Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies

Nuria Pedreño-Lopez, Christine M. Dang, Brandon C. Rosen, Michael J. Ricciardi, Varian K. Bailey, Martin J. Gutman, Lucas Gonzalez-Nieto, Matthias G. Pauthner, Khoa Le, Ge Song, Raiees Andrabi, Kim L. Weisgrau, Nicholas Pomplun, José M. Martinez-Navio, Sebastian P. Fuchs, Jens Wrammert, Eva G. Rakasz, Jeffrey D. Lifson, Mauricio A. Martins, Dennis R. BurtonDavid I. Watkins, Diogo M. Magnani

Research output: Contribution to journalArticle

Abstract

Structural characterization of the HIV-1 Envelope (Env) glycoprotein has facilitated the development of Env probes to isolate HIV-specific monoclonal antibodies (mAbs). However, preclinical studies have largely evaluated these virus-specific mAbs against chimeric viruses, which do not naturally infect non-human primates, in contrast to the unconstrained simian immunodeficiency virus (SIV)mac239 clone. Given the paucity of native-like reagents for the isolation of SIV-specific B cells, we examined a method to isolate SIVmac239-specific mAbs without using Env probes. We first activated virus-specific B cells by inducing viral replication after the infusion of a CD8β-depleting mAb or withdrawal of antiretroviral therapy in SIVmac239-infected rhesus macaques. Following the rise in viremia, we observed 2- to 4-fold increases in the number of SIVmac239 Env-reactive plasmablasts in circulation. We then sorted these activated B cells and obtained 206 paired Ab sequences. After expressing 122 mAbs, we identified 14 Env-specific mAbs. While these Env-specific mAbs bound to both the SIVmac239 SOSIP.664 trimer and to infected primary rhesus CD4+ T cells, five also neutralized SIVmac316. Unfortunately, none of these mAbs neutralized SIVmac239. Our data show that this method can be used to isolate virus-specific mAbs without antigenic probes by inducing bursts of contemporary replicating viruses in vivo.

Original languageEnglish (US)
Pages (from-to)225-237
Number of pages13
JournalMolecular Therapy - Methods and Clinical Development
Volume16
DOIs
StatePublished - Mar 13 2020

Keywords

  • antiretroviral therapy interruption
  • CD8b depletion
  • monoclonal antibodies
  • rhesus macaques
  • SIV

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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  • Cite this

    Pedreño-Lopez, N., Dang, C. M., Rosen, B. C., Ricciardi, M. J., Bailey, V. K., Gutman, M. J., Gonzalez-Nieto, L., Pauthner, M. G., Le, K., Song, G., Andrabi, R., Weisgrau, K. L., Pomplun, N., Martinez-Navio, J. M., Fuchs, S. P., Wrammert, J., Rakasz, E. G., Lifson, J. D., Martins, M. A., ... Magnani, D. M. (2020). Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies. Molecular Therapy - Methods and Clinical Development, 16, 225-237. https://doi.org/10.1016/j.omtm.2020.01.010