Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 15, Pages 5663-5668Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112391109
Keywords
conformational equilibrium; viral evasion; X-ray crystallography
Categories
Funding
- National Institutes of Health (NIH)
- International AIDS Vaccine Initiative's Neutralizing Antibody Consortium
- US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
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The HIV-1 envelope (Env) spike (gp120(3)/gp41(3)) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full-length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a ground state for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from snapping into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e. g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry.
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