title: Polymorphisms in the α4 integrin of neotropical primates: insights for binding of natural ligands and HIV-1 gp120 to the human α4β7.
abstract: The α4 integrin subunit associates with β7 and β1 and plays important roles in immune function and cell trafficking. The gut-homing receptor α4β7 has been recently described as a new receptor for HIV. Here, we describe polymorphisms of ITGA4 gene in New World primates (NWP), and tested their impact on the binding to monoclonal antibodies, natural ligands (MAdCAM and VCAM), and several gp120 HIV-1 envelope proteins. Genomic DNA of NWP specimens comprising all genera of the group had their exons 5 and 6 (encoding the region of binding to the ligands studied) analyzed. The polymorphisms found were introduced into an ITGA4 cDNA clone encoding the human α4 subunit. Mutant α4 proteins were co-expressed with β7 and were tested for binding of mAbs, MAdCAM, VCAM and gp120 of HIV-1, which was compared to the wild-type (human) α4. Mutant α4 proteins harboring the K201E/I/N substitution had reduced binding of all ligands tested, including HIV-1 gp120 envelopes. The mAbs found with reduced biding included one from which a clinically-approved drug for the treatment of neurological disorders has been derived. α4 polymorphisms in other primate species may influence outcomes in the development and treatment of infectious and autoimmune diseases in humans and in non-human primates.
authors.affiliation: Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mirela
authors.initials: M
authors.lastname: Darc
authors.forename: Sabrina H
authors.initials: SH
authors.lastname: Hait
authors.forename: Esmeralda A
authors.initials: EA
authors.lastname: Soares
authors.forename: Claudia
authors.initials: C
authors.lastname: Cicala
authors.forename: Hector N
authors.initials: HN
authors.lastname: Seuanez
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Machado
authors.forename: James A
authors.initials: JA
authors.lastname: Arthos
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Soares
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002417:Cattle; D005838:Genotype; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D051078:Platyrrhini; D011110:Polymorphism, Genetic; D011485:Protein Binding; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015699:HIV Envelope Protein gp120; D016023:Integrins; D008024:Ligands; D019010:Vascular Cell Adhesion Molecule-1; C514793:gp120 protein, Human immunodeficiency virus 1; C071777:integrin alpha4beta7