Enhanced ability of plant-derived PGT121 glycovariants to eliminate HIV-1-infected cells

Sai Priya Anand, Shilei Ding, William D. Tolbert, Jérémie Prévost, Jonathan Richard, Hwi Min Gil, Gabrielle Gendron-Lepage, Wing Fai Cheung, Haifeng Wang, Rebecca Pastora, Hirak Saxena, Warren Wakarchuk, Halima Medjahed, Bruce D. Wines, Mark Hogarth, George M. Shaw, Malcom A. Martin, Dennis R. Burton, Lars Hangartner, David T. EvansMarzena Pazgier, Doug Cossar, Michael D. McLean, Andrés Finzi

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The activity of broadly neutralizing antibodies (bNAbs) targeting HIV-1 depends on pleiotropic functions, including viral neutralization and the elimination of HIV-1-infected cells. Several in vivo studies have suggested that passive administration of bNAbs represents a valuable strategy for the prevention or treatment of HIV-1. In addition, different strategies are currently being tested to scale up the production of bNAbs to obtain the large quantities of antibodies required for clinical trials. Production of antibodies in plants permits low-cost and large-scale production of valuable therapeutics; furthermore, pertinent to this work, it also includes an advanced glycoengineering platform. In this study, we used Nicotiana benthamiana to produce different Fc-glycovariants of a potent bNAb, PGT121, with near-homogeneous profiles and evaluated their antiviral activities. Structural analyses identified a close similarity in overall structure and glycosylation patterns of Fc regions for these plant-derived Abs and mammalian cell-derived Abs. When tested for Fc-effector activities, afucosylated PGT121 showed significantly enhanced FcgRIIIa interaction and antibody dependent cellular cytotoxicity (ADCC) against primary HIV-1infected cells, both in vitro and ex vivo. However, the overall galactosylation profiles of plant PGT121 did not affect ADCC activities against infected primary CD41 T cells. Our results suggest that the abrogation of the Fc N-linked glycan fucosylation of PGT121 is a worthwhile strategy to boost its Fc-effector functionality. IMPORTANCE PGT121 is a highly potent bNAb and its antiviral activities for HIV-1 prevention and therapy are currently being evaluated in clinical trials. The importance of its Fc-effector functions in clearing HIV-1-infected cells is also under investigation. Our results highlight enhanced Fc-effector activities of afucosylated PGT121 MAbs that could be important in a therapeutic context to accelerate infected cell clearance and slow disease progression. Future studies to evaluate the potential of plant-produced afucosylated PGT121 in controlling HIV-1 replication in vivo are warranted.

Original languageEnglish
Article numbere00796-21
JournalJournal of Virology
Volume95
Issue number18
DOIs
StatePublished - Sep 2021
Externally publishedYes

Keywords

  • ADCC
  • Broadly neutralizing antibodies
  • Env glycoproteins
  • Envelope glycoproteins
  • FcgRIIIa
  • Fucose
  • Galactose
  • Glycosylation
  • HIV-1
  • HIV-1
  • Neutralizing antibodies
  • Nicotiana benthamiana
  • PGT121
  • Plant antibodies
  • Plant antibodies

Fingerprint

Dive into the research topics of 'Enhanced ability of plant-derived PGT121 glycovariants to eliminate HIV-1-infected cells'. Together they form a unique fingerprint.

Cite this