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Journal of Virology, March 2008, p. 2367-2375, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02161-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

4E10-Resistant Variants in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Individual with an Anti-Membrane-Proximal External Region-Neutralizing Antibody Response{triangledown}

Elin S. Gray,1 Penny L. Moore,1 Frederic Bibollet-Ruche,3 Hui Li,3 Julie M. Decker,3 Tammy Meyers,2 George M. Shaw,3 and Lynn Morris1*

AIDS Virus Research Unit, National Institute for Communicable Diseases,1 Harriet Shezi Clinic, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa,2 University of Alabama at Birmingham, Birmingham, Alabama 352943

Received 3 October 2007/ Accepted 12 December 2007

The broadly neutralizing monoclonal antibody (MAb) 4E10 recognizes a linear epitope in the C terminus of the membrane-proximal external region (MPER) of gp41. This epitope is particularly attractive for vaccine design because it is highly conserved among human immunodeficiency virus type 1 (HIV-1) strains and neutralization escape in vivo has not been observed. Multiple env genes were cloned from an HIV-1 subtype C virus isolated from a 7-year-old perinatally infected child who had anti-MPER neutralizing antibodies. One clone (TM20.13) was resistant to 4E10 neutralization as a result of an F673L substitution in the MPER. Frequency analysis showed that F673L was present in 33% of the viral variants and in all cases was linked to the presence of an intact 2F5 epitope. Two other envelope clones were sensitive to 4E10 neutralization, but TM20.5 was 10-fold less sensitive than TM20.6. Substitutions at positions 674 and 677 within the MPER rendered TM20.5 more sensitive to 4E10 but had no effect on TM20.6. Using chimeric and mutant constructs of these two variants, we further demonstrated that the lentivirus lytic peptide-2 domain in the cytoplasmic tail affected the accessibility of the 4E10 epitope, as well as virus infectivity. Collectively, these genetic changes in the face of a neutralizing antibody response to the MPER strongly suggested immune escape from antibody responses targeting this region.

* Corresponding author. Mailing address: National Institute for Communicable Diseases, Johannesburg, Private Bag X4, Sandringham 2131, Johannesburg, South Africa. Phone: 27-11-386-6332. Fax: 27-11-386-6333. E-mail: lynnm{at}nicd.ac.za

{triangledown} Published ahead of print on 19 December 2007.

Journal of Virology, March 2008, p. 2367-2375, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02161-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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