4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms

Abstract

Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope.

Closing the door to human immunodeficiency virus

“…Co-administration of 4E10 and 2F5 results in a synergistic neutralizing effect in vitro (Zwick et al, 2001b). To note, substitutions in the MPER contributed to the resistance to 4E10 (Gray et al, 2008;Nakamura et al, 2010). The safety and tolerability of 4E10 for clinical use have also been confirmed by a phase 2 clinical study (Joos et al, 2006).…”

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

“…The study demonstrated that W680G point mutation was necessary to confer 4E10 resistant phenotype (Nakamura et al, 2011). In another subject a W680R point mutation caused variable resistant to 4E10 (Nakamura et al, 2011). A fourth subject possessed a F673L point mutation also associated with 4E10 resistance (Nakamura et al, 2011).…”

“…Mutagenesis studies have shown that the amino acid residues W672, F673 and W680 are indispensable for recognition by 4E10 (Zwick et al, 2005). Indeed, a recently published study describing four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization has shown that three subjects had W680 polymorphism, including a W680G point mutation (Nakamura et al, 2011). The study demonstrated that W680G point mutation was necessary to confer 4E10 resistant phenotype (Nakamura et al, 2011).…”

“…Indeed, a recently published study describing four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization has shown that three subjects had W680 polymorphism, including a W680G point mutation (Nakamura et al, 2011). The study demonstrated that W680G point mutation was necessary to confer 4E10 resistant phenotype (Nakamura et al, 2011). In another subject a W680R point mutation caused variable resistant to 4E10 (Nakamura et al, 2011).…”

“…In another subject a W680R point mutation caused variable resistant to 4E10 (Nakamura et al, 2011). A fourth subject possessed a F673L point mutation also associated with 4E10 resistance (Nakamura et al, 2011). Earlier, an independent study conducted in South Africa also showed that an HIV-1 subtype C virus isolated from a 7-year-old perinatally infected child with F673L point mutation was resistant to 4E10 (Gray et al, 2008).…”