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PubMed1998

Glut1 glucose transporter in the primate choroid plexus endothelium.

The objective of the present study was to define the cellular location of the Glut1 glucose transporter in the primate choroid plexus. Immunogold electron microscopy indicated that Glut1 epitopes were associated primarily with choroid plexus endothelial cells. Digitized analyses of electron microscopic images provided quantitative estimates of the relative number of Glut1 glucose transporter epitopes on luminal and abluminal endothelial cell membranes within the choroid plexuses. We recorded a high density of Glut1 in the microvascular endothelium of primate choroid plexus, which was consistent in vervet monkeys (5-10 Glut1 gold particles per micrometer of endothelial cell plasma membrane), as well as in baboons (5-20 Glut1 gold particles per micrometer of capillary plasma membrane). In the baboon choroid plexus, we observed that perivascular cells (presumed to be pericytes) were also Glut1-positive, but with substantially reduced activity compared with endothelial cells. Occasional Glut1-immunogold particles were also seen in the basolateral membranes of the choroid plexus cuboidal cells. Light microscopic immunocytochemistry confirmed the abundance of Glut1 immunoreactivity in choroid plexus endothelial cells of vervet monkeys and baboons. A similar pattern was observed in surgically resected human choroid plexus, suggesting differences between primates, including humans and laboratory animals. The only difference was that erythrocytes within the human choroid plexus exhibited a florid Glut1-positive response, but were weakly immunoreactive in nonhuman primates. The observation of high glucose transporter densities in choroid plexus endothelial cells is consistent with the suggestion that choroidal epithelia and capillaries provide a metabolic work capability for maintaining ionic gradients and secretory functions across the blood-CSF barriers.

Animals↗
PubMed1981

Preparation, characterization, and primate testing of monoclonal antithymocyte globulin.

Monoclonal antibodies specific for T cells from both the human and rhesus primate species were detected by their ability to inhibit T cell rosette formation with sheep erythrocytes. The antibodies were shown by fluorescence techniques to react with all thymocytes and peripheral blood T cells but not to B cells, monocytes, platelets, or erythrocytes. Rosette inhibition titers of these antibodies were 30-fold lower when rhesus, rather than human T, cells were used as the rosette-forming cell in assay. Nonetheless, two monoclonal antibodies, of the IgG3 isotype, termed antithymocyte monoclonal (ATM) e.1 and 2.2, were shown to depress selectively circulating T cells to nondetectable levels following single dose administration to rhesus primates and to prolong skin allograft survival in a rhesus primate given a 6-dose course of treatment. The rhesus primates suffered no ill effects and no peripheral blood cellular component other than T cells was depressed. Monoclonal antibody secreting hybridoma cells are capable of producing ATM 3.1 and 3.2 in quantity when grown as peritoneal tumors in selected mouse hybrids. Purification of ATM 3.1 or 3.2 is easily accomplished by affinity chromatography on protein A. These properties suggest that ATM antibodies may become useful immunosuppressive agents in clinical transplantation.

Animals↗
PubMed1996

Assessment of hyperacute rejection in a rat-to-primate cardiac xenograft model.

We studied a rat-to-cynomolgous monkey model for xenotransplantation of vascularized organs and found that a rat heart was rejected in 5.5 +/- 1.4 min (n = 10). This hyperacute rejection (HAR) was consistent with kinetic experiments in vitro that showed damage to rat endothelial cells (ECs) after 3 min of incubation with primate serum. Histopathology and ultrastructural analysis of rejected hearts showed marked EC damage and early adherence of platelets and polymorphonuclear leukocytes to the endothelium. Immunohistochemical analysis revealed deposition along endothelial surfaces of IgG, IgM, and complement (C) components of the classical but not the alternative pathway, suggesting that, as in the pig-to-primate model, HAR is mediated by the binding of recipient xenogeneic natural antibodies and C activation. The effect of C depletion on xenograft survival was evaluated in two recipients that were treated with cobra venom factor (CVF). CVF caused complete C inactivation, demonstrated by lack of serum hemolytic activity and C-dependent EC cytotoxicity at engraftment and until the animals died. The rat cardiac transplants survived for at least 9 hr and 77 hr. Histology showed massive interstitial hemorrhage, edema, and cellular infiltration with scanty fibrin deposits. These results in CVF-treated recipient monkeys indicate that C activation mediates the development of HAR in this rat-to-primate model. We suggest that the model may be of interest as an alternative to the more expensive and time-consuming pig-to-primate model for testing the efficacy of transgenic modification of donor organs to prolong xenograft survival and for studying mechanisms of discordant xenograft rejection.

Animals↗
PubMed2000

Long-term functional islet mass and metabolic function after xenoislet transplantation in primates.

BACKGROUND: Pancreatic islet transplantation (PIT) is an attractive alternative for patients with type I diabetes mellitus. PIT is not yet an effective clinical reality due in part to the high incidence of rejection and early loss of functional islet mass. In addition, current immunosuppressive drugs have toxic effects on islets and increase the risk of morbidity and mortality. In the present study, the effects of PIT on glycemic parameters were assessed in spontaneously diabetic primates. METHODS: Five insulinopenic nonhuman primates (three Macacca fascicularis, one Ceropithecus aethiops, and one Macacca mulatta) were studied. All required twice-daily treatment with 4-10 U of insulin. For immunosuppression, the animals received anti-CD3-immunotoxin (100 microg/kg(initially infused 2 hr before transplantation and again on day +1), cyclosporine (CsA) (20 mg/kg(i.v./2 hr before transplantation), cyclosporine microemulsion (Neoral) 60 mg/kg/b.i.d. on days +1 to +3 with dose adjusted by blood levels, and methylprednisolone (15 mg/kg day 0 to +3). Three recipients were given islets from a single donor (M mulatta). The islets were prepared by a semiautomated technique using Liberase. A mean of 13,136 islet equivalents/kg was infused into the portal vein. Two animals (M fascicularis and M mulatta) were used as a diabetic, nontransplanted control. Several metabolic parameters were evaluated. RESULTS: All monkeys that underwent transplantation experienced reversal of diabetes mellitus with normalization of all diabetic glycemic parameters. In the nontransplanted primates given the same immunosuppression but no PIT, diabetic metabolic parameters were unchanged after 9 months of follow-up. In contrast, all three PIT recipients established fasting and nonfasting euglycemia within 1-2 weeks, and none required exogenous insulin after day 10. Normal intravenous glucose tolerance tests were observed at day 15, and no significant differences in the glucose disappearance rate (Kg) were observed at days 15, 45, 190, and 365 days after transplantation. The acute insulin response to glucose indicated no significant reduction of functional islet mass. CONCLUSIONS: PIT in severely insulinopenic type I diabetes mellitus primates resulted in restoration of normal glycemic parameters and durable islet mass. Operational tolerance was achieved with only 4 days of drug administration, sparing the animals from chronic exposure to potentially diabetogenic immunosuppressive drugs. These results offer an exciting new potential for type I diabetes mellitus treatment.

Animals↗
PubMed2005

The effect of pinealectomy on scoliosis development in young nonhuman primates.

STUDY DESIGN: Prospective study on pinealectomy in primates. OBJECTIVE: To evaluate whether pinealectomy in a bipedal nonhuman primate model will result in the development of scoliosis. SUMMARY OF BACKGROUND DATA: Pinealectomy in newborn chickens consistently resulted in scoliosis development. Published data suggest that the surgical removal of the pineal, loss of melatonin secretion, and a bipedal posture are important elements in the development of scoliosis in lower animal models. METHOD: There were 18 rhesus monkeys between 8 and 11 months old that underwent pineal excision. All monkeys were kept in a regulated 12-hour light-dark cycle. Monthly radiographs assessed scoliosis development. Completeness of pineal excision was assessed by measurement of a major metabolite of melatonin in the urine, 6-sulfatoxymelatonin, using an enzyme-linked immunosorbent assay assessed. RESULTS: Mean follow-up was 28 months (range 10-41). Seven monkeys died prematurely, and 11 survived to date; the data from those that died could still be used, although follow-up was shortened. At the latest follow-up or death, scoliosis did not develop in any of the monkeys. Urinary 6-sulfatoxymelatonin measurements revealed 3 patterns. Group 1 consisted of 10 monkeys, which showed definite evidence of complete pineal excision. Group 2 consisted of an uncertain group of 2 monkeys in which the nighttime melatonin level is slightly high. Group 3 consisted of 6 monkeys that had incomplete pineal excision or ectopic melatonin production. CONCLUSIONS: To our knowledge, this is the first report of pinealectomy in nonhuman primates. Of the 18 monkeys, 10 had a loss of melatonin secretion, for a mean of 29 months after surgery. Because none of the monkeys had scoliosis develop, this study strongly suggests that the possible etiologic factors producing idiopathic scoliosis in lower animals are different from primates, and findings in lower animals cannot necessarily be extrapolated to human beings.

Animals↗
PubMed2006

Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept.

BACKGROUND: Pig islets xenotransplantation remains associated with a strong humoral and cellular xenogeneic immune responses. The aim of this study was to assess the long-term biocompatibility of alginate encapsulated pig islets after transplantation in primates. METHODS: Adult pig islets encapsulated in alginate under optimal conditions (n=7) or not (n=5) were transplanted under the kidney capsule of nondiabetic Cynomolgus maccacus. Additional primates received empty capsules (n=1) and nonencapsulated pig islets (n=2) as controls. Capsule integrity, cellular overgrowth, pig islet survival, porcine C-peptide and anti-pig IgM/IgG antibodies were examined up to 6 months after implantation. RESULTS: Nonencapsulated islets and islets encapsulated in nonoptimal capsules were rapidly destroyed. In seven primates receiving perfectly encapsulated pig islets, part of the islets survived up to 6 months after implantation without immunosuppression. Porcine C-peptide was detected after 1 month in 71% of the animals. The majority of grafts (86%) were intact and completely free of cellular overgrowth or capsule fibrosis. Explanted capsules, after 135 (n=2/2) and 180 (n=2/3) days, demonstrated residual insulin content and responses to glucose challenge (stimulation index of 2.2). Partial islet survival was obtained despite an elicited anti-pig IgG humoral response. CONCLUSIONS: Optimal alginate encapsulation significantly prolonged adult pig islet survival into primates for up to 6 months, even in the presence of antibody response.

Alginates↗
PubMed2003

Cyclooxygenase-2 expression associated with spreading depression in a primate model.

The authors previously provided evidence that spreading depression (SD) can be evoked in primates. Cyclooxygenase-2 (COX-2) expression has been found to increase in the rodent cortex undergoing SD, and the authors sought to determine whether this association exists in primate brain. In the present study, neuronal COX-2 expression was induced during SD in the primate cortex. The mean expression ratio of COX-2 messenger RNA in animals with SD was significantly higher than that measured in controls (1.69 vs. 0.5; P = 0.02). Induction of COX-2 in these animals was also detected by human microarray analysis. Results show that, as in rodents, neuronal COX-2 is induced in the primate cortex in response to SD.

Animals↗
PubMed2003

Rapid acquisition of an alarm response by a neotropical primate to a newly introduced avian predator.

Predation is an important selective pressure in natural ecosystems. Among non-human primates, relatively little is known about how predators hunt primate prey and how primates acquire adaptive responses to counteract predation. In this study we took advantage of the recent reintroduction of radio-tagged harpy eagles (Harpia harpyja) to Barro Colorado Island (BCI), Panama to explore how mantled howler monkeys (Alouatta palliata), one of their primary prey, acquire anti-predator defences. Based on the observation that harpies follow their prey prior to attack, and often call during this pursuit period, we broadcast harpy eagle calls to howlers on BCI as well as to a nearby control population with no harpy predation. Although harpies have been extinct from this area for 50-100 years, results indicate that BCI howlers rapidly acquired an adaptive anti-predator response to harpy calls, while showing no response to other avian vocalizations; howlers maintained this response several months after the removal of the eagles. These results not only show that non-human primates can rapidly acquire an alarm response to a newly introduced predator, but that they can detect and identify predators on the basis of acoustic cues alone. These findings have significant implications both for the role of learning mechanisms in the evolution of prey defence and for conservation strategies, suggesting that the use of 'probing' approaches, such as auditory playbacks, may highly enhance an a priori assessment of the impact of species reintroduction.

Alouatta↗
PubMed2003

Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates.

Comparative DNA sequence studies between humans and nonhuman primates will be important for understanding the genetic basis of the phenotypic differences between these species. Here we compare approximately 27 Mb of human chromosome 21 with chimpanzee DNA sequences identifying 57 genomic rearrangements (deletions and insertions ranging in size from 0.2 to 8.0 kb) between the two species. These rearrangements are distributed along the entire length of chromosome 21, with approximately 35% found in genomic intervals encoding genes (genic intervals), and have occurred in the genomes of both humans and chimpanzees. Comparison of approximately 9 Mb of human chromosome 21 with orangutan, rhesus macaque, and woolly monkey DNA sequences identified a combined total of 114 genomic rearrangements between humans and nonhuman primates. Analysis of these rearrangements revealed that they are randomly distributed with respect to genic and nongenic intervals and identified one deletion that has likely resulted in the inactivation of a gene (beta1,3-galactosyltransferase) in the woolly monkey. Our data show that genomic rearrangements have occurred frequently during primate genome evolution and significantly contribute to the DNA differences between these species. These DNA rearrangements are commonly found in genic intervals, and thus provide natural starting points for focused investigations of qualitative and quantitative gene expression differences between humans and other primates.

Animals↗
PubMed2004

Expression of CTLA-4 in nonhuman primate lymphocytes and its use as a potential target for specific immunotoxin-mediated apoptosis: results of in vitro studies.

T-cell-mediated immunoregulation is one of the main mechanisms implicated in induction and maintenance of transplantation tolerance. In this regard, deletion or modulation of xeno/alloantigen-specific T cells, as well as blocking of their interactions with other cell populations, are currently being pursued for tolerance induction in humans as well as nonhuman primates. In order to investigate whether cytotoxic T-lymphocyte antigen-4 (CTLA-4) may represent a suitable target for a T cell depletion approach in nonhuman primate models, we analysed CTLA-4 expression in peripheral blood mononuclear cells (PBMCs) from nonhuman primates and the potential role of two anti-CTLA-4 saporin-conjugated immunotoxins. The analysis was performed in PBMCs from 8 cynomolgus monkeys from Philippines and from Mauritius both at protein level by flow cytometry and at transcriptional level by RT-PCR. In addition, the apoptotic role of the immunotoxins was investigated. The results showed that CTLA-4 was expressed at variable levels depending on the origin of the cynomolgus monkeys and the resting or activated cell condition. CTLA-4 was not expressed on resting Mauritius PBMCs and showed a lower up-regulation upon PMA/PHA activation compared to the Philippines PBMCs that expressed CTLA-4 also before activation. Two CTLA-4 RNA transcripts (672 and 550 bp) were detected with levels variations after cell stimulation. Two anti-CTLA-4 immunotoxins induced in vitro apoptosis of activated PBMCs from both sources of cynomolgus monkeys. This is the first report that documents CTLA-4 expression both at protein and transcriptional level by nonhuman primate PBMCs and provides novel perspectives of xeno/allograft rejection immunotherapy based on CTLA-4 targeting.

Animals↗
PubMed2005

Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts.

BACKGROUND: We have previously shown that pig-to-primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non-immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non-human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. METHODS: Liver specimens were collected at sacrifice from seven non-immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real-time reverse transcription polymerase chain reaction (RT-PCR) for species-specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer-efficiencies and normalized to cyclophilin expression. RESULTS: Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post-transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig), significantly increased between early and late time points together with expression of MIP-1alpha, regulated on activation normal T expressed and secreted protein (RANTES) and MCP-1. CCR5 showed only a marginal, non-significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post-transplant. CONCLUSIONS: Our data suggest that CXCR3, with ligands IP-10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non-human primates. Upregulation of RANTES and MIP-1alpha transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP-1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T-cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3-mediated chemoattractant pathway as an immunosuppressive target in pig-to-primate islet xenotransplantation.

Animals↗
PubMed2006

Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft.

The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated ES cells) weeks, or control fetal primate cells into the striatum of hemi-parkinsonian rats. Partial behavioral recovery in amphetamine-induced rotation was correlated with the number of ES-derived tyrosine hydroxylase-positive (TH+) neurons in the grafts (r=0.5, P<0.05). Post mortem analysis of ES-derived grafts revealed TH+neurons with mature morphology, similar to fetal DA neurons, and expression of midbrain transcription factors, such as Engrailed (En) and Nurr-1. While the total number of TH+neurons was not different between the two groups, TH/En co-expression was significantly higher (>90%) in grafts from differentiated ES cells than in grafts derived from progenitor cells (<50%), reflecting a more heterogeneous cellular composition. Within the grafts there was an overlap between ES-derived TH+axonal arbors and clusters of primate ES-derived striatal neurons expressing brain factor 1 (Bf-1, Foxg1) and DA and cAMP-regulated phosphoprotein (DARPP-32). Such overlap was never observed for other regional transcription factors that define neighboring forebrain domains in the developing brain, such as Nkx2.1 (medial ganglionic eminence), Nkx2.2 (pallidal and diencephalic progenitors) or Pax6 (dorsal telencephalic progenitors). Despite the heterogeneity of ES-derived graft cell composition, these results demonstrate normal phenotypic specification, conserved natural axonal target selectivity and functionality of DA neurons derived from primate ES cells.

Animals↗
PubMed1989

Characterization of 5-HT receptors mediating contraction of canine and primate basilar artery by use of GR43175, a selective 5-HT1-like receptor agonist.

1. The aim of this study was to characterize the 5-hydroxytryptamine (5-HT) receptor which mediates contraction of canine and primate isolated basilar artery by use of a variety of selective 5-HT agonists and antagonists. 2. 5-HT, alpha-methyl 5-HT and the selective 5-HT1-like receptor agonists, GR43175 and 5-carboxamidotryptamine (5-CT), each caused contraction of canine and primate basilar artery with a rank order of agonist potency of 5-CT greater than or equal to 5-HT greater than GR43175 greater than alpha-methyl 5-HT. The 5-HT1-like receptor agonists, GR43175 and 5-CT, produced maximum effects which were less than that produced by 5-HT or alpha-methyl 5-HT. 3. In canine basilar artery, ketanserin (0.1-1 microM) caused some depression of the maximum effect of 5-HT but produced little or no shift of the concentration-effect curve. The contractile effects of GR43175 were not modified by ketanserin (1 microM), MDL72222 (1 microM) or cyanopindolol (1 microM). However, the effects of 5-HT and GR43175 were specifically antagonized by methiothepin (0.1 microM); the mean agonist concentration-ratios were 33 and 48 respectively. 4. In primate basilar artery, ketanserin (1 microM) again caused a small depression of the 5-HT maximum response but had not effect against GR43175-induced contractions. In contrast, methiothepin (0.1 microM) antagonized both 5-HT- and GR43175-induced contractions; the mean agonist concentration-ratios were 35 for both. 5. These results demonstrate that a large component of the effects of 5-HT in canine and primate basilar artery is produced by stimulation of a 5-HT1-like receptor. This receptor can be characterized by the high potency of the novel, selective agonist, GR43175, and susceptibility to blockade by methiothepin. However, there also appears to be a population of 5-HT2 receptors in these prepAarations which contribute to the contractile effects of 5-HT.

Animals↗
PubMed2004

Use of florfenicol in non-human primates.

Studies were undertaken to determine if florfenicol, an antimicrobial agent structurally similar to chloramphenicol, could be used as an effective broad spectrum antibiotic for the treatment of bacterial infections in primates. Florfenicol was developed as an injectable antibiotic for use in cattle on an every other day dosing schedule. Its broad spectrum activity, long duration of action following i.m. administration, and its safety as compared with chloramphenicol made it an attractive antibiotic for use in non-human primates. Previous studies had shown that florfenicol is effective against common primate pathogens such as Salmonella, Klebsiella, Escherichia coli, Bordetella bronchiseptica, Streptococcus pneumoniae, Staphylococcus spp., and Yersinia pseudotuberculosis. We performed experiments on a total of 15 macaques. The animals were given florfenicol at 50 mg/kg i.m. and blood samples taken at various time points. Serum was evaluated for florfenicol absorption. Necropsies were also performed to determine if major organs were affected and to determine the effects of i.m. injection of florfenicol. We determined that florfenicol given every 48 hours in rhesus macaques results in blood levels that were acceptable for therapeutic use. The effect on muscle tissue of i.m. injection was similar to ketamine and normal saline. There were no gross lesions observed and no changes with tissues submitted for histology. Our work shows that with further studies, florfenicol may be useful when injectable antibiotic therapy is required in non-human primates.

Analysis of Variance↗
PubMed2007

Evolutionary relationships of "Candidatus Riesia spp.," endosymbiotic enterobacteriaceae living within hematophagous primate lice.

The primary endosymbiotic bacteria from three species of parasitic primate lice were characterized molecularly. We have confirmed the characterization of the primary endosymbiont (P-endosymbiont) of the human head/body louse Pediculus humanus and provide new characterizations of the P-endosymbionts from Pediculus schaeffi from chimpanzees and Pthirus pubis, the pubic louse of humans. The endosymbionts show an average percent sequence divergence of 11 to 15% from the most closely related known bacterium "Candidatus Arsenophonus insecticola." We propose that two additional species be added to the genus "Candidatus Riesia." The new species proposed within "Candidatus Riesia" have sequence divergences of 3.4% and 10 to 12% based on uncorrected pairwise differences. Our Bayesian analysis shows that the branching pattern for the primary endosymbionts was the same as that for their louse hosts, suggesting a long coevolutionary history between primate lice and their primary endosymbionts. We used a calibration of 5.6 million years to date the divergence between endosymbionts from human and chimpanzee lice and estimated an evolutionary rate of nucleotide substitution of 0.67% per million years, which is 15 to 30 times faster than previous estimates calculated for Buchnera, the primary endosymbiont in aphids. Given the evidence for cospeciation with primate lice and the evidence for fast evolutionary rates, this lineage of endosymbiotic bacteria can be evaluated as a fast-evolving marker of both louse and primate evolutionary histories.

Animals↗
PubMed1977

Virulence and immunogenicity of a temperature-sensitive dengue-2 virus in lower primates.

Clones of dengue-2 virus were tested for virulence by inoculation of rhesus monkeys and chimpanzees. Although primates showed no overt signs of illness, inoculation with the parent virus or a subline of a large-plaque clone resulted in a viremia lasting 1 to 7 days. By these criteria, sublines of a small-plaque clone were significantly less virulent and produced little or no viremia in primate hosts. Although they had a substantially reduced viremia, primates inoculated with the small-plaque sublines showed stimulation of complement-fixing, hemagglutination-inhibiting, and neutralizing antibodies. The protection afforded rhesus monkeys 3 months after inoculation with two of the small-plaque sublines was demonstrated by a lack of viremia and a failure to escalate preexisting antibody levels after challenge with the parent virus. Both the S-1 subline and the parent virus had a limited capacity to produce central nervous system pathology in monkeys inoculated intrathalamically and intrathecally. Evidence thus far accumulated for primates indicates that the S-1 subline of dengue-2 virus has potential value as a candidate vaccine virus.

Animals↗
PubMed1994

Comparison of nonhuman primate antibodies against Haemophilus influenzae type b polysaccharide with human antibodies in oligoclonality and in vivo protective potency.

Nonhuman primates are often used as a model for studying vaccines for humans. However, it is not always clear how closely the antibody responses in these species mimic human responses. Recent studies have characterized the human antibody response to Haemophilus influenzae type b (Hib) in great detail. In this study, we have compared the antibody response to Hib of humans with those of other primates. Studies of isoelectric points and V kappa subgroup usage show that, like humans, nonhuman primates produce oligoclonal antibodies. Also, monkey antibodies to the Hib polysaccharide are as protective as human antibodies in an in vivo model of Hib infection. Thus, we conclude that nonhuman primates produce antibodies to Hib polysaccharide that are structurally and functionally similar to human antibodies and are a good model for testing human vaccines.

Animals↗
PubMed2001

Evolutionary relationships among parvoviruses: virus-host coevolution among autonomous primate parvoviruses and links between adeno-associated and avian parvoviruses.

The current classification of parvoviruses is based on virus host range and helper virus dependence, while little data on evolutionary relationships among viruses are available. We identified and analyzed 472 sequences of parvoviruses, among which there were (virtually) full-length genomes of all 41 viruses currently recognized as individual species within the family Parvoviridae. Our phylogenetic analysis of full-length genomes as well as open reading frames distinguished three evolutionary groups of parvoviruses from vertebrates: (i) the human helper-dependent adeno-associated virus (AAV) serotypes 1 to 6 and the autonomous avian parvoviruses; (ii) the bovine, chipmunk, and autonomous primate parvoviruses, including human viruses B19 and V9; and (iii) the parvoviruses from rodents (except for chipmunks), carnivores, and pigs. Each of these three evolutionary groups could be further subdivided, reflecting both virus-host coevolution and multiple cross-species transmissions in the evolutionary history of parvoviruses. No parvoviruses from invertebrates clustered with vertebrate parvoviruses. Our analysis provided evidence for negative selection among parvoviruses, the independent evolution of their genes, and recombination among parvoviruses from rodents. The topology of the phylogenetic tree of autonomous human and simian parvoviruses matched exactly the topology of the primate family tree, as based on the analysis of primate mitochondrial DNA. Viruses belonging to the AAV group were not evolutionarily linked to other primate parvoviruses but were linked to the parvoviruses of birds. The two lineages of human parvoviruses may have resulted from independent ancient zoonotic infections. Our results provide an argument for reclassification of Parvovirinae based on evolutionary relationships among viruses.

Animals↗