The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
| Autor: | John W. Shiver, Celia C. LaBranche, Adonis A. Rubio, Joseph G. Joyce, Peter S. Kim, Benjamin N. Bell, David C. Montefiori, Maria V. Filsinger Interrante |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
Repetitive Sequences Amino Acid 0301 basic medicine Enfuvirtide Sexual transmission media_common.quotation_subject Guinea Pigs Antibody Affinity Fc receptor HIV Infections HIV Antibodies Gp41 Neutralization 03 medical and health sciences 0302 clinical medicine HIV Seropositivity medicine Animals Humans Amino Acid Sequence media_common Antiserum Multidisciplinary biology Immune Sera Receptors IgG Virus Internalization Antibodies Neutralizing Virology HIV Envelope Protein gp41 Heptad repeat 030104 developmental biology Immunoglobulin G HIV-1 Commentary biology.protein Immunization Antibody 030215 immunology medicine.drug |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2018027118 |
| Popis: | The HIV-1 gp41 N-heptad repeat (NHR) region of the pre-hairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the FDA-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared to those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine. |
| Databáze: | OpenAIRE |
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