Dataset Information

Blocking α₄β₇ integrin delays viral rebound in SHIV_SF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies.

ABSTRACT: Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α₄β₇ with an anti-α₄β₇ monoclonal antibody (Rh-α₄β₇) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α₄β₇ integrin blockade, SHIV_SF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α₄β₇ or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α₄β₇ and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α₄β₇ integrin blockade may prolong virologic control by bNAbs in SHIV_SF162P3-infected macaques.

SUBMITTER: Frank I

PROVIDER: S-EPMC8977869 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Blocking α4β7 integrin delays viral rebound in SHIVSF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies.

Frank Ines I Cigoli Mariasole M Arif Muhammad S MS Fahlberg Marissa D MD Maldonado Stephanie S Calenda Giulia G Pegu Amarendra A Yang Eun Sung ES Rawi Reda R Chuang Gwo-Yu GY Geng Hui H Liu Cuiping C Zhou Tongqing T Kwong Peter D PD Arthos James J Cicala Claudia C Grasperge Brooke F BF Blanchard James L JL Gettie Agegnehu A Fennessey Christine M CM Keele Brandon F BF Vaccari Monica M Hope Thomas J TJ Fauci Anthony S AS Mascola John R JR Martinelli Elena E

Science translational medicine 20210801 607

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaqu ...[more]

PMID: 34408080

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Project description: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.

Dataset Information

Blocking α₄β₇ integrin delays viral rebound in SHIV_SF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies.

Publications

Blocking α<sub>4</sub>β<sub>7</sub> integrin delays viral rebound in SHIV<sub>SF162P3</sub>-infected macaques treated with anti-HIV broadly neutralizing antibodies.

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