Potent neutralizing antibodies in humans infected with zoonotic simian foamy viruses target conserved epitopes located in the dimorphic domain of the surface envelope protein.

Human diseases of zoonotic origin are a major public health problem. Simian foamy viruses (SFVs) are complex retroviruses which are currently spilling over to humans. Replication-competent SFVs persist over the lifetime of their human hosts, without spreading to secondary hosts, suggesting the presence of efficient immune control. Accordingly, we aimed to perform an in-depth characterization of neutralizing antibodies raised by humans infected with a zoonotic SFV. We quantified the neutralizing capacity of plasma samples from 58 SFV-infected hunters against primary zoonotic gorilla and chimpanzee SFV strains, and laboratory-adapted chimpanzee SFV. The genotype of the strain infecting each hunter was identified by direct sequencing of the env gene amplified from the buffy coat with genotype-specific primers. Foamy virus vector particles (FVV) enveloped by wild-type and chimeric gorilla SFV were used to map the envelope region targeted by antibodies. Here, we showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain. Epitopes recognized by neutralizing antibodies have been conserved during the cospeciation of SFV with their nonhuman primate host. Greater neutralization breadth in plasma samples of SFV-infected humans was statistically associated with smaller SFV-related hematological changes. The neutralization patterns provide evidence for persistent expression of viral proteins and a high prevalence of coinfection. In conclusion, neutralizing antibodies raised against zoonotic SFV target immunodominant and conserved epitopes located in the receptor binding domain. These properties support their potential role in restricting the spread of SFV in the human population.

Hematocrit and Hemoglobin Levels of Nonhuman Apes at Moderate Altitudes: A Comparison with Humans.

Mortola, Jacopo P. and DeeAnn Wilfong. Hematocrit and hemoglobin levels of nonhuman apes at moderate altitudes: a comparison with humans. High Alt Med Biol. 17:323-335, 2016.-We asked to what extent the hematologic response (increase in hematocrit [Hct] and in blood hemoglobin concentration [Hb]) of humans to altitude hypoxia was shared by our closest relatives, the nonhuman apes. Data were collected from 29 specimens of 7 species of apes at 2073 m altitude (barometric pressure Pb = 598 mm Hg); additional data originated from apes located at a lower altitude (1493 m, Pb = 639 mm Hg). The human altitude profiles of Hct and Hb between sea level and 3000 m were constructed from a compilation of literature sources that (all combined) comprised data sets of 10,000-12,000 subjects for each gender. These human data were binned for 0-250 m altitude (sea level) and for each 500 m of progressively higher altitudes. Values of Hb and Hct of both men and women were significantly higher than at sea level at the 1500 bin (1250-1750 m); hence, the altitude threshold for the human hematological responses must be between 1000 and 1500 m. In the nonhuman apes, no increase in Hct or Hb was apparent at 1500 m; at 2000 m, the increase was significant only for the Hb of females. At either altitude in the group of nonhuman apes, the increase in Hct was much less than in humans, and that of Hb was significantly less at 1500 m. We conclude that lack of, or minimal, hematopoietic response to moderate altitude can occur in mammalian species that are not genetically adapted to high altitudes. Polycythemia is not a common response to altitude hypoxia and, at least at moderate altitudes, the degree of the human response may represent the exception among apes rather than the rule.

Lineage-Specific Changes in Biomarkers in Great Apes and Humans.

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.

Functional, spectroscopic and structural properties of haemoglobin from chamois (Rupicapra rupicapra) and steinbock (Capra hircus ibex).

The functional and spectroscopic properties of chamois (Rupicapra rupicapra) and steinbock (Capra hircus ibex) haemoglobin (Hb) have been studied with special reference to the action of allosteric effectors and temperature. Moreover, the amino acid sequences of the N-terminal segments of the alpha- and beta-chains have been determined. The present results indicate that chamois and steinbock Hbs display a low affinity for O2, which appears to be modulated in vivo by Cl- ions rather than 2,3-bisphosphoglycerate. The Bohr effect for O2 binding to chamois and steinbock Hb is higher than for reindeer and bovine Hbs, being similar to that of human Hb. Moreover, the temperature-dependence of oxygenation appears intermediate between that of human and reindeer Hbs. E.p.r. and absorption spectroscopic properties of the ferrous nitrosylated derivative of chamois and steinbock Hbs suggest that both haemoproteins are in a low-affinity conformation even in the absence of InsP6. The reduced effect of polyphosphates on the functional and spectroscopic properties of chamois and steinbock Hb agree with amino acid differences in the N-terminal segment of the beta-chains (i.e. the deletion of Val(NA1) and the replacement of His(NA2), present in human Hb, and Gln(NA2), present in horse Hb, by Met). The molecular mechanism modulating the basic reaction of O2 with chamois and steinbock Hb may be linked to specific physiological needs related to the high-altitude habitats of these two animals.

The 60 and 63 kDa proteolytic peptides of the red cell membrane band-3 protein: their prevalence in human and non-human primates.

Three phenotypes based on the polymorphism of band-3 protein from human red cells are described. Limited proteolysis of intact red cells from most individuals (homozygotes) yields a peptide of 60 kDa, but in some cases (heterozygotes), there is also a 63-kDa peptide, and rarely only the single peptide of 63 kDa is found. This is the first description of the 63-kDa homozygote. The interpretation that the three phenotypes are controlled by two alleles of a single autosomal locus, with no dominance, is supported by population and family studies. The frequencies of the allele, which we designate as p63, is 0.041 +/- 0.0068 in Caucasoids and 0.125 +/- 0.0121 in Negroids. The electrophoretic profiles and molecular weights of the peptides obtained with several commercial proteases from Streptomyces griseus are similar to those obtained with chymotrypsin. Whereas band-3 protein in two New-World monkeys (Saimiri and Cebus) resisted pronase attack, an Old-World monkey (Macaca mulatta) was monomorphic for a 63-kDa fragment, and in an ape (Pan troglodytes), a doublet of 62 kDa and 64 kDa was found. Band-3 protein polymorphism appears to be a good marker for genetic differentiation in human populations.

Comparison of human and siamang ABH and MN blood groups using monoclonal antibodies.

Comparison of human and siamang ABHIi and MNSs blood groups using monoclonal antibodies and enzyme-modified erythrocytes showed a different organization of ABHIi in the siamang, and a greatly altered expression of the sialoglycoproteins that express MNSs. While several monoclonal antibodies to human MNSs sialoglycoproteins failed to agglutinate siamang erythrocytes, MoAb145, a monoclonal antibody that reacts with the MN sialoglycoprotein, agglutinated siamang erythrocytes to almost the same titer as human red blood cells. These studies suggest the potential usefulness of monoclonal antibodies in seroprimatology.

Oncornavirus lytic activity in the serum of gibbon apes.

Fresh blood serum from normal gibbon apes (Hylobates lar) contained heat-sensitive lytic activity for various mammalian oncornaviruses. Lytic activity quantitatively similar to that in gibbon serum was demonstrated in serum from three other primate species, including man; it was demonstrated to be low or absent in lower mammalian species with the exception of domestic cats, which had intermediate levels of serum lytic activity. Gibbons that acquired infectious gibbon ape leukemia virus, either naturally by exposure to a virus-shedding ape or experimentally by deliberate virus inoculation, had the same levels of serum lytic activity as did unexposed gibbons that had no detectable antibodies to gibbon ape leukemia virus. A leukemic-viremic gibbon had low or absent serum oncornavirus lytic activity. These results indicated that serum lytic activity does not necessarily protect against infection by oncornaviruses, although it may limit virus replication and/or dissemination.