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EBioMedicine. 2016 Oct;12:196-207. doi: 10.1016/j.ebiom.2016.08.045. Epub 2016 Aug 31.

Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity.

Author information

1
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: todd.bradley@duke.edu.
2
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
3
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
4
Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
5
Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Novartis Vaccines and Diagnostics, Inc., Cambridge, MA, USA.
7
Center for AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa; Columbia University, New York, NY 10032, USA.
8
Stanford University, Palo Alto, CA 94305, USA.
9
University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Boston University, Boston, MA 02118, USA.
11
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
12
National Institute for Communicable Diseases, Johannesburg 2131, South Africa; Center for AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2131, South Africa.
13
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: barton.haynes@duke.edu.

Abstract

Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env. Similarly, a single change in the MPER in a second virus from another infected-individual also conferred enhanced neutralization sensitivity. These gp41 single-residue changes thus transformed tier-2 viruses into tier-1 viruses that were sensitive to vaccine-elicited tier-1 neutralizing antibodies. These data demonstrate that Env amino acid changes within the MPER bnAb epitope of naturally-selected escape viruses can increase neutralization sensitivity to multiple types of neutralizing antibodies, and underscore the critical importance of the MPER for maintaining the integrity of the tier-2 HIV-1 trimer.

PMID:
27612593
PMCID:
PMC5078591
DOI:
10.1016/j.ebiom.2016.08.045
[Indexed for MEDLINE]
Free PMC Article

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