Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Wilson, Cara C.; Palmer, Brent E.; Southwood, Scott; Sidney, John; Higashimoto, Yuichiro; Appella, Ettore; Chesnut, Robert W.; Sette, Alessandro; Livingston, Brian

doi:10.1128/jvi.75.9.4195-4207.2001

Cited by 101 publications

(103 citation statements)

References 51 publications

(39 reference statements)

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“…Our approach is based on the combination of assays of binding to preponderant HLA-DR molecules and of primary stimulation assays using CD4 1 T lymphocytes collected in seronegative donors. The use of binding assays to select promiscuous binders is consistent with many studies supporting the role of good affinity in the T-cell-stimulating properties of peptides [20,28,29]. In vitro priming experiments appear suitable to evaluate peptide immunogenicity because it reproduces in vitro the T-cell repertoire conditions encountered in vivo upon injection of prophylactic vaccines.…”

Section: Discussionsupporting

confidence: 71%

“…It is not known whether immune response specific for accessory or regulatory HIV proteins leads to immune escape, which has a fitness cost on the virus. Moreover, despite the requirement of CD4 1 T lymphocytes to sustain both humoral and cellular responses, the CD4 1 T-cell response specific for Tat and Vpr is poorly documented in humans [3,19], in contrast to other HIV proteins [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

“…Because of the polymorphism of HLA II molecules, immunoprevalence of the T-cell epitopes is expected to rely on their capacity to bind to HLA II molecules. Peptides that are promiscuous for multiple HLA-DR molecules [20,28,29] or that bind to preponderant HLA II molecules as HLA-DP4 [30] generally exhibit a high immunoprevalence. Inter-individual variations in the T-cell response also result from the disparity of the Tcr repertoire [29,30].…”

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confidence: 99%

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Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

et al. 2008

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Recent studies have suggested including nonstructural proteins as Tat and Vpr in HIV vaccines. However, little is known about the CD4 1 T-cell response that these small proteins induce in humans. We have therefore evaluated these responses by in vitro priming experiments of CD4 1 T lymphocytes harvested in healthy donors. In the Tat protein, only one peptide primed CD4 1 T cells of eight HLA unrelated healthy donors. T cells induced by this peptide recognized immature DC loaded with the native Tat protein and are restricted by multiple HLA-DR molecules, in agreement with its binding capacity. This peptide was therefore processed in an appropriate manner and was highly immunoprevalent. CD4 1 T-cell response to Vpr peptides was more disperse and involved six different peptides depending on the HLA-DR molecules of the donors. Two overlapping peptides were T-cell stimulating in at least half of the donors. T-cell response to Vpr in multiple donors is the result of a combination of several CD4 1 T-cell epitopes with good to moderate immunoprevalence. Altogether, our results show that the frequency of responders to HIV Tat or Vpr proteins relies on one or multiple CD4 1 T-cell epitopes, respectively.Key words: CD4 1 T cells . Epitopes . HIV . HLA class II . MHC IntroductionTwenty years after the discovery of HIV, an effective prophylactic or therapeutic vaccine is still not available. Current approaches are mainly based on the introduction of structural antigens into viral vectors, their combination with strong adjuvants or their injection as DNA vaccine [1]. Alternative or complementary approaches aim at neutralizing accessory or regulatory proteins because they disturb the immune system and counteract its beneficial role [2,3]. Transacting protein (Tat) is a small regulatory protein that is expressed early in the viral cycle and is essential for viral replication [4]. Besides its transactivating activity, Tat exerts a wide range of activities. It diminishes T-cell function and provokes immunosuppression [5]. It enhances DC maturation [6] and exhibits an adjuvant activity [7]. Tat also regulates apoptosis of infected and noninfected cells by a variety of possible mechanisms including downregulation of Bcl-2 and upregulation of . In contrast to Tat, the Virus protein R (Vpr) accessory protein is expressed late in the virus cycle and is also essential for in vivo viral replication [9]. Vpr impairs DC maturation and T-cell activation [10]. Both Vpr and Tat proteins could be targeted by CD8 1 T-cells in seropositive donors [11][12][13][14][15] and hence constitute potential candidates to elicit an HIV-specific cellular response. Multiple forms of Tat peptides elicit neutralizing antibodies in monkeys and lead to promising but controversial results in terms of protection [16][17][18]. It is not known whether immune response specific for accessory or regulatory HIV proteins leads to immune escape, which has a fitness cost on the virus. Moreover, despite the requirement of CD4 1 T lymphocytes to sustain both humoral and cel...

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

et al. 2008

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“…The IC 50 value represents the amount of peptide required for 50% inhibition of binding of a fluorescein-labeled reference peptide. An IC 50 value of 1000 nM has previously been shown to represent the affinity threshold associated with immunogenicity (38,42). Moreover, 8 of the 10 polymerase peptides bound at least four of these frequent DR molecules.…”

Section: Selection Of Highly Cross-reactive Hla-dr Binding Peptidesmentioning

confidence: 99%

“…Ten HBV polymerase peptides that contained either the HLA-DR supermotif (36) (peptides 5, 7, 9 -11, and 13) or the DR3 motif (37) (peptides 4,6,8, and 12) were tested for binding to a panel of HLA DR B1, B3, B4, and B5 alleles (38). These HLA-DR molecules were selected as representative of the most common HLA variants expressed in the majority of the world's ethnic population (38).…”

Section: Selection Of Highly Cross-reactive Hla-dr Binding Peptidesmentioning

confidence: 99%

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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CD4+ T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8+ T cell and B cell responses. We have identified and characterized 10 CD4+ T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-γ ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-γ responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-γ production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p = 0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.

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The Th1 immune response against HIV‐1 Gag p24‐derived peptides in mice expressing HLA‐A02.01 and HLA‐DR1

et al. 2007

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Using HLA‐DR1‐transgenic H‐2 class II knockout mice, we identified two new HLA‐DR1‐restricted HIV‐1 Gag p24‐derived epitopes (Gag321–340 and Gag331–350) and confirmed the immunogenicity of seven that have been previously described. The human relevance was confirmed for the two new ones (Gag321–340 and Gag331–350) assaying peripheral blood mononuclear cells from HLA‐DR1+ HIV‐1‐infected long‐term asymptomatic subjects and showing that Gag331–350 could prime CD4+ T cells from two HLA‐DR1+ HIV‐1 seronegative donors in vitro. Seven of these epitopes, structurally conserved among HIV‐1 clade B isolates, were selected for a comparative evaluation of their Th1 helper potential by immunizing HLA‐A02.01/HLA‐DR1‐transgenic, H‐2 class I/class II knockout mice with recombinant mouse invariant chain constructs in which each helper epitope was inserted in association with two reporter HIV‐1‐derived HLA‐A02.01‐restricted CD8+ T cell epitopes. A T helper effect was demonstrated in all cases, and was particularly strong with epitopes Gag301–320, Gag321–340 and Gag271–290, which should, therefore, be considered in the design of new vaccines.

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Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Abstract: Human immunodeficiency virus (HIV)-specific helper T lymphocytes (HTL) play a key role in the immune

Cited by 101 publications

References 51 publications

Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

Cellular Immune Responses to the Hepatitis B Virus Polymerase

The Th1 immune response against HIV‐1 Gag p24‐derived peptides in mice expressing HLA‐A02.01 and HLA‐DR1

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Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Abstract: Human immunodeficiency virus (HIV)-specific helper T lymphocytes (HTL) play a key role in the immune

Cited by 101 publications

References 51 publications

Immunoprevalence of the CD4+ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

Immunoprevalence of the CD4+ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

Cellular Immune Responses to the Hepatitis B Virus Polymerase

The Th1 immune response against HIV‐1 Gag p24‐derived peptides in mice expressing HLA‐A02.01 and HLA‐DR1

Contact Info

Product

Resources

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Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively