesus macaque () develops a spontaneous endometriosis that is very similar to that seen in women. We hypothesized that specific major histocompatibility complex (MHC) alleles may contribute to the pathogenesis of endometriosis. As part of a collaboration between the Biomedical Primate Research Centre (BPRC) in the Netherlands and the New England Primate Research Center (NEPRC) in the United States, we analyzed DNA sequences of MHC class I () and class II () alleles from rhesus macaques with endometriosis and compared the allele frequencies with those of age-matched healthy macaques. We demonstrate that two MHC class I alleles are overrepresented in diseased macaques compared to controls: , 33.3 % in BPRC animals with endometriosis vs. 11.6 % in healthy macaques (  0.007), and , 21.9 % NEPRC rhesus macaques vs. 6.7 %, (  0.003). We provide evidence that select MHC class I alleles are associated with endometriosis in rhesus macaques and suggest that the disease pathogenesis contribution of MHC class I warrants further research.
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http://dx.doi.org/10.5194/pb-4-117-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041536PMC
June 2017

Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails.

Tuberculosis (Edinb) 2017 05 20;104:46-57. Epub 2017 Feb 20.

Biomedical Primate Research Centre (BPRC), Lange Kleiweg 161, 2288-GJ, Rijswijk, The Netherlands.

M.bovis BCG vaccination against tuberculosis (TB) notoriously displays variable protective efficacy in different human populations. In non-human primate studies using rhesus macaques, despite efforts to standardise the model, we have also observed variable efficacy of BCG upon subsequent experimental M. tuberculosis challenge. In the present head-to-head study, we establish that the protective efficacy of standard parenteral BCG immunisation varies among different rhesus cohorts. This provides different dynamic ranges for evaluation of investigational vaccines, opportunities for identifying possible correlates of protective immunity and for determining why parenteral BCG immunisation sometimes fails. We also show that pulmonary mucosal BCG vaccination confers reduced local pathology and improves haematological and immunological parameters post-infection in animals that are not responsive to induction of protection by standard intra-dermal BCG. These results have important implications for pulmonary TB vaccination strategies in the future.
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http://dx.doi.org/10.1016/j.tube.2017.02.003DOI Listing
May 2017

Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting.

PLoS Genet 2016 Nov 11;12(11):e1006427. Epub 2016 Nov 11.

Imprinting and Cancer group, Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.

Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methylation in humans. With the exception of a few known paternally methylated germline differentially methylated regions (DMRs) associated with known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage of development. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage and uniquely persist as transiently methylated DMRs only in the placenta. Furthermore, we demonstrate that this phenomenon is exclusive to primates, since no placenta-specific maternal methylation was observed in mouse. Utilizing single cell RNA-seq datasets from human preimplantation embryos we show that following embryonic genome activation the maternally methylated transient DMRs can orchestrate imprinted expression. However despite showing widespread imprinted expression of genes in placenta, allele-specific transcriptional profiling revealed that not all placenta-specific DMRs coordinate imprinted expression and that this maternal methylation may be absent in a minority of samples, suggestive of polymorphic imprinted methylation.
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http://dx.doi.org/10.1371/journal.pgen.1006427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106035PMC
November 2016

Peptococcus simiae sp. nov., isolated from rhesus macaque faeces and emended description of the genus Peptococcus.

Int J Syst Evol Microbiol 2016 Dec 9;66(12):5187-5191. Epub 2016 Sep 9.

Animal Science Department, Biomedical Primate Research Center, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.

A study of the faecal microbiome in three healthy female rhesus macaques revealed the presence of a novel obligately anaerobic, chemoorganoheterotrophic, non-sporing, coccoid, non-motile, Gram-stain-positive bacterial species. Three strains of this species, designated as M108T, M916-1/1, and M919-2/1, were non-haemolytic, H2S-positive, catalase-positive, bile- and NaCl-sensitive and required peptone for growth. Strains also were asaccharolytic, able to utilize sulfite, thiosulfate and elemental sulfur as electron acceptors, and produced acetic and butyric acids as metabolic end-products. Strain M108T is characterized by the prevalence of C14 : 0, C16 : 0 and C18 : 1ω9cis dimethyl acetal among the cellular fatty acids, and the presence of MK-10 menaquinone. The DNA G+C content was found to be 51 mol%. Phylogenetic analysis of partial 16S rRNA gene sequences of strains M108T, M916-1/1 and M919-2/1 placed these strains into the genus Peptococcus (family Peptococcaceae). On the basis of phenotypic and genotypic properties we conclude that these strains represent a novel bacterial species for which the name Peptococcus simiae sp. nov. is proposed. The type strain is M108T (=DSM 100347T=VKM B-2932T).
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http://dx.doi.org/10.1099/ijsem.0.001494DOI Listing
December 2016

Role of microbial translocation in soluble CD14 up-regulation in HIV-, but not in HCV-, infected chimpanzees.

J Gen Virol 2016 10 16;97(10):2599-2607. Epub 2016 Aug 16.

Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands.

During human immunodeficiency virus (HIV) infection, soluble CD14 (sCD14) is up-regulated as a consequence of pathological disruption of the gut epithelial barrier, and subsequent increased microbial translocation. Also in hepatitis C virus (HCV)-infected patients with advanced liver fibrosis, increased levels of sCD14 have been reported. Since the liver plays an important role in clearance of translocated bacterial products, hepatic fibrosis may negatively affect clearance and thus contribute to higher sCD14 levels. Chimpanzees (Pan troglodytes) infected with HCV typically show no signs of liver fibrosis. Here, we have tested the hypothesis that increased levels of sCD14 occur in the absence of hepatic fibrosis or microbial translocation in chimpanzees chronically infected with HCV. sCD14 was up-regulated in both HIV/simian immunodeficiency virus (SIV)- and HCV-infected chimpanzees. In HIV/SIV-infected chimpanzees, intestinal fatty acid-binding protein, a marker for gut perturbation, lipopolysaccharide (LPS)-binding-protein and LPS core antibodies, confirm that sCD14 up-regulation was caused by increased microbial translocation. In HCV-infected chimpanzees, no evidence was found for increased microbial translocation despite up-regulation of sCD14. Additionally, the impact of liver fibrosis on microbial translocation was addressed by direct comparison of chimpanzees with a high HCV load and human patients with advanced fibrosis. These data suggest that only in a small minority of HCV patients, hepatic fibrosis corroborates microbial translocation.
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http://dx.doi.org/10.1099/jgv.0.000577DOI Listing
October 2016

Functional Implications of Human-Specific Changes in Great Ape microRNAs.

PLoS One 2016 22;11(4):e0154194. Epub 2016 Apr 22.

IBE, Institute of Evolutionary Biology (Universitat Pompeu Fabra-CSIC), Department of Experimental and Health Sciences, Barcelona, Catalonia, Spain.

microRNAs are crucial post-transcriptional regulators of gene expression involved in a wide range of biological processes. Although microRNAs are highly conserved among species, the functional implications of existing lineage-specific changes and their role in determining differences between humans and other great apes have not been specifically addressed. We analyzed the recent evolutionary history of 1,595 human microRNAs by looking at their intra- and inter-species variation in great apes using high-coverage sequenced genomes of 82 individuals including gorillas, orangutans, bonobos, chimpanzees and humans. We explored the strength of purifying selection among microRNA regions and found that the seed and mature regions are under similar and stronger constraint than the precursor region. We further constructed a comprehensive catalogue of microRNA species-specific nucleotide substitutions among great apes and, for the first time, investigated the biological relevance that human-specific changes in microRNAs may have had in great ape evolution. Expression and functional analyses of four microRNAs (miR-299-3p, miR-503-3p, miR-508-3p and miR-541-3p) revealed that lineage-specific nucleotide substitutions and changes in the length of these microRNAs alter their expression as well as the repertoires of target genes and regulatory networks. We suggest that the studied molecular changes could have modified crucial microRNA functions shaping phenotypes that, ultimately, became human-specific. Our work provides a frame to study the impact that regulatory changes may have in the recent evolution of our species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841587PMC
March 2017

Epigenomic annotation of gene regulatory alterations during evolution of the primate brain.

Nat Neurosci 2016 Mar 25;19(3):494-503. Epub 2016 Jan 25.

Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.

Although genome sequencing has identified numerous noncoding alterations between primate species, which of those are regulatory and potentially relevant to the evolution of the human brain is unclear. Here we annotated cis-regulatory elements (CREs) in the human, rhesus macaque and chimpanzee genomes using chromatin immunoprecipitation followed by sequencing (ChIP-seq) in different anatomical regions of the adult brain. We found high similarity in the genomic positioning of rhesus macaque and human CREs, suggesting that the majority of these elements were already present in a common ancestor 25 million years ago. Most of the observed regulatory changes between humans and rhesus macaques occurred before the ancestral separation of humans and chimpanzees, leaving a modest set of regulatory elements with predicted human specificity. Our data refine previous predictions and hypotheses on the consequences of genomic changes between primate species and allow the identification of regulatory alterations relevant to the evolution of the brain.
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http://dx.doi.org/10.1038/nn.4229DOI Listing
March 2016

Complete Genome Sequence of a Novel Chimpanzee Polyomavirus from a Western Common Chimpanzee.

Genome Announc 2016 Jan 21;4(1). Epub 2016 Jan 21.

Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands

We report here the full-length genome sequence of a novel chimpanzee polyomavirus. Viral sequences were recovered from colon, bladder, and ureter tissue from a western common chimpanzee. The virus is genetically closely related to the human BK polyomavirus.
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http://dx.doi.org/10.1128/genomeA.01406-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722253PMC
January 2016

Origins of De Novo Genes in Human and Chimpanzee.

PLoS Genet 2015 Dec 31;11(12):e1005721. Epub 2015 Dec 31.

Evolutionary Genomics Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain.

The birth of new genes is an important motor of evolutionary innovation. Whereas many new genes arise by gene duplication, others originate at genomic regions that did not contain any genes or gene copies. Some of these newly expressed genes may acquire coding or non-coding functions and be preserved by natural selection. However, it is yet unclear which is the prevalence and underlying mechanisms of de novo gene emergence. In order to obtain a comprehensive view of this process, we have performed in-depth sequencing of the transcriptomes of four mammalian species--human, chimpanzee, macaque, and mouse--and subsequently compared the assembled transcripts and the corresponding syntenic genomic regions. This has resulted in the identification of over five thousand new multiexonic transcriptional events in human and/or chimpanzee that are not observed in the rest of species. Using comparative genomics, we show that the expression of these transcripts is associated with the gain of regulatory motifs upstream of the transcription start site (TSS) and of U1 snRNP sites downstream of the TSS. In general, these transcripts show little evidence of purifying selection, suggesting that many of them are not functional. However, we find signatures of selection in a subset of de novo genes which have evidence of protein translation. Taken together, the data support a model in which frequently-occurring new transcriptional events in the genome provide the raw material for the evolution of new proteins.
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http://dx.doi.org/10.1371/journal.pgen.1005721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697840PMC
December 2015

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis.

Cell Res 2015 Dec 20;25(12):1333-51. Epub 2015 Oct 20.

CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS), Département of Tuberculosis and Infection Biology, Toulouse, France.

The human CD14(+) monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16(+) monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16(+)CD163(+)MerTK(+)pSTAT3(+) phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16(+)CD163(+)MerTK(+)pSTAT3(+) cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16(+)CD163(+)MerTK(+)pSTAT3(+) monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.
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http://dx.doi.org/10.1038/cr.2015.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670988PMC
December 2015

Simian Immunodeficiency Virus Infection of Chimpanzees (Pan troglodytes) Shares Features of Both Pathogenic and Non-pathogenic Lentiviral Infections.

PLoS Pathog 2015 Sep 11;11(9):e1005146. Epub 2015 Sep 11.

Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

The virus-host relationship in simian immunodeficiency virus (SIV) infected chimpanzees is thought to be different from that found in other SIV infected African primates. However, studies of captive SIVcpz infected chimpanzees are limited. Previously, the natural SIVcpz infection of one chimpanzee, and the experimental infection of six chimpanzees was reported, with limited follow-up. Here, we present a long-term study of these seven animals, with a retrospective re-examination of the early stages of infection. The only clinical signs consistent with AIDS or AIDS associated disease was thrombocytopenia in two cases, associated with the development of anti-platelet antibodies. However, compared to uninfected and HIV-1 infected animals, SIVcpz infected animals had significantly lower levels of peripheral blood CD4+ T-cells. Despite this, levels of T-cell activation in chronic infection were not significantly elevated. In addition, while plasma levels of β2 microglobulin, neopterin and soluble TNF-related apoptosis inducing ligand (sTRAIL) were elevated in acute infection, these markers returned to near-normal levels in chronic infection, reminiscent of immune activation patterns in 'natural host' species. Furthermore, plasma soluble CD14 was not elevated in chronic infection. However, examination of the secondary lymphoid environment revealed persistent changes to the lymphoid structure, including follicular hyperplasia in SIVcpz infected animals. In addition, both SIV and HIV-1 infected chimpanzees showed increased levels of deposition of collagen and increased levels of Mx1 expression in the T-cell zones of the lymph node. The outcome of SIVcpz infection of captive chimpanzees therefore shares features of both non-pathogenic and pathogenic lentivirus infections.
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http://dx.doi.org/10.1371/journal.ppat.1005146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567047PMC
September 2015

Safety, Biodistribution, and Efficacy of an AAV-5 Vector Encoding Human Interferon-Beta (ART-I02) Delivered via Intra-Articular Injection in Rhesus Monkeys with Collagen-Induced Arthritis.

Hum Gene Ther Clin Dev 2015 Jun;26(2):103-12

1 Arthrogen B.V., Amsterdam 1105 BA, The Netherlands .

Preclinical studies to assess biodistribution, safety, and initial efficacy of ART-I02, an adeno-associated type 5 (rAAV5) vector expressing human interferon β (hIFN-β), were performed in a total of 24 rhesus monkeys with collagen-induced arthritis. All monkeys were naïve or showed limited neutralizing antibody (Nab) titers to AAV5 at the start of the study. Animals were injected with a single intra-articular dose of ART-I02 or placebo, consisting of 3.2×10(13) vg (Dose A=maximum feasible dose), 4.58×10(12) vg (Dose B), or placebo in the first affected finger joint, the ipsilateral knee, and ankle joint at the same time point. Animals were monitored for clinical parameters and well-being with a maximum of 4 weeks, with the option that the severity of arthritis could necessitate an earlier time point of sacrifice. No adverse events were noted after injection of ART-I02. No abnormalities were observed after histological evaluation of all organs. At both dose levels, immunohistochemical staining indicated expression of hIFN-β. In animals injected with Dose A, we observed stabilization or a reduction in swelling in the finger joint in which vector was administered. The highest copy numbers of vector DNA were detected in synovial tissue of the injected joint and the draining lymph node of the injected knee. High titers of Nab to rAAV5 were observed at the end of the study. Five monkeys developed an rAAV5-specific T-cell response. Two monkeys developed Nab to hIFN-β. In conclusion, intra-articular injection of ART-I02 was well-tolerated and did not induce adverse events. After administration of Dose A of ART-I02, we observed a beneficial effect on joint swelling, substantiated by decreased histological inflammation and bone erosion scores. A GMP vector for clinical application has been manufactured and is currently being tested in GLP rodent studies, with the aim to move forward to a clinical trial.
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http://dx.doi.org/10.1089/humc.2015.009DOI Listing
June 2015

Advantages and Risks of Husbandry and Housing Changes to Improve Animal Wellbeing in a Breeding Colony of Common Marmosets (Callithrix jacchus).

J Am Assoc Lab Anim Sci 2015 May;54(3):273-9

Animal Science Department, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

Between 1975 and 2014, housing conditions for laboratory-housed marmosets changed dramatically after the introduction of new guidelines designed to improve their care and wellbeing. According to these guidelines, our facility provided marmosets with outside enclosures, switched to deep litter as bedding material, and discontinued the use of disinfectant agents in animal enclosures. However, both deep litter and access to outside enclosures hypothetically increase the risk of potential exposure to pathogenic microorganisms. We evaluated whether these housing and husbandry modifications constituted an increased veterinary risk for laboratory-housed common marmosets (Callithrix jacchus). After the animals had been exposed to these new housing conditions for 2.5 y, we examined their intestinal bacterial flora and feces, the deep litter, and insects present in the housing. In addition, we assessed the marmosets' general health and the effect of outdoor housing on, for example, vitamin D levels. Although numerous bacterial strains--from nonpathogenic to potentially pathogenic--were cultured, we noted no increase in illness, mortality, or breeding problems related to this environmental microflora. Housing laboratory marmosets in large enriched cages, with both indoor and outdoor enclosures, providing them with deep litter, and eliminating the use of disinfectants present an increased veterinary risk. However, after evaluating all of the collected data, we estimate that the veterinary risk of the new housing conditions is minimal to none in terms of clinical disease, disease outbreaks, abnormal behavior, and negative effects on reproduction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460939PMC
May 2015

Pandemic Swine-Origin H1N1 Influenza Virus Replicates to Higher Levels and Induces More Fever and Acute Inflammatory Cytokines in Cynomolgus versus Rhesus Monkeys and Can Replicate in Common Marmosets.

PLoS One 2015 6;10(5):e0126132. Epub 2015 May 6.

Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

The close immunological and physiological resemblance with humans makes non-human primates a valuable model for studying influenza virus pathogenesis and immunity and vaccine efficacy against infection. Although both cynomolgus and rhesus macaques are frequently used in influenza virus research, a direct comparison of susceptibility to infection and disease has not yet been performed. In the current study a head-to-head comparison was made between these species, by using a recently described swine-origin pandemic H1N1 strain, A/Mexico/InDRE4487/2009. In comparison to rhesus macaques, cynomolgus macaques developed significantly higher levels of virus replication in the upper airways and in the lungs, involving both peak level and duration of virus production, as well as higher increases in body temperature. In contrast, clinical symptoms, including respiratory distress, were more easily observed in rhesus macaques. Expression of sialyl-α-2,6-Gal saccharides, the main receptor for human influenza A viruses, was 50 to 73 times more abundant in trachea and bronchus of cynomolgus macaques relative to rhesus macaques. The study also shows that common marmosets, a New World non-human primate species, are susceptible to infection with pandemic H1N1. The study results favor the cynomolgus macaque as model for pandemic H1N1 influenza virus research because of the more uniform and high levels of virus replication, as well as temperature increases, which may be due to a more abundant expression of the main human influenza virus receptor in the trachea and bronchi.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126132PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422689PMC
April 2016

Helicobacter hepaticus infection in BALB/c mice abolishes subunit-vaccine-induced protection against M. tuberculosis.

Vaccine 2015 Apr 4;33(15):1808-14. Epub 2015 Mar 4.

The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, UK. Electronic address:

BCG, the only licensed vaccine against tuberculosis (TB), provides geographically variable protection, an effect ascribed to exposure to environmental mycobacteria (EM). Here we show that altering the intestinal microbiota of mice by early-life infection with the commensal bacterium Helicobacter hepaticus (Hh) increases their susceptibility to challenge with Mycobacterium tuberculosis (Mtb). Furthermore Hh-infected mice immunised parenterally with the recombinant subunit vaccine, human adenovirus type 5 expressing the immunodominant antigen 85A of Mtb (Ad85A), display a reduced lung immune response and protection against Mtb challenge is also reduced. Expression of interleukin 10 (IL10) messenger RNA is increased in the colon of Hh infected mice. Treatment of Hh-infected Ad85A-immunised mice with anti-IL10 receptor antibody, following challenge with Mtb, restores the protective effect of the vaccine. These data show for the first time that alteration of the intestinal microbiota by addition of a single commensal organism can profoundly influence protection induced by a TB subunit vaccine via an IL10-dependent mechanism, a result with implications for the deployment of such vaccines in the field.
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http://dx.doi.org/10.1016/j.vaccine.2015.02.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377097PMC
April 2015

Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases.

J Neurosci 2015 Jan;35(2):678-87

Alternatives Unit,

Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β (IL-1β). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1β expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglial secretion of IL-1β is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of strategies to modulate innate immune responses in the brain.
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http://dx.doi.org/10.1523/JNEUROSCI.2510-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605364PMC
January 2015

Vaccine-induced protection of rhesus macaques against plasma viremia after intradermal infection with a European lineage 1 strain of West Nile virus.

PLoS One 2014 13;9(11):e112568. Epub 2014 Nov 13.

Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands.

The mosquito-borne West Nile virus (WNV) causes human and animal disease with outbreaks in several parts of the world including North America, the Mediterranean countries, Central and East Europe, the Middle East, and Africa. Particularly in elderly people and individuals with an impaired immune system, infection with WNV can progress into a serious neuroinvasive disease. Currently, no treatment or vaccine is available to protect humans against infection or disease. The goal of this study was to develop a WNV-vaccine that is safe to use in these high-risk human target populations. We performed a vaccine efficacy study in non-human primates using the contemporary, pathogenic European WNV genotype 1a challenge strain, WNV-Ita09. Two vaccine strategies were evaluated in rhesus macaques (Macaca mulatta) using recombinant soluble WNV envelope (E) ectodomain adjuvanted with Matrix-M, either with or without DNA priming. The DNA priming immunization was performed with WNV-DermaVir nanoparticles. Both vaccination strategies successfully induced humoral and cellular immune responses that completely protected the macaques against the development of viremia. In addition, the vaccine was well tolerated by all animals. Overall, The WNV E protein adjuvanted with Matrix-M is a promising vaccine candidate for a non-infectious WNV vaccine for use in humans, including at-risk populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231036PMC
August 2015

Experimental infection of rhesus macaques and common marmosets with a European strain of West Nile virus.

PLoS Negl Trop Dis 2014 Apr 17;8(4):e2797. Epub 2014 Apr 17.

Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

West Nile virus (WNV) is a mosquito-borne flavivirus that infects humans and other mammals. In some cases WNV causes severe neurological disease. During recent years, outbreaks of WNV are increasing in worldwide distribution and novel genetic variants of the virus have been detected. Although a substantial amount of data exists on WNV infections in rodent models, little is known about early events during WNV infection in primates, including humans. To gain a deeper understanding of this process, we performed experimental infections of rhesus macaques and common marmosets with a virulent European WNV strain (WNV-Ita09) and monitored virological, hematological, and biochemical parameters. WNV-Ita09 productively infected both monkey species, with higher replication and wider tissue distribution in common marmosets compared to rhesus macaques. The animals in this study however, did not develop clinical signs of WNV disease, nor showed substantial deviations in clinical laboratory parameters. In both species, the virus induced a rapid CD56dimCD16bright natural killer response, followed by IgM and IgG antibody responses. The results of this study show that healthy rhesus macaques and common marmosets are promising animal models to study WNV-Ita09 infection. Both models may be particularly of use to evaluate potential vaccine candidates or to investigate WNV pathogenesis.
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http://dx.doi.org/10.1371/journal.pntd.0002797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990483PMC
April 2014

Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.

Epigenetics 2014 Apr 16;9(4):533-45. Epub 2014 Jan 16.

Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.

CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.
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http://dx.doi.org/10.4161/epi.27689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121364PMC
April 2014

Loss of memory CD4+ T-cells in semi-wild mandrills (Mandrillus sphinx) naturally infected with species-specific simian immunodeficiency virus SIVmnd-1.

J Gen Virol 2014 Jan 8;95(Pt 1):201-212. Epub 2013 Nov 8.

University of Cambridge, Department of Veterinary Medicine, Cambridge CB3 0ES, UK.

Simian immunodeficiency virus (SIV) infection is found in a number of African primate species and is thought to be generally non-pathogenic. However, studies of wild primates are limited to two species, with SIV infection appearing to have a considerably different outcome in each. Further examination of SIV-infected primates exposed to their natural environment is therefore warranted. We performed a large cross-sectional study of a cohort of semi-wild mandrills with naturally occurring SIV infection, including 39 SIV-negative and 33 species-specific SIVmnd-1-infected animals. This study was distinguished from previous reports by considerably greater sample size, examination of exclusively naturally infected animals in semi-wild conditions and consideration of simian T-lymphotropic virus (STLV) status in addition to SIVmnd-1 infection. We found that SIVmnd-1 infection was associated with a significant and progressive loss of memory CD4(+) T-cells. Limited but significant increases in markers of immune activation in the T-cell populations, significant increases in plasma neopterin and changes to B-cell subsets were also observed in SIV-infected animals. However, no increase in plasma soluble CD14 was observed. Histological examination of peripheral lymph nodes suggested that SIVmnd-1 infection was not associated with a significant disruption of the lymph node architecture. Whilst this species has evolved numerous strategies to resist the development of AIDS, significant effects of SIV infection could be observed when examined in a natural environment. STLVmnd-1 infection also had significant effects on some markers relevant to understanding SIV infection and thus should be considered in studies of SIV infection of African primates where present.
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http://dx.doi.org/10.1099/vir.0.059808-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917062PMC
January 2014