Potent in vivo NK cellmediated elimination of HIV-1-infected cells mobilized by a gp120-bispecific and hexavalent broadly neutralizing fusion protein

Ariola Bardhi, Yanling Wu, Weizao Chen, Wei Li, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C. Kappes, Dimiter S. Dimitrov, Tianlei Ying, Harris Goldstein

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate > 80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.

Original languageEnglish (US)
Article numbere00937-17
JournalJournal of virology
Volume91
Issue number20
DOIs
StatePublished - Oct 1 2017

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Keywords

  • Human immunodeficiency virus
  • NK cell

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Bardhi, A., Wu, Y., Chen, W., Li, W., Zhu, Z., Zheng, J. H., Wong, H., Jeng, E., Jones, J., Ochsenbauer, C., Kappes, J. C., Dimitrov, D. S., Ying, T., & Goldstein, H. (2017). Potent in vivo NK cellmediated elimination of HIV-1-infected cells mobilized by a gp120-bispecific and hexavalent broadly neutralizing fusion protein. Journal of virology, 91(20), [e00937-17]. https://doi.org/10.1128/JVI.00937-17