Details

Autor(en) / Beteiligte

• Arrode-Brusés, Géraldine
• Goode, Diana
• Kleinbeck, Kyle
• Wilk, Jolanta
• Frank, Ines
• Byrareddy, Siddappa
• Arthos, James
• Grasperge, Brooke
• Blanchard, James
• Zydowsky, Thomas
• Gettie, Agegnehu
• Martinelli, Elena

Titel

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

Ist Teil von

• PLoS pathogens, 2016-06, Vol.12 (6)

Ort / Verlag

Public Library of Science

Erscheinungsjahr

2016

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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].sub.4 [beta].sub.7 have been implicated in favoring the transmission process and the infusion of an anti-[alpha].sub.4 [beta].sub.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].sub.4 [beta].sub.7 expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target [alpha].sub.4 [beta].sub.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].sub.4 [beta].sub.7 with ELN, an orally available anti-[alpha].sub.4 small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 ([alpha].sub.4 [beta].sub.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].sub.4 [beta].sub.7 mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of [alpha].sub.4 [beta].sub.7, while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of [alpha].sub.4 [beta].sub.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.