Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection
Autor: | Hua-Xin Liao, Guido Ferrari, Punnee Pitisuttithum, Thomas N. Denny, Justin Pollara, Nicole L. Yates, Georgia D. Tomaras, Florian Hladik, George M. Shaw, Barton F. Haynes, M. Juliana McElrath, Georgeanna Morton, Katharine Westerberg, Tiffany Hensley-McBain, Shi-Mao Xia, Linh Mach, Sampa Santra, Benjamin Mildenberg, Gregory J. Mize, Ranjit Warrier, Rena D. Astronomo, Jaranit Kaewkungwal, Christina Ochsenbauer, Sorachai Nitayapan, Supachai Rerks-Ngarm, Lamar Ballweber-Fleming, Laura L. Sutherland, David C. Montefiori |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Immunoglobulin A Non-human primate rectal challenge model Vaginal explants Simian Acquired Immunodeficiency Syndrome pIgR Polymeric IgA receptor GI Gastrointestinal HIV Infections ADCC Antibody-dependent cell-mediated cytotoxicity HIV Antibodies Immunoglobulin G sIgA Secretory IgA Leukocytes T/F Transmitted/founder CD4bs CD4 binding site Antibody-dependent cell-mediated cytotoxicity biology General Medicine Isotype 3. Good health mIgA Monomeric IgA dIgA Dimeric IgA Vagina Mucosal immunology Female Simian Immunodeficiency Virus Antibody MPER Membrane-proximal external region IDV Indinivir IgA Research Paper AZT Zidovudine ARV Anti-retroviral IgG nnAb Non-neutralizing antibody 030106 microbiology LED Lowest effective dose Neutralizing antibodies General Biochemistry Genetics and Molecular Biology snLuc Secreted nanoluciferase Antibodies Immunophenotyping GalCer Galactosyl ceramide 03 medical and health sciences Neutralization Tests SC Secretory component Animals Humans FcRn Neonatal Fc receptor Immunity Mucosal IMC Infectious molecular clone bnAb Broadly neutralizing antibody Mucous Membrane Virology Antibodies Neutralizing Macaca mulatta Disease Models Animal 030104 developmental biology Immunoglobulin class switching Immunology biology.protein HIV-1 mAb Monoclonal antibody GU Genitourinary Ex vivo Biomarkers |
Zdroj: | EBioMedicine |
ISSN: | 2352-3964 |
DOI: | 10.1016/j.ebiom.2016.11.024 |
Popis: | HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development. Highlights • Only broadly-neutralizing IgG and IgA Abs were protective in two relevant mucosal models of HIV-1 infection. • IgG isotype variants were typically more protective than the IgA isotype variants against vaginal or rectal challenge. • Neutralization rather than IgA-specific functions may afford better protection against mucosal HIV-1 infection. Antibodies are likely to play a key role in preventing HIV-1 infection following mucosal exposure. We used two mucosal models, in conjunction with IgG and IgA versions of the same antibodies, to identify protective antibody properties relevant to vaginal and rectal transmission. Antibodies that can potently neutralize most HIV-1 strains were protective against viral challenge, but those without this capability were non-protective. The IgA antibodies were no more protective than their IgG counterparts even though IgA antibody forms are more abundant in the mucosa. These findings can help prioritize vaccine designs to those that induce potent broadly neutralizing IgG antibodies. |
Databáze: | OpenAIRE |
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