Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity.

TitleMurine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity.
Publication TypeJournal Article
Year of Publication2015
AuthorsHu JK, Crampton JC, Cupo A, Ketas T, van Gils MJ, Sliepen K, de Taeye SW, Sok D, Ozorowski G, Deresa I, Stanfield R, Ward AB, Burton DR, Klasse P J, Sanders RW, Moore JP, Crotty S
JournalJ Virol
Volume89
Issue20
Pagination10383-98
Date Published10/01/2015
ISSN1098-5514
KeywordsAnimals, Antibodies, Neutralizing, Antibody Specificity, Antigens, Viral, B-Lymphocytes, env Gene Products, Human Immunodeficiency Virus, Epitope Mapping, Epitopes, Gene Expression, HEK293 Cells, HIV Antibodies, HIV Infections, HIV-1, Humans, Immunization, Immunoglobulin G, Mice, Models, Molecular, Protein Binding, Protein Engineering, Protein Multimerization, Receptors, Antigen, B-Cell, Recombinant Proteins, Solubility
Abstract

UNLABELLED: Generating neutralizing antibodies (nAbs) is a major goal of many current HIV-1 vaccine efforts. To be of practical value, these nAbs must be both potent and cross-reactive in order to be capable of preventing the transmission of the highly diverse and generally neutralization resistant (Tier-2) HIV-1 strains that are in circulation. The HIV-1 envelope glycoprotein (Env) spike is the only target for nAbs. To explore whether Tier-2 nAbs can be induced by Env proteins, we immunized conventional mice with soluble BG505 SOSIP.664 trimers that mimic the native Env spike. Here, we report that it is extremely difficult for murine B cells to recognize the Env epitopes necessary for inducing Tier-2 nAbs. Thus, while trimer-immunized mice raised Env-binding IgG Abs and had high-quality T follicular helper (Tfh) cell and germinal center (GC) responses, they did not make BG505.T332N nAbs. Epitope mapping studies showed that Ab responses in mice were specific to areas near the base of the soluble trimer. These areas are not well shielded by glycans and likely are occluded on virions, which is consistent with the lack of BG505.T332N nAbs. These data inform immunogen design and suggest that it is useful to obscure nonneutralizing epitopes presented on the base of soluble Env trimers and that the glycan shield of well-formed HIV Env trimers is virtually impenetrable for murine B cell receptors (BCRs).

IMPORTANCE: Human HIV vaccine efficacy trials have not generated meaningful neutralizing antibodies to circulating HIV strains. One possible hindrance has been the lack of immunogens that properly mimic the native conformation of the HIV envelope trimer protein. Here, we tested the first generation of soluble, native-like envelope trimer immunogens in a conventional mouse model. We attempted to generate neutralizing antibodies to neutralization-resistant circulating HIV strains. Various vaccine strategies failed to induce neutralizing antibodies to a neutralization-resistant HIV strain. Further analysis revealed that mouse antibodies targeted areas near the bottom of the soluble envelope trimers. These areas are not easily accessible on the HIV virion due to occlusion by the viral membrane and may have resulted from an absence of glycan shielding. Our results suggest that obscuring the bottom of soluble envelope trimers is a useful strategy to reduce antibody responses to epitopes that are not useful for virus neutralization.

DOI10.1128/JVI.01653-15
Alternate JournalJ. Virol.
PubMed ID26246566
PubMed Central IDPMC4580201
Grant ListUM1-AL100663 / / PHS HHS / United States
CHAVI-ID: 
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