An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes.

TitleAn HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes.
Publication TypeJournal Article
Year of Publication2016
AuthorsChen Y, Wilson R, O'Dell S, Guenaga J, Feng Y, Tran K, Chiang C-I, Arendt HE, DeStefano J, Mascola JR, Wyatt RT, Li Y
JournalJ Immunol
Volume197
Issue10
Pagination3982-3998
Date Published11/15/2016
ISSN1550-6606
Abstract

Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120. To preferentially expose the CD4bs and direct the immune response away from the bridging sheet, resulting in an altered angle of approach, we engineered an immunogen consisting of gp120 core in complex with the prototypic CD4-induced Ab, 17b. This mAb directly contacts the bridging sheet but not the CD4bs. The complex was further stabilized by chemical crosslinking to prevent dissociation. Rabbits immunized with the crosslinked complex displayed earlier affinity maturation, achieving tier 1 virus neutralization compared with animals immunized with gp120 core alone. Immunization with the crosslinked complex induced transient Ab responses with binding specificity similar to the CD4bs-directed bNAbs. mAbs derived from complex-immunized rabbits displayed footprints on gp120 more distal from the bridging sheet as compared with previous vaccine-elicited CD4bs Abs, indicating that Env-Ab complexes effectively dampen immune responses to undesired immunodominant bridging sheet determinants.

DOI10.4049/jimmunol.1601134
Alternate JournalJ. Immunol.
PubMed ID27815444
PubMed Central IDPMC5117957
Grant ListP01 AI104722 / AI / NIAID NIH HHS / United States
P30 AI036214 / AI / NIAID NIH HHS / United States
R01 AI102766 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
1
Cover Picture: