Rena D. AstronomoSampa SantraLamar Ballweber-FlemingKatharine G. WesterbergLinh MachTiffany Hensley-McBainLaura SutherlandBenjamin MildenbergGeorgeanna MortonNicole L. YatesGregory J. MizeJustin PollaraFlorian HladikChristina OchsenbauerThomas N. DennyRanjit WarrierSupachai Rerks-NgarmPunnee PitisuttithumSorachai NitayapanJaranit KaewkungwalGuido FerrariGeorge M. ShawShi Mao XiaHua Xin LiaoDavid C. MontefioriGeorgia D. TomarasBarton F. HaynesM. Juliana McElrathFred Hutchinson Cancer Research CenterBeth Israel Deaconess Medical CenterDuke UniversityUniversity of Washington, SeattleUniversity of Alabama at BirminghamUniversity of PennsylvaniaThailand Ministry of Public HealthMahidol UniversityArmed Forces Research Institute of Medical Sciences, Thailand2018-12-112019-03-142018-12-112019-03-142016-12-01EBioMedicine. Vol.14, (2016), 97-111235239642-s2.0-85003794530https://repository.li.mahidol.ac.th/handle/20.500.14594/42826© 2016 The Authors 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-CSFand HIV-1Bal26infection. 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1016/j.ebiom.2016.11.024