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Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7.
- Source :
-
PLoS pathogens [PLoS Pathog] 2018 Aug 28; Vol. 14 (8), pp. e1007278. Date of Electronic Publication: 2018 Aug 28 (Print Publication: 2018). - Publication Year :
- 2018
-
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 α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7 and a soluble α4β7 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 α4β7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7 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-α4β7 interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7 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.<br />Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JA, CC and ASF are inventors of patent 20160075786 submitted by the NIAID, NIH that covers the study of reagents that serve as antagonists of the interaction between HIV gp120 and α4β7 mAb. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Subjects :
- AIDS Vaccines chemistry
AIDS Vaccines immunology
AIDS Vaccines metabolism
Animals
Antibodies, Monoclonal
Binding Sites immunology
Cell Line, Tumor
Epitopes chemistry
Epitopes immunology
HIV Antibodies chemistry
HIV Antibodies immunology
HIV Antibodies metabolism
HIV Infections immunology
HIV-1 immunology
Macaca
Protein Binding
Protein Interaction Domains and Motifs immunology
SAIDS Vaccines chemistry
SAIDS Vaccines immunology
SAIDS Vaccines metabolism
Simian Acquired Immunodeficiency Syndrome immunology
Simian Immunodeficiency Virus immunology
Vaccination methods
HIV Envelope Protein gp120 chemistry
HIV Envelope Protein gp120 immunology
HIV Envelope Protein gp120 metabolism
HIV Infections prevention & control
Integrins metabolism
Simian Acquired Immunodeficiency Syndrome prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 14
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 30153309
- Full Text :
- https://doi.org/10.1371/journal.ppat.1007278