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Myers S.,University of Oxford | Bowden R.,University of Oxford | Tumian A.,University of Oxford | Bontrop R.E.,Biomedical Primate Research Center | And 5 more authors.
Science | Year: 2010

Although present in both humans and chimpanzees, recombination hotspots, at which meiotic crossover events cluster, differ markedly in their genomic location between the species. We report that a 13-base pair sequence motif previously associated with the activity of 40% of human hotspots does not function in chimpanzees and is being removed by self-destructive drive in the human lineage. Multiple lines of evidence suggest that the rapidly evolving zinc-finger protein PRDM9 binds to this motif and that sequence changes in the protein may be responsible for hotspot differences between species. The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change. © 2010 American Association for the Advancement for Science. All Rights Reserved.


de Groot N.G.,Biomedical Primate Research Center | Bontrop R.E.,Biomedical Primate Research Center | Bontrop R.E.,University Utrecht
Retrovirology | Year: 2013

An HIV-1 infection progresses in most human individuals sooner or later into AIDS, a devastating disease that kills more than a million people worldwide on an annual basis. Nonetheless, certain HIV-1-infected persons appear to act as long-term non-progressors, and elite control is associated with the presence of particular MHC class I allotypes such as HLA-B*27 or -B*57. The HIV-1 pandemic in humans arose from the cross-species transmission of SIVcpz originating from chimpanzees. Chimpanzees, however, appear to be relatively resistant to developing AIDS after HIV-1/SIVcpz infection. Mounting evidence illustrates that, in the distant past, chimpanzees experienced a selective sweep resulting in a severe reduction of their MHC class I repertoire. This was most likely caused by an HIV-1/SIV-like retrovirus, suggesting that chimpanzees may have experienced long-lasting host-virus relationships with SIV-like viruses. Hence, if natural selection is allowed to follow its course, prospects for the human population may look grim, thus underscoring the desperate need for an effective vaccine. © 2013 de Groot and Bontrop; licensee BioMed Central Ltd.


de Groot N.,Biomedical Primate Research Center
Immunogenetics | Year: 2014

A panel of 15 carefully selected microsatellites (short tandem repeats, STRs) has allowed us to study segregation and haplotype stability in various macaque species. The STRs span the major histocompatibility complex (MHC) region and map in more detail from the centromeric part of the Mhc-A to the DR region. Two large panels of Indian rhesus and Indonesian/Indochinese cynomolgus macaques have been subjected to pedigree analysis, allowing the definition of 161 and 36 different haplotypes and the physical mapping of 10 and 5 recombination sites, respectively. Although most recombination sites within the studied section of the Indian rhesus monkey MHC are situated between the Mhc-A and Mhc-B regions, the resulting recombination rate for this genomic segment is low and similar to that in humans. In contrast, in Indonesian/Indochinese macaques, two recombination sites, which appear to be absent in rhesus macaques, map between the class III and II regions. As a result, the mean recombination frequency of the core MHC, Mhc-A to class II, is higher in Indonesian/Indochinese cynomolgus than in Indian rhesus macaques, but as such is comparable to that in humans. The present communication demonstrates that the dynamics of recombination 'hot/cold spots' in the MHC, as well as their frequencies, may differ substantially between highly related macaque species.


Younga D.,Imperial College London | Verreck F.A.W.,Biomedical Primate Research Center
Tuberculosis | Year: 2012

The remarkable advances in TB vaccinology over the last decade have been driven by a pragmatic approach to moving candidates along the development pipeline to clinical trials, fuelled by encouraging data on protection in animal models. Efficacy data from Phase IIb trials of the first generation of new candidates are anticipated over the next 1-2 years. As outlined in the TB Vaccines Strategic Blueprint, to exploit this information and to inspire design of next generation candidates, it is important that this empirical approach is complemented by progress in understanding of fundamental immune mechanisms and improved translational modalities. Current trends towards improved experimental and computational approaches for studying biological complexity will be an important element in the developing science of TB vaccinology. © 2012 Elsevier Ltd. All rights reserved.


Ottenhoff T.H.M.,Biomedical Primate Research Center | Ellner J.J.,Boston University | Kaufmann S.H.E.,Max Planck Institute for Infection Biology
Tuberculosis | Year: 2012

The availability of tuberculosis (TB) biomarkers of protection (or: "surrogate endpoints of protection against active TB" (Biomarkers Definitions Working Group, 2001)) would greatly facilitate and accelerate TB vaccine development and increase the likelihood of success. TB biomarkers of protection could determine which vaccines in clinical trials are the most efficacious; which vaccine candidates and strategies are the most promising in early stages in the preclinical development pipeline (including relevant antigens, antigen delivery, live vaccines); and which combination vaccines (prime/boost) would be the most effective. Here we discuss ten major challenges for biomarker identification and validation in TB. Current major roadblocks and critical limitations in understanding TB pathogenesis are highlighted, and new solutions and strategies proposed. © 2012 Elsevier Ltd. All rights reserved.


Persengiev S.,Biomedical Primate Research Center | Kondova I.,Biomedical Primate Research Center | Bontrop R.,Biomedical Primate Research Center
Frontiers in Molecular Neuroscience | Year: 2013

MicroRNAs (miRNAs) are regulatory genetic elements that coordinate the expression of thousands of genes and play important roles in brain aging and neurodegeneration. DNA polymorphisms affecting miRNA biogenesis, dosage, and gene targeting may represent potentially functional variants. The consequences of single nucleotide polymorphisms affecting miRNA function were previously demonstrated by both experimental and computational methods. However, little is known about how copy number variations (CNVs) influence miRNA metabolism and regulatory networks. We discuss potential mechanisms of CNVs-mediated effects on miRNA function and regulation that might have consequences for brain aging. We argue that CNVs, which potentially can alter miRNA expression, regulation or target gene recognition, are possible functional variants and should be considered high priority candidates in genotype-phenotype mapping studies of brain-related disorders. © 2013 Persengiev, Kondova and Bontrop.


Verstrepen B.E.,Biomedical Primate Research Center | Boonstra A.,Erasmus University Rotterdam | Koopman G.,Biomedical Primate Research Center
World Journal of Hepatology | Year: 2015

Hepatitis C virus (HCV) infection is characterized by a high propensity for development of life-long viral persistence. An estimated 170 million people suffer from chronic hepatitis caused by HCV. Currently, there is no approved prophylactic HCV vaccine available. With the near disappearance of the most relevant animal model for HCV, the chimpanzee, we review the progression that has been made regarding prophylactic vaccine development against HCV. We describe the results of the individual vaccine evaluation experiments in chimpanzees, in relation to what has been observed in humans. The results of the different studies indicate that partial protection against infection can be achieved, but a clear correlate of protection has thus far not yet been defined. © The Author(s) 2015.


Immune responses against multiple epitopes are required for the prevention of hepatitis C virus (HCV) infection, and the progression to phase I trials of candidates may be guided by comparative immunogenicity studies in non-human primates. Four vectors, DNA, SFV, human serotype 5 adenovirus (HuAd5) and Modified Vaccinia Ankara (MVA) poxvirus, all expressing hepatitis C virus Core, E1, E2 and NS3, were combined in three prime-boost regimen, and their ability to elicit immune responses against HCV antigens in rhesus macaques was explored and compared. All combinations induced specific T-cell immune responses, including high IFN-γ production. The group immunized with the SFV+MVA regimen elicited higher E2-specific responses as compared with the two other modalities, while animals receiving HuAd5 injections elicited lower IL-4 responses as compared with those receiving MVA. The IFN-γ responses to NS3 were remarkably similar between groups. Only the adenovirus induced envelope-specific antibody responses, but these failed to show neutralizing activity. Therefore, the two novel regimens failed to induce superior responses as compared with already existing HCV vaccine candidates. Differences were found in response to envelope proteins, but the relevance of these remain uncertain given the surprisingly poor correlation with immunogenicity data in chimpanzees, underlining the difficulty to predict efficacy from immunology studies.Gene Therapy advance online publication, 4 August 2016; doi:10.1038/gt.2016.55. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Venn O.,Oxford Genetics | Turner I.,Oxford Genetics | Mathieson I.,Oxford Genetics | Mathieson I.,Harvard University | And 3 more authors.
Science | Year: 2014

Germline mutation determines rates of molecular evolution, genetic diversity, and fitness load. In humans, the average point mutation rate is 1.2 × 10-8 per base pair per generation, with every additional year of father's age contributing two mutations across the genome and males contributing three to four times as many mutations as females. To assess whether such patterns are shared with our closest living relatives, we sequenced the genomes of a nine-member pedigree of Western chimpanzees, Pan troglodytes verus. Our results indicate a mutation rate of 1.2 × 10-8 per base pair per generation, but a male contribution seven to eight times that of females and a paternal age effect of three mutations per year of father's age. Thus, mutation rates and patterns differ between closely related species.


Zeeman A.M.,Biomedical Primate Research Center
Methods in molecular biology (Clifton, N.J.) | Year: 2013

Long-term in vitro cultures of blood-stage parasites are so far feasible only for Plasmodium falciparum and P. knowlesi. In this chapter, we describe short-term ex vivo culturing of P. cynomolgi and P. vivax. We also describe long-term in vitro culturing of P. knowlesi as well as some techniques for synchronizing parasites. Cultured parasites can be used for a variety of purposes, e.g., for in vitro drug assays and antibody-mediated growth inhibition assays.

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