A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity
| Autor: | Benjamin N. Bell, Adonis A. Rubio, Peter S. Kim, Celia C. LaBranche, Theodora U J Bruun, Clayton L. Brown, David C. Montefiori, Maria V. Filsinger Interrante |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Enfuvirtide medicine.drug_class Anti-HIV Agents prehairpin intermediate Immunology HIV Infections virus Gp41 Monoclonal antibody Antibodies Viral Microbiology Neutralization Cell Line 03 medical and health sciences 0302 clinical medicine Protein Domains Virology Vaccines and Antiviral Agents medicine antibodies Humans HIV vaccine biology Antibodies Monoclonal biology.organism_classification Antibodies Neutralizing HIV Envelope Protein gp41 Heptad repeat 030104 developmental biology HEK293 Cells Insect Science Lentivirus biology.protein HIV-1 Antibody 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Virology |
| ISSN: | 1098-5514 0022-538X |
| Popis: | HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date, these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in the 50% inhibitory dose (ID50) against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values of 90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date, anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development. |
| Databáze: | OpenAIRE |
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