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TitleThermostability of Well-Ordered HIV Spikes Correlates with the Elicitation of Autologous Tier 2 Neutralizing Antibodies.
Journal, issue, pagesPLoS Pathog, Vol. 12, Issue 8, Page e1005767, Year 2016
Publish dateAug 3, 2016
AuthorsYu Feng / Karen Tran / Shridhar Bale / Shailendra Kumar / Javier Guenaga / Richard Wilson / Natalia de Val / Heather Arendt / Joanne DeStefano / Andrew B Ward / Richard T Wyatt /
PubMed AbstractIn the context of HIV vaccine design and development, HIV-1 spike mimetics displaying a range of stabilities were evaluated to determine whether more stable, well-ordered trimers would more ...In the context of HIV vaccine design and development, HIV-1 spike mimetics displaying a range of stabilities were evaluated to determine whether more stable, well-ordered trimers would more efficiently elicit neutralizing antibodies. To begin, in vitro analysis of trimers derived from the cysteine-stabilized SOSIP platform or the uncleaved, covalently linked NFL platform were evaluated. These native-like trimers, derived from HIV subtypes A, B, and C, displayed a range of thermostabilities, and were "stress-tested" at varying temperatures as a prelude to in vivo immunogenicity. Analysis was performed both in the absence and in the presence of two different adjuvants. Since partial trimer degradation was detected at 37°C before or after formulation with adjuvant, we sought to remedy such an undesirable outcome. Cross-linking (fixing) of the well-ordered trimers with glutaraldehyde increased overall thermostability, maintenance of well-ordered trimer integrity without or with adjuvant, and increased resistance to solid phase-associated trimer unfolding. Immunization of unfixed and fixed well-ordered trimers into animals revealed that the elicited tier 2 autologous neutralizing activity correlated with overall trimer thermostability, or melting temperature (Tm). Glutaraldehyde fixation also led to higher tier 2 autologous neutralization titers. These results link retention of trimer quaternary packing with elicitation of tier 2 autologous neutralizing activity, providing important insights for HIV-1 vaccine design.
External linksPLoS Pathog / PubMed:27487086 / PubMed Central
MethodsEM (single particle)
Resolution20.0 Å
Structure data

EMDB-8268:
HIV NFL trimer cross-linked with Glutaraldehyde and in complex with bnAb VRC01
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-8269:
HIV NFL trimer WT in complex with bnAb VRC01
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-8270:
HIV NFL trimer WT
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-8271:
HIV NFL trimer cross-linked with Glutaraldehyde
Method: EM (single particle) / Resolution: 20.0 Å

Source
  • Human immunodeficiency virus 1

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