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Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice

Hur, Eun Mi and Patel, Sonal N. and Shimizu, Saki and Rao, Dinesh S. and Gnanapragasam, Priyanthi N. P. and An, Dong Sung and Yang, Lili and Baltimore, David (2012) Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood, 120 (23). pp. 4571-4582. ISSN 0006-4971. PMCID PMC3512234. https://resolver.caltech.edu/CaltechAUTHORS:20130206-144107544

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Abstract

HIV-1 infections are generally initiated at mucosal sites. Thus, IgA antibody, which plays pivotal roles in mucosal immunity, might efficiently prevent HIV infection. However, mounting a highly effective HIV-specific mucosal IgA response by conventional immunization has been challenging and the potency of HIV-specific IgA against infection needs to be addressed in vivo. Here we show that the polymeric IgA form of anti-HIV antibody inhibits HIV mucosal transmission more effectively than the monomeric IgA or IgG1 form in a comparable range of concentrations in humanized mice. To deliver anti-HIV IgA in a continual manner, we devised a hematopoietic stem/progenitor cell (HSPC)–based genetic approach using an IgA gene. We transplanted human HSPCs transduced with a lentiviral construct encoding a class-switched anti-HIV IgA (b12-IgA) into the humanized bone marrow-liver-thymus (BLT) mice. The transgene was expressed specifically in B cells and plasma cells in lymphoid organs and mucosal sites. After vaginal HIV-1 challenge, mucosal CD4^+ T cells in the b12-IgA–producing mice were protected from virus-mediated depletion. Similar results were also obtained in a second humanized model, “human immune system mice.” Our study demonstrates the potential of anti-HIV IgA in immunoprophylaxis in vivo, emphasizing the importance of the mucosal IgA response in defense against HIV/AIDS.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1182/blood-2012-04-422303 DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3512234/PubMed CentralArticle
ORCID:
AuthorORCID
Rao, Dinesh S.0000-0002-0794-9337
Baltimore, David0000-0001-8723-8190
Additional Information:© 2012 The American Society of Hematology. Submitted April 7, 2012; Accepted September 20, 2012. The authors thank G. Nabel (National Institute of Allergy and Infectious Diseases) for the b12-IgG plasmid; B. Corthésy (University State Hospital [CHUV], Switzerland) for human IgA2 plasmids; A. Balazs (California Institute of Technology) for lentiviral vectors; and P. Bjorkman and A. West (both from California Institute of Technology) for the purified proteins. This work was supported by the Bill & Melinda Gates Foundation, National Institutes of Health (NIH) grant HHSN266200500035C, and NIH career development award 5K08CA133521 (D.S.R.). Contribution: E.M.H. and D.B. conceived the study with assistance from L.Y.; E.M.H. designed the experiments; E.M.H. and S.N.P. performed experiments and analyzed the data; S.S. performed transplantation to generate hu-BLT mice with direction from D.S.A.; D.S.R. assisted with analysis of immunohistochemistry; P.N.P.G. performed in vitro neutralization assay of antibodies; and E.M.H. and D.B. wrote the paper with contributions from all authors. Conflict-of-interest disclosure: The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationUNSPECIFIED
NIHHHSN266200500035C
NIH5K08CA133521
Issue or Number:23
PubMed Central ID:PMC3512234
Record Number:CaltechAUTHORS:20130206-144107544
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130206-144107544
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36799
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:07 Feb 2013 23:28
Last Modified:16 Apr 2020 18:45

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