4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms.
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.
Nakamura
Kyle J
KJ
Department of Pediatrics, Childrens Hospital of Los Angeles, Los Angeles, California, United States of America.
Gach
Johannes S
JS
Jones
Laura
L
Semrau
Katherine
K
Walter
Jan
J
Bibollet-Ruche
Frederic
F
Decker
Julie M
JM
Heath
Laura
L
Decker
William D
WD
Sinkala
Moses
M
Kankasa
Chipepo
C
Thea
Donald
D
Mullins
James
J
Kuhn
Louise
L
Zwick
Michael B
MB
Aldrovandi
Grace M
GM
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
D015686:Gene Products, env; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins