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4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms
- Source :
- PLoS ONE, Vol 5, Iss 3, p e9786 (2010), PLoS ONE
- Publication Year :
- 2010
- Publisher :
- Public Library of Science (PLoS), 2010.
-
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.
- Subjects :
- Genotype
Recombinant Fusion Proteins
Pediatrics and Child Health
Mothers
Zambia
Mutagenesis (molecular biology technique)
lcsh:Medicine
Sequence alignment
Virology/Immune Evasion
Gp41
Neutralization
Inhibitory Concentration 50
03 medical and health sciences
0302 clinical medicine
Neutralization Tests
Humans
030212 general & internal medicine
lcsh:Science
030304 developmental biology
Genetics
Likelihood Functions
0303 health sciences
Polymorphism, Genetic
Multidisciplinary
biology
Point mutation
lcsh:R
Infant, Newborn
Gene Products, env
Infant
Infectious Diseases/HIV Infection and AIDS
Phenotype
Virology
HIV Envelope Protein gp41
3. Good health
Virology/Immunodeficiency Viruses
HIV-2
HIV-1
Mutagenesis, Site-Directed
biology.protein
Female
lcsh:Q
Antibody
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 5
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....bf55987f494da172bcbc55a20e3c8211