Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir

Jyothi K. Rajashekar, Jonathan Richard, Jagadish Beloor, Jérémie Prévost, Sai Priya Anand, Guillaume Beaudoin-Bussières, Liang Shan, Dietmar Herndler-Brandstetter, Gabrielle Gendron-Lepage, Halima Medjahed, Catherine Bourassa, Fleur Gaudette, Irfan Ullah, Kelly Symmes, Andrew Peric, Emily Lindemuth, Frederic Bibollet-Ruche, Jun Park, Hung Ching Chen, Daniel E. KaufmannBeatrice H. Hahn, Joseph Sodroski, Marzena Pazgier, Richard A. Flavell, Amos B. Smith, Andrés Finzi, Priti Kumar

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.

Original languageEnglish
Pages (from-to)904-916.e6
JournalCell Host and Microbe
Volume29
Issue number6
DOIs
StatePublished - Jun 9 2021

Keywords

  • CD4i Abs
  • HIV-1
  • NK cell
  • SRG-15
  • State 2A
  • antibody-dependent cellular cytotoxicity
  • envelope glycoprotein
  • humanized mice

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