HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane.
Although rarely elicited during natural human infection, the most broadly neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus (HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral gp41. To gain insight into MPER antigenicity, immunogenicity, and viral function, we studied its structure in the lipid environment by a combination of nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR) techniques. The analyses revealed a tilted N-terminal alpha helix (aa 664-672) connected via a short hinge to a flat C-terminal helical segment (675-683). This metastable L-shaped structure is immersed in viral membrane and, therefore, less accessible to immune attack. Nonetheless, the 4E10 BNAb extracts buried W672 and F673 after initial encounter with the surface-embedded MPER. The data suggest how BNAbs may perturb tryptophan residue-associated viral fusion involving the mobile N-terminal MPER segment and, given conservation of MPER sequences in HIV-1, HIV-2, and SIV, have important implications for structure-guided vaccine design.
Sun
Zhen-Yu J
ZY
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Oh
Kyoung Joon
KJ
Kim
Mikyung
M
Yu
Jessica
J
Brusic
Vladimir
V
Song
Likai
L
Qiao
Zhisong
Z
Wang
Jia-huai
JH
Wagner
Gerhard
G
Reinherz
Ellis L
EL
D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology; D004578:Electron Spin Resonance Spectroscopy; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017433:Protein Structure, Secondary; D020349:Surface Plasmon Resonance
D000956:Antigens, Viral; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41