title: Thermostability of Well-Ordered HIV Spikes Correlates with the Elicitation of Autologous Tier 2 Neutralizing Antibodies.
abstract: 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.
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Yu
authors.identifier: 0000-0003-1564-4098
authors.initials: Y
authors.lastname: Feng
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Tran
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bale
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Kumar
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.
authors.forename: Javier
authors.initials: J
authors.lastname: Guenaga
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: de Val
authors.affiliation: IAVI Design and Development Lab, Department of Research and Development, International AIDS Vaccine Initiative, Brooklyn, New York, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Arendt
authors.affiliation: IAVI Design and Development Lab, Department of Research and Development, International AIDS Vaccine Initiative, Brooklyn, New York, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: DeStefano
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: IAVI Neutralizing Center at TSRI, Department of Research and Development, International AIDS Vaccine Initiative, La Jolla, California, United States of America.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D005976:Glutaral / Q000737:chemistry; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D000071497:Immunogenicity, Vaccine / Q000276:immunology; D055503:Protein Multimerization / Q000276:immunology*; D055550:Protein Stability; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus; D005976:Glutaral