UMMS Affiliation

Department of Medicine

Publication Date

2018-08-28

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Digestive System | Immunology and Infectious Disease | Pathogenic Microbiology | Virology | Virus Diseases | Viruses

Abstract

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin alpha4beta7, a gut-homing receptor. Using both cell-surface expressed alpha4beta7 and a soluble alpha4beta7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of alpha4beta7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to alpha4beta7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, alpha4beta7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to alpha4beta7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to alpha4beta7. It includes the canonical LDV/I alpha4beta7 binding site, a cryptic epitope that lies 7-9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-alpha4beta7 interactions. These mAbs recognize conformations absent from the beta- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-alpha4beta7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

Keywords

HIV, SIV, Macaque, Antibodies, Virions, T cells, Binding analysis, Cations

Rights and Permissions

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

DOI of Published Version

10.1371/journal.ppat.1007278

Source

PLoS Pathog. 2018 Aug 28;14(8):e1007278. doi: 10.1371/journal.ppat.1007278. eCollection 2018 Aug. Link to article on publisher's site

Journal/Book/Conference Title

PLoS pathogens

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

30153309

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons 1.0 Public Domain Dedication.

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