title: A Small Molecule, Which Competes with MAdCAM-1, Activates Integrin α4β7 and Fails to Prevent Mucosal Transmission of SHIV-SF162P3.
abstract: Mucosal HIV-1 transmission is inefficient. However, certain viral and host characteristics may play a role in facilitating HIV acquisition and systemic expansion. Cells expressing high levels of integrin α4β7 have been implicated in favoring the transmission process and the infusion of an anti-α4β7 mAb (RM-Act-1) prior to, and during a repeated low-dose vaginal challenge (RLDC) regimen with SIVmac251 reduced SIV acquisition and protected the gut-associated lymphoid tissues (GALT) in the macaques that acquired SIV. α4β7 expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target α4β7 have been shown to be effective in treating inflammatory conditions of the intestine, such as inflammatory bowel disease (IBD). To determine if blocking α4β7 with ELN, an orally available anti-α4 small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 (α4β7 natural ligand) and HIV-gp120 binding in vitro. We studied the pharmacokinetic profile of ELN after oral and vaginal delivery in macaques. Twenty-six macaques were divided into 3 groups: 9 animals were treated with ELN orally, 9 orally and vaginally and 8 were used as controls. All animals were challenged intra-vaginally with SHIV-SF162P3 using the RLDC regimen. We found that ELN did not protect macaques from SHIV acquisition although it reduced the SHIV-induced inflammatory status during the acute phase of infection. Notably, integrins can exist in different activation states and, comparing the effect of ELN and the anti-α4β7 mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of α4β7, while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of α4β7 activation may be necessary to reduce susceptibility to SIV/SHIV infection and highlight the complexity of anti-integrins therapeutic approach in HIV as well as in IBD and other autoimmune diseases.
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Arrode-Brusés
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Goode
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Kyle
authors.initials: K
authors.lastname: Kleinbeck
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wilk
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Ines
authors.initials: I
authors.lastname: Frank
authors.affiliation: University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Siddappa
authors.initials: S
authors.lastname: Byrareddy
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Arthos
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, Louisiana, United States of America.
authors.forename: Brooke
authors.initials: B
authors.lastname: Grasperge
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, Louisiana, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zydowsky
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Martinelli
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D009088:Mucoproteins / Q000378:metabolism*; D009092:Mucous Membrane / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000635:transmission*; D015302:Simian Immunodeficiency Virus; D014621:Vagina / Q000821:virology; D019562:Viral Load
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; C071777:integrin alpha4beta7; C543529:vedolizumab