Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity.
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.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: todd.bradley@duke.edu.
Todd
T
Bradley
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Ashley
A
Trama
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
Nancy
N
Tumba
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
Elin
E
Gray
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Xiaozhi
X
Lu
Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
Navid
N
Madani
Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Fatemeh
F
Jahanbakhsh
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Amanda
A
Eaton
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Shi-Mao
SM
Xia
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Robert
R
Parks
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Krissey E
KE
Lloyd
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Laura L
LL
Sutherland
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Richard M
RM
Scearce
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Cindy M
CM
Bowman
Novartis Vaccines and Diagnostics, Inc., Cambridge, MA, USA.
Susan
S
Barnett
Center for AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa; Columbia University, New York, NY 10032, USA.
Salim S
SS
Abdool-Karim
Stanford University, Palo Alto, CA 94305, USA.
Scott D
SD
Boyd
University of Pennsylvania, Philadelphia, PA 19104, USA.
Bruno
B
Melillo
University of Pennsylvania, Philadelphia, PA 19104, USA.
Amos B
AB
Smith
Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
Joseph
J
Sodroski
Boston University, Boston, MA 02118, USA.
Thomas B
TB
Kepler
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
S Munir
SM
Alam
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Feng
F
Gao
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Mattia
M
Bonsignori
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Hua-Xin
HX
Liao
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
M Anthony
MA
Moody
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
David
D
Montefiori
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Sampa
S
Santra
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.
Lynn
L
Morris
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: barton.haynes@duke.edu.
Barton F
BF
Haynes
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D000940:Antigenic Variation; D004195:Disease Models, Animal; D015870:Gene Expression; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008253:Macaca mulatta; D009154:Mutation; D009500:Neutralization Tests; D054730:Protein Interaction Domains and Motifs / Q000235:genetics* / Q000276:immunology*
D016915:AIDS Vaccines; D019138:Antibodies, Blocking; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41