Mammalian C-type retroviruses are inactivated by human serum, following triggering of the classical complement cascade. This may have inhibited transmission to humans of C-type oncoviruses from other mammals. Indeed, the retroviruses human immunodeficiency virus and human T-cell leukaemia virus are resistant to human complement. Antibody-independent activation of human C1q, the first component of the classical pathway, by retroviral envelope proteins has been described. However, retroviruses produced from human cells are resistant to inactivation by human complement and human serum is known to contain antibodies directed against carbohydrates on retroviral envelopes. Gal(alpha 1-3)Gal terminal carbohydrates are expressed by most mammals but are absent in humans, which lack a functional (alpha 1-3)galactosyltransferase gene. Here, we demonstrate that anti-Gal(alpha 1-3)Gal antibodies in human serum inactivate retroviruses produced from animal cells. Expression of porcine (alpha 1-3)galactosyltransferase in human cells renders the cells and the retroviruses they produce sensitive to human serum.
No definitive biologic function has been associated with the human ABO histoblood group polymorphism, or any other terminal carbohydrate differences within or between closely related species. We have experimentally addressed the question of whether viral particles can become glycosylated as determined by the glycosylation (eg, ABO) status of the producer cell and as a result be affected by human serum containing specific natural antibodies (NAbs). Measles virus was produced in cells transfected with cDNA encoding, either human A-transferase, B-transferase, an inactive "O-transferase," or a pig ␣1-3galactosyltransferase (␣1-3GT) synthesizing the Gal␣1-3Gal structure. The viruses were shown to carry the same ABO structures as the cells; that is, A but not B if produced in A-type cells, and B but not A if produced in B-type cells. Only O was detected on the virus produced from O-type cells, whereas reduced amounts of O appeared on the Aand B-type viral particles. In addition, the Gal␣1-3Gal structure was transferred onto measles only when grown in human cells expressing this structure. When subjected to human preimmune sera, the A-type, the B-type, and the Gal␣1-3Gal viral particles were partially neutralized in a complement-dependent manner. However, the O-type or the Gal␣1-3Gal-negative viral particles were not neutralized. The neutralization appeared to be mediated by specific NAb, as judged by specific inhibition using synthetic A and IntroductionThe ABO (or ABH) histo-blood group system is characterized by the expression of polymorphic carbohydrate termini on several cell types. The genetic basis for this polymorphism in humans is explained by the existence of allelic forms of a single gene encoding glycosyltransferases with specificity for different monosaccharides. 1 They appear to be evolutionarily old, being present on glycosylated structures in different eukaryotic as well as prokaryotic organisms, and established their present day polymorphic form in humans at the latest during early primate evolution (for a review, see Blancher et al 2 ). Hence, it would be surprising if the ABO structures did not serve an important purpose. No definitive biologic function has, however, as yet been identified, 3 although suggestions have often centered on immunologic explanations. [4][5][6][7] Another very similar terminal carbohydrate structure, the Gal␣1-3Gal1-4GlcNAc-R (referred to as Gal␣1-3Gal) is present in other mammals but not in humans and other Old World primates. 8 Bacteria mimicking vertebrate terminal carbohydrates may have given rise to selection pressures favoring polymorphic glycans. 9 In addition, many pathogens and their toxins bind to specific terminal carbohydrate structures and may consequently produce selection pressures affecting the evolution of terminal carbohydrate structures. 7,10 It has also been previously suggested that viruses may carry ABO structures as part of their envelope 11,12 and consequently serve as potential selective forces influencing ABO genotype frequencies in a population....
Human serum contains natural antibodies (NAb), which can bind to endothelial cell surface antigens of other mammals. This is believed to be the major initiating event in the process of hyperacute rejection of pig to primate xenografts. Recent work has implicated galactosyl alpha 1,3 galactosyl beta 1,4 N-acetyl-glucosaminyl carbohydrate epitopes, on the surface of pig endothelial cells, as a major target of human natural antibodies. This epitope is made by a specific galactosyltransferase (alpha 1,3 GT) present in pigs but not in higher primates. We have now cloned and sequenced a full-length pig alpha 1,3 GT cDNA. The predicted 371 amino acid protein sequence shares 85% and 76% identity with previously characterized cattle and mouse alpha 1,3 GT protein sequences, respectively. By using fluorescence and isotopic in situ hybridization, the GGTA1 gene was mapped to the region q2.10-q2.11 of pig chromosome 1, providing further evidence of homology between the subterminal region of pig chromosome 1q and human chromosome 9q, which harbors the locus encoding the AB0 blood group system as well as a human pseudogene homologous to the pig GGTA1 gene.
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