A Small Molecule, Which Competes with MAdCAM-1, Activates Integrin alpha(4)beta(7) and Fails to Prevent Mucosal Transmission of SHIV-SF162P3

作者：Arrode Bruses Geraldine; Goode Diana; Kleinbeck Kyle; Wilk Jolanta; Frank Ines; Byrareddy Siddappa; Arthos James; Grasperge Brooke; Blanchard James; Zydowsky Thomas; Gettie Agegnehu; Martinelli Elena

来源：PLoS Pathogens, 2016, 12(6): e1005720.

DOI：10.1371/journal.ppat.1005720

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 alpha(4)beta(7) have been implicated in favoring the transmission process and the infusion of an anti-alpha(4)beta(7) 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. alpha(4)beta(7) expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target alpha(4)beta(7) have been shown to be effective in treating inflammatory conditions of the intestine, such as inflammatory bowel disease (IBD). To determine if blocking alpha(4)beta(7) with ELN, an orally available anti-alpha(4) small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 (alpha(4)beta(7) 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-alpha(4)beta(7) mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of alpha(4)beta(7), while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of alpha(4)beta(7) 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.

• 出版日期2016-6