Influence of Disulfide-Stabilized Structure on the Specificity of Helper T-Cell and Antibody Responses to HIV Envelope Glycoprotein gp120

Mirano-Bascos, Denise; Steede, N. Kalaya; Robinson, James E.; Landry, Samuel J.

doi:10.1128/jvi.02242-09

Cited by 19 publications

(29 citation statements)

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“…In humans, HLA variation is expected to influence the identity of immunodominant and immunoprevalent antigens in specific individuals. Model systems have identified additional factors controlling epitope choice for CD4 T cells, including naïve T-cell repertoire (5), antigen abundance (6), antigen folding (7), protease processing and epitopeflanking regions (8), and antigenic competition (9).…”

mentioning

confidence: 99%

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Jing

Schiffer

Chong

et al. 2013

J Virol

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Little is known concerning immunodominance within the CD4 T-cell response to viral infections and its persistence into longterm memory. We tested CD4 T-cell reactivity against each viral protein in persons immunized with vaccinia virus (VV), Immunodominance refers to the proportion of T cells specific for a defined epitope in relation to the entire set of T cells reacting to a complex antigen (1). For infectious pathogens encoding many polypeptides, the immunodominance of an open reading frame (ORF) is the proportion of the total pathogen-specific response accounted for by T cells reacting with this ORF. Immunoprevalence is a related concept, referring to the proportion of a population responding to an immunogen (2). The CD8 T-cell response to complex microbes can show remarkably strong immunodominance in humans and inbred animals.As antigen processing differs between T-cell subsets, it is not clear that immunodominance also applies to CD4 T-cell responses. For VV, memory CD4 T-cell responses in inbred mice are quite polyclonal and do not exhibit dominance. The top 14 epitopes account for only 20% of the total VV-specific CD4 T-cell response (3). Data for the human CD4 T-cell response to cytomegalovirus, in contrast, were somewhat consistent with immunodominance. Subjects recognized a median of 12 ORFs per person (of 213 ORFs studied), with the top 6 ORFs accounting for about 40% of the overall response (4). In humans, HLA variation is expected to influence the identity of immunodominant and immunoprevalent antigens in specific individuals. Model systems have identified additional factors controlling epitope choice for CD4 T cells, including naïve T-cell repertoire (5), antigen abundance (6), antigen folding (7), protease processing and epitopeflanking regions (8), and antigenic competition (9).Vaccinia virus is an orthopoxvirus that causes an infection that resolves completely in several weeks in immunocompetent hosts. CD4 T-cell memory persists for decades despite the absence of antigen reexposure, but little is known about the detailed architecture of long-term memory. The monotonic decline of specific antibody levels supports lack of intermittent boosting (10). VV has over 200 ORFs, so each human has a myriad of potential CD4 reactive T-cell specificities. Herpes simplex virus 1 (HSV-1) also has a complex proteome, but in contrast to self-limited VV infections, HSV-1 infections are chronic with intermittent reactivations. Following initial epithelial replication, the virus establishes persistence in the innervating sensory ganglia. Intermittent reactivation of latent HSV-1 in essentially all HSV-1-infected persons (11) results in periodic viral antigen exposure to HSV-1-specific memory T cells (12).To determine the breadth and persistence of CD4 T-cell immunodominance in acute and chronic human viral infections, we compared patterns of CD4 T-cell immunodominance between recent and remote VV recipients. The immune responses of persons chronically infected with HSV-1 were also investigated as an example of a c...

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mentioning

confidence: 99%

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Jing

Schiffer

Chong

et al. 2013

J Virol

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“…These results indicate that disulfide bonds can limit T-cell responses, but it remains unclear whether disulfide bonds influence T-cell responses in individuals that have normal GILT function. Following immunization of BALB/c mice, we noted a distinct absence of T-cell responses from regions of HIV gp120 that are enriched in disulfide bonds, but elimination of individual disulfide bonds caused broad reductions in the T-cell response, rather than local increases (30). We attributed the reductions to proteolytic destruction of the antigen, which reduced the amount of antigen fragments available for presentation.…”

Section: T He Specificity and Phenotype Of Cd4mentioning

confidence: 87%

“…Elimination of the 298-to-331 or 385-to-441 disulfides caused severe defects in folding, assembly, or export of the proteins, whereas elimination of the 378-to-441 disulfide had no consequence for expression or function. We found that elimination of any one of these three disulfides affected the conformation of gp120 and reduced the T-cell responses in BALB/c mice (30). Deletion of the 298-to-331 and 385-to-414 disulfides caused severe and moderate destabilization of gp120, respectively, resulting in globally reduced T-cell responses.…”

Section: T He Specificity and Phenotype Of Cd4mentioning

confidence: 93%

“…The gp120 DNA from HIV1 strain 89.6 was cloned into the pFastBac-1 vector as previously described (22). Expression and preparation of His 6 -tagged gp120 protein and its disulfide variants from HIV-1 strain 89.6 were the same as reported previously (30). The 38 peptides (20-mers overlapping by 10 residues) spanning residues 40 to 109 and 180 to 508 of the HIV 89.6 ENV gp120 sequence were synthesized as the carboxy amidomethyl derivatives and aliquoted onto microtiter plates by JPT Peptide Technologies GmbH.…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4⁺Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

Steede

Nguyen

et al. 2014

J Virol

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Helper T-cell epitope dominance in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is not adequately explained by peptide binding to major histocompatibility complex (MHC) proteins. Antigen processing potentially influences epitope dominance, but few, if any, studies have attempted to reconcile the influences of antigen processing and MHC protein binding for all helper T-cell epitopes of an antigen. Epitopes of gp120 identified in both humans and mice occur on the C-terminal flanks of flexible segments that are likely to be proteolytic cleavage sites. In this study, the influence of gp120 conformation on the dominance pattern in gp120 from HIV strain 89.6 was examined in CBA mice, whose MHC class II protein has one of the most well defined peptide-binding preferences. Only one of six dominant epitopes contained the most conserved element of the I-A k binding motif, an aspartic acid. Destabilization of the gp120 conformation by deletion of single disulfide bonds preferentially enhanced responses to the cryptic I-A k motif-containing sequences, as reported by T-cell proliferation or cytokine secretion. Conversely, inclusion of CpG in the adjuvant with gp120 enhanced responses to the dominant CD4 ؉ T-cell epitopes. The gp120 destabilization affected secretion of some cytokines more than others, suggesting that antigen conformation could modulate T-cell functions through mechanisms of antigen processing. IMPORTANCE CD4؉ helper T cells play an essential role in protection against HIV and other pathogens. Thus, the sites of helper T-cell recognition, the dominant epitopes, are targets for vaccine design; and the corresponding T cells may provide markers for monitoring infection and immunity. However, T-cell epitopes are difficult to identify and predict. It is also unclear whether CD4 ؉ T cells specific for one epitope are more protective than T cells specific for other epitopes. This work shows that the three-dimensional (3D) structure of an HIV protein partially determines which epitopes are dominant, most likely by controlling the breakdown of HIV into peptides. Moreover, some types of signals from CD4 ؉ T cells are affected by the HIV protein 3D structure; and thus the protectiveness of a particular peptide vaccine could be related to its location in the 3D structure.

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“…It has been documented [19] that the Fc fragment does not bind to Ags but acts as initiation of the complement cascade, a process that leads to the lysis of the target cells or mediates phagocytosis [20][21].…”

Section: Discussionmentioning

confidence: 99%

CpG Motif in Phage Genome DNA Enhanced the Efficacy of Phage Therapy by Immunostimulation

Golkar

Jamil²

2012

Cureus

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Influence of Disulfide-Stabilized Structure on the Specificity of Helper T-Cell and Antibody Responses to HIV Envelope Glycoprotein gp120

Cited by 19 publications

References 50 publications

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4⁺Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

CpG Motif in Phage Genome DNA Enhanced the Efficacy of Phage Therapy by Immunostimulation

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Influence of Disulfide-Stabilized Structure on the Specificity of Helper T-Cell and Antibody Responses to HIV Envelope Glycoprotein gp120

Cited by 19 publications

References 50 publications

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

CpG Motif in Phage Genome DNA Enhanced the Efficacy of Phage Therapy by Immunostimulation

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Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4⁺Epitope Immunogenicity in HIV-1 Envelope Glycoprotein