A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity

• Published in: Journal of virology 2021-07, Vol.95 (15), p.e0235020-e0235020
• Main Authors: Rubio, Adonis A, Filsinger Interrante, Maria V, Bell, Benjamin N, Brown, Clayton L, Bruun, Theodora U J, LaBranche, Celia C, Montefiori, David C, Kim, Peter S
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - pharmacology; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Cell Line; Enfuvirtide - pharmacology; HEK293 Cells; HIV Envelope Protein gp41 - antagonists & inhibitors; HIV Envelope Protein gp41 - immunology; HIV Infections - immunology; HIV Infections - prevention & control; HIV-1 - immunology; Humans; Protein Domains - immunology; Vaccines and Antiviral Agents
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.02350-20

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 (ID ) 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 ID 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 activit