title: HIV-1 gp41 core with exposed membrane-proximal external region inducing broad HIV-1 neutralizing antibodies.
abstract: The membrane-proximal external region (MPER) of the HIV-1 gp41 consists of epitopes for the broadly cross-neutralizing monoclonal antibodies 2F5 and 4E10. However, antigens containing the linear sequence of these epitopes are unable to elicit potent and broad neutralizing antibody responses in vaccinated hosts, possibly because of inappropriate conformation of these epitopes. Here we designed a recombinant antigen, designated NCM, which comprises the N- and C-terminal heptad repeats that can form a six-helix bundle (6HB) core and the MPER domain of gp41. Two mutations (T569A and I675V) previously reported to expose the neutralization epitopes were introduced into NCM to generate mutants named NCM(TA), NCM(IV), and NCM(TAIV). Our results showed that NCM and its mutants could react with antibodies specific for 6HB and MPER of gp41, suggesting that these antigens are in the form of a trimer of heterodimer (i.e., 6HB) with three exposed MPER tails. Antigen with double mutations, NCM(TAIV), elicited much stronger antibody response in rabbits than immunogens with single mutation, NCM(TA) and NCM(IV), or no mutation, NCM. The purified MPER-specific antibodies induced by NCM(TAIV) exhibited broad neutralizing activity, while the purified 6HB-specific antibodies showed no detectable neutralizing activity. Our recombinant antigen design supported by an investigation of its underlying molecular mechanisms provides a strong scientific platform for the discovery of a gp41 MPER-based AIDS vaccine.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.forename: Pei
authors.initials: P
authors.lastname: Tong
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhou
authors.forename: Liling
authors.initials: L
authors.lastname: Xu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Ying-hua
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41