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.IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and 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 SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated 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.
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Authors | 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 |
Journal | Journal of virology
(J Virol)
Vol. 91
Issue 20
(10 15 2017)
ISSN: 1098-5514 [Electronic] United States |
PMID | 28794022
(Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2017 American Society for Microbiology. |
Chemical References |
- Antibodies, Bispecific
- Antibodies, Neutralizing
- CD4 Antigens
- HIV Envelope Protein gp120
- Recombinant Proteins
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Topics |
- Animals
- Antibodies, Bispecific
(immunology)
- Antibodies, Neutralizing
(immunology)
- Antibody-Dependent Cell Cytotoxicity
- CD4 Antigens
(immunology)
- Disease Models, Animal
- HIV Envelope Protein gp120
(chemistry)
- HIV Infections
(immunology, virology)
- HIV-1
(isolation & purification, physiology)
- Killer Cells, Natural
(immunology)
- Leukocytes, Mononuclear
(virology)
- Macaca mulatta
- Mice
- Recombinant Proteins
(genetics, immunology, isolation & purification, metabolism)
- Simian Acquired Immunodeficiency Syndrome
(immunology, virology)
- Simian Immunodeficiency Virus
(immunology)
- Virus Latency
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