HIV-1 Vpu restricts Fc-mediated effector functions in vivo

Jérémie Prévost*, Sai Priya Anand, Jyothi Krishnaswamy Rajashekar, Li Zhu, Jonathan Richard, Guillaume Goyette, Halima Medjahed, Gabrielle Gendron-Lepage, Hung Ching Chen, Yaozong Chen, Joshua A. Horwitz, Michael W. Grunst, Susan Zolla-Pazner, Barton F. Haynes, Dennis R. Burton, Richard A. Flavell, Frank Kirchhoff, Beatrice H. Hahn, Amos B. Smith, Marzena PazgierMichel C. Nussenzweig, Priti Kumar, Andrés Finzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.

Original languageEnglish
Article number111624
JournalCell Reports
Volume41
Issue number6
DOIs
StatePublished - 8 Nov 2022
Externally publishedYes

Keywords

  • ADCC
  • CD4 mimetics
  • CP: Immunology
  • Env
  • Fc-effector functions
  • HIV-1
  • Vpu
  • broadly neutralizing antibodies
  • humanized mice
  • immune evasion
  • non-neutralizing antibodies

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