Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity
Lloyd, Krissey E.
Sutherland, Laura L.
Scearce, Richard M.
Bowman, Cindy M.
Abdool-Karim, Salim S.
Boyd, Scott D.
Smith, Amos B.
Kepler, Thomas B.
Moody, M. Anthony
Haynes, Barton F.Note: Order does not necessarily reflect citation order of authors.
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CitationBradley, T., A. Trama, N. Tumba, E. Gray, X. Lu, N. Madani, F. Jahanbakhsh, et al. 2016. “Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity.” EBioMedicine 12 (1): 196-207. doi:10.1016/j.ebiom.2016.08.045. http://dx.doi.org/10.1016/j.ebiom.2016.08.045.
AbstractMost 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.
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