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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.

ABSTRACT: A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, 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-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-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-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3936991 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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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.

Zhang Jinsong J Alam S Munir SM Bouton-Verville Hilary H Chen Yao Y Newman Amanda A Stewart Shelley S Jaeger Frederick H FH Montefiori David C DC Dennison S Moses SM Haynes Barton F BF Verkoczy Laurent L

Journal of immunology (Baltimore, Md. : 1950) 20140124 4

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, 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. Imm ...[more]

PMID: 24465011

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Project description:IntroductionThe present work sought to identify MHC-I-restricted peptide signatures for arbovirus using in silico and in vitro peptide microarray tools.MethodsFirst, an in-silico analysis of immunogenic epitopes restricted to four of the most prevalent human MHC class-I was performed by identification of MHC affinity score. For that, more than 10,000 peptide sequences from 5 Arbovirus and 8 different viral serotypes, namely Zika (ZIKV), Dengue (DENV serotypes 1-4), Chikungunya (CHIKV), Mayaro (MAYV) and Oropouche (OROV) viruses, in addition to YFV were analyzed. Haplotype HLA-A*02.01 was the dominant human MHC for all arboviruses. Over one thousand HLA-A2 immunogenic peptides were employed to build a comprehensive identity matrix. Intending to assess HLAA*02:01 reactivity of peptides in vitro, a peptide microarray was designed and generated using a dimeric protein containing HLA-A*02:01.ResultsThe comprehensive identity matrix allowed the identification of only three overlapping peptides between two or more flavivirus sequences, suggesting poor overlapping of virus-specific immunogenic peptides amongst arborviruses. Global analysis of the fluorescence intensity for peptide-HLA-A*02:01 binding indicated a dose-dependent effect in the array. Considering all assessed arboviruses, the number of DENV-derived peptides with HLA-A*02:01 reactivity was the highest. Furthermore, a lower number of YFV-17DD overlapping peptides presented reactivity when compared to non-overlapping peptides. In addition, the assessment of HLA-A*02:01-reactive peptides across virus polyproteins highlighted non-structural proteins as "hot-spots". Data analysis supported these findings showing the presence of major hydrophobic sites in the final segment of non-structural protein 1 throughout 2a (Ns2a) and in nonstructural proteins 2b (Ns2b), 4a (Ns4a) and 4b (Ns4b).DiscussionTo our knowledge, these results provide the most comprehensive and detailed snapshot of the immunodominant peptide signature for arbovirus with MHC-class I restriction, which may bring insight into the design of future virus-specific vaccines to arboviruses and for vaccination protocols in highly endemic areas.

Project description:Glycoprotein Env of human immunodeficiency virus type 1 (HIV-1) mediates viral entry through membrane fusion. Composed of gp120 and gp41 subunits arranged as a trimer-of-heterodimers, Env adopts a metastable, highly dynamic conformation on the virion surface. This structural plasticity limits the temporospatial exposure of many highly conserved, neutralizing epitopes, contributing to the difficulty in developing effective HIV-1 vaccines. Here, we employed antibody neutralization of HIV-1 infectivity to investigate how inter- and intra-gp120 interactions mediated by variable loops V1/V2 and V3 at the Env apex regulate accessibility of the gp41 membrane-proximal external region (MPER) at the Env base. Swapping the V3 loop from EnvSF162 into the EnvHXB2 background shifted MPER exposure from the prefusogenic state to a functional intermediate conformation that was distinct from the prehairpin-intermediate state sensitive to gp41-targeted fusion inhibitors. The V3-loop swap had a profound impact on global protein dynamics, biasing the equilibrium to a closed conformation resistant to most anti-gp120 antibodies, stabilizing the protein to both cold- and soluble CD4-induced Env inactivation, and increasing the CD4 requirements for viral entry. Further dissection of the EnvHXB2 V3 loop revealed that residue 306 uniquely modulated epitope exposure and trimer stability. The R306S substitution substantially decreased sensitivity to antibodies targeting the gp41 MPER and, surprisingly, the gp120 V3-loop crown (residues 312-315), but had only modest effects on exposure of intervening gp120 epitopes. Furthermore, the point mutation reduced soluble CD4-induced inactivation, but had no impact on cold inactivation. The residue appeared to exert its effects by electrostatically modifying the strength of intra-subunit interactions between the V1/V2 and V3 loops. The distinct patterns of neutralization and stability pointed to a novel prefusogenic Env conformation along the receptor activation pathway and suggested that apical Env-regulation of gp41 MPER exposure can be decoupled from much of the dynamics of gp120 subunits.

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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.

Publications

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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