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Anti-HIV IgM protects against mucosal SHIV transmission

Gong, Siqia,b,*; Tomusange, Khamisa,*; Kulkarni, Viraja; Adeniji, Opeyemi S.a,b; Lakhashe, Samir K.a; Hariraju, Dinesha; Strickland, Amandaa; Plake, Elizabetha; Frost, Patrice A.c; Ratcliffe, Sarah J.d; Wang, Lipinge; Lafer, Eileen M.e; Ruprecht, Ruth M.a,b,c

doi: 10.1097/QAD.0000000000001857
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Objective: Worldwide, most new HIV infections occur through mucosal exposure. Immunoglobulin M (IgM) is the first antibody class generated in response to infectious agents; IgM is present in the systemic circulation and in mucosal fluids as secretory IgM. We sought to investigate for the first time the role of IgM in preventing AIDS virus acquisition in vivo.

Design: Recombinant polymeric monoclonal IgM was generated from the neutralizing monoclonal IgG1 antibody 33C6-IgG1, tested in vitro, and given by passive intrarectal immunization to rhesus macaques 30 min before intrarectal challenge with simian-human immunodeficiency virus (SHIV) that carries an HIV-1 envelope gene.

Results: In vitro, 33C6-IgM captured virions more efficiently and neutralized the challenge SHIV with a 50% inhibitory molar concentration (IC50) that was 1 log lower than that for 33C6-IgG1. The IgM form also exhibited significantly higher affinity and avidity compared with 33C6-IgG1. After intrarectal administration, 33C6-IgM prevented viremia in four out of six rhesus macaques after high-dose intrarectal SHIV challenge. Five out of six rhesus macaques given 33C6-IgG1 were protected at a five times higher molar concentration compared with the IgM form; all untreated controls became highly viremic. Rhesus macaques passively immunized with 33C6-IgM with breakthrough infection had notably early development of autologous neutralizing antibody responses.

Conclusion: Our primate model data provide the first proof-of-concept that mucosal IgM can prevent mucosal HIV transmission and have implications for HIV prevention and vaccine development.

aDepartment of Virology and Immunology, Texas Biomedical Research Institute

bDepartment of Microbiology, Immunology & Molecular Genetics, The University of Texas Health Science Center at San Antonio

cSouthwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas

dDivision of Biostatistics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia

eDepartment of Biochemistry and Structural Biology, Center for Biomedical Neuroscience, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

Correspondence to Ruth M. Ruprecht, MD, PhD, Texas Biomedical Research Institute, 8715 W Military Dr, San Antonio, TX 78227, USA. Tel: +1 210 258 9568; fax: +1 210 258 9155; e-mail: rruprecht@txbiomed.org

Received 21 March, 2018

Revised 11 April, 2018

Accepted 13 April, 2018

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

Copyright © 2018 Wolters Kluwer Health, Inc.