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.

Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

“…HIV-1 gp120 has been reported to interact with integrin α 4 β 7 expressed on primary lymphocytes and such interaction has been well studied (Arthos J, et al, 2008;Cicala C, et al, 2009;Darc M, et al, 2011;Jelicic K, et al, 2013;Li H, et al, 2011). However, whether gp120-α 4 β 7 interaction mediates the binding of HIV-1 virions to target cells remains to be further clarifi ed (Arthos J, et al, 2008;Etemad B, et al, 2012).…”

“…Recent studies indicate that HIV-1 envelope glycoprotein (Env) gp120 is capable of interacting with integrin α 4 β 7 to potentially increase viral infection (Arthos J, et al, 2008;Cicala C, et al, 2009;Darc M, et al, 2011;Li H, et al, 2011;Nawaz F, et al, 2011;Richardson S I, et al, 2013;Tjomsland V, et al, 2013). α 4 β 7 is expressed on lymphoid cells and mediates cell homing to gut-associated lymphoid tissue (GALT), the dominant site of CD4 + T cell depletion shortly after HIV-1 acquisition and local propagation (Berlin C, et al, 1993;Mehandru S, et al, 2004;Sattentau Q, 2008;Veazey R S, et al, 1998).…”

Conservation of the α4β7Lymphocyte Homing Receptor in HIV-Infected Patients with Distinct Transmission Routes and Disease Progression Profiles

“…Recently, our group showed that variants of ITGA4 exons 5 and 6 present in New World primates (NWP) displayed significant loss of avidity for HIV-1 gp120, which likely contributes to NWP resistance to lentiviral infections. 10 In the present study we hypothesized whether polymorphisms could be found in the genomic regions corresponding to exons 5, 6, and 28 of ITGA4 and to exons 15 and 16 of ITGB7 in HIV-infected patients that could be linked to specific HIV transmission routes or to disease progression outcomes.…”

“…Changes in exon 6 of ITGA4 have been highlighted as the most influential in binding efficiency of MAdCAM, VCAM, and, more significantly, the hypervariable V2 region of HIV gp120. 10 Twenty IAs and 19 VICs (three slow, six rapid, and 10 typical progressors) were screened for ITGA4 exon 6, but again all deduced amino acid sequences were shown to be identical to the reference sequence. Cloning of fragments corresponding to ITGA4 exons 5 and 6 from pediatric and adult seropositive patients was also carried out.…”

“…S1; Supplementary Data are available online at www.liebertpub.com/aid), in accordance to previous work by our group. 10 Sequences of a 4 b 7 cytoplasmic tails from varied primates, including the chimpanzee (Pan troglodytes), the Sumatran orangutan (Pongo abelli), the gibbon (Leucogenys nomascus), the olive baboon (Papio anubis), the bonobo (Pan paniscus), and the rhesus macaque (Macaca mulatta), as well as from other mammals such as horse (Equus caballus), cow (Bos taurus), rat (Rattus novergicus), and sheep (Ovis aries), were also evaluated. There was a great conservation of amino acids within the salt bridge domain between the two subunits (amino acids 969-999 and 728-779 of the a 4 and b 7 mature peptides, respectively; Supplementary Fig.…”