title: 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.
authors.affiliation: Department of Pediatrics, Childrens Hospital of Los Angeles, Los Angeles, California, United States of America.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Nakamura
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Gach
authors.forename: Laura
authors.initials: L
authors.lastname: Jones
authors.forename: Katherine
authors.initials: K
authors.lastname: Semrau
authors.forename: Jan
authors.initials: J
authors.lastname: Walter
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Laura
authors.initials: L
authors.lastname: Heath
authors.forename: William D
authors.initials: WD
authors.lastname: Decker
authors.forename: Moses
authors.initials: M
authors.lastname: Sinkala
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.forename: Donald
authors.initials: D
authors.lastname: Thea
authors.forename: James
authors.initials: J
authors.lastname: Mullins
authors.forename: Louise
authors.initials: L
authors.lastname: Kuhn
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.forename: Grace M
authors.initials: GM
authors.lastname: Aldrovandi
mesh_terms: D005260:Female; D015686:Gene Products, env / Q000378:metabolism; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000378:metabolism; D015498:HIV-2 / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020128:Inhibitory Concentration 50; D016013:Likelihood Functions; D009035:Mothers; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D010641:Phenotype; D011110:Polymorphism, Genetic; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015024:Zambia
chemical_list: D015686:Gene Products, env; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins