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Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection

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Abstract

α4β7 integrin–expressing CD4+ T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4+ T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

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Figure 1: Kinetics of plasma viral load and tissue and organ specific pro-viral DNA loads.
Figure 2: Frequency of lymphocyte subsets from infected macaque peripheral blood mononuclear cells (PBMCs) and inhibition of MAdCAM or SIVmac251 gp120 by α4β7-mAb.

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Acknowledgements

This work was supported by a grant from the NIH-NIAID AI-098628-01 (to A.A.A.), the NIAID NIH Intramural Research Program and OD 51POD1113 to the Yerkes National Primate Research Center. We are grateful to F. Connor-Stroud for help with the cytobrush studies and to the veterinary staff and animal caretakers of the Yerkes National Primate Center of Emory University, specially S. Ehnert and her team. The authors also acknowledge the assistance of M. Piatak for performing the ultrasensitive PCR analysis and R. Kaul and L.R. McKinnon for sharing with us their finding on cervical brush analyses in Africa and advising us on how to proceed in adapting their human findings to our nonhuman primates. Recombinant mAbs were produced by the Nonhuman Primate Reagent Resource (NIAID, NIH contract # HHSN272200900037C). The virus stock of SIVmac251 was obtained courtesy of N. Miller (NIAID, NIH). We apologize to all the authors whose publications we failed to cite. The findings in this report are those of the authors and do not necessarily reflect the views of the US Centers for Disease Control and Prevention.

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The day-to-day scheduling of the experiments were carried out under the laboratory supervision of A.E.M., technically performed by S.N.B., B.K., P.D., T.V. and D.L. The experiments described in Figure 2d–h were performed by F.N. and J.H. The overall planning and direction of the studies was carried out by A.A.A. C.C., F.V. and P.J.S. in regularly scheduled consultation with E.N.K., J.M.M. and T.G.P. D.H. provided the statistical planning of the studies and performed the statistical analyses of the data obtained. K.A.R. consulted and provided the large-scale preparation of the recombinant α4β7 monoclonal antibody and the normal rhesus IgG mAbs. M.B. and L.W. performed the major histocompatibility complex typing of the animals, and K.R. performed the Fc receptor typing of the animals. A.A.A. and T.G.P. prepared the draft of this manuscript with input from all the authors. A.S.F. provided helpful discussions and review and revision of the manuscript.

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Correspondence to Aftab A Ansari.

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The authors declare no competing financial interests.

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Byrareddy, S., Kallam, B., Arthos, J. et al. Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med 20, 1397–1400 (2014). https://doi.org/10.1038/nm.3715

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