NDLI: Modulation of Nonneutralizing HIV-1 gp41 Responses by an MHC-Restricted TH Epitope Overlapping Those of Membrane Proximal External Region Broadly Neutralizing Antibodies

Content Provider	PubMed Central
Author	Zhang, Jinsong Alam, S. Munir Hilary, Bouton-verville Chen, Yao Newman, Amanda Stewart, Shelley Jaeger, Frederick H. Montefiori, David Dennison, S. Moses Haynes, Barton F. Laurent, Verkoczy
Abstract	A goal of HIV-1 vaccine development is to elicit broadly neutralizing antibodies (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce non-neutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope (Env), we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2d-congenic strains had more rapid, sustained, and elevated MPER+ Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime/boost regimen used, including formulations designed to provide T-cell help. H-2d restricted MPER+ serum Ab responses depended on CD4 TH interactions with Class II (as revealed in immunized intra-H-2d/b congenic or CD154-/- H-2d strains, and by selective abrogation of MPER re-stimulated, H-2d-restricted primed splenocytes by Class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2d restricted MPER+ responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as non-neutralizing B-cell/Ab binding residues. We propose that Class II-restriction contributes to the general heterogeneity of non- neutralizing gp41 responses induced by Env. Moreover, the proximity of TH and B-cell epitopes in this restriction may have to be considered in re-designing minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER+ BnAbs.
Related Links	http://dx.doi.org/10.4049/jimmunol.1302511
Ending Page	1706
Page Count	14
Starting Page	1693
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	4
Volume Number	192
Language	English
Publisher Date	2014-02-15
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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Modulation of Nonneutralizing HIV-1 gp41 Responses by an MHC-Restricted TH Epitope Overlapping Those of Membrane Proximal External Region Broadly Neutralizing Antibodies

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