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  • Title: Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity.
    Author: Bradley T, Trama A, Tumba N, Gray E, Lu X, Madani N, Jahanbakhsh F, Eaton A, Xia SM, Parks R, Lloyd KE, Sutherland LL, Scearce RM, Bowman CM, Barnett S, Abdool-Karim SS, Boyd SD, Melillo B, Smith AB, Sodroski J, Kepler TB, Alam SM, Gao F, Bonsignori M, Liao HX, Moody MA, Montefiori D, Santra S, Morris L, Haynes BF.
    Journal: EBioMedicine; 2016 Oct; 12():196-207. PubMed ID: 27612593.
    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.
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