Identification of novel consensus CD4 T-cell epitopes from clade B HIV-1 whole genome that are frequently recognized by HIV-1 infected patients

Fonseca, Simone Gonçalves; Coutinho-Silva, Adriana; Fonseca, Luiz Augusto Marcondes; Segurado, Aluísio Cotrim; Moraes, Sandra Lúcia de; Rodrigues, H.; Hammer, Juergen; Kallas, Esper G.; Sidney, John; Sette, Alessandro; Kalil, Jorge; Cunha-Neto, Edécio

doi:10.1097/01.aids.0000253353.48331.5f

Cited by 52 publications

(69 citation statements)

References 42 publications

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“…None of these sequences have yet been reported. Only peptides 52-66 and 65-79 overlap the CD4 1 T-cell epitopes identified recently in the clade B consensus sequences [37]. In complete agreement with the binding data, we observed that Vpr 35-49 T-cell response could be restricted to the DRB5 allele, Vpr 48-64 to DRB5, Vpr 52-66 to DR11 and DRB5, Vpr 65-79 to DR11, and Vpr 70-84 to DR3, DR11 and DRB5.…”

Section: Discussionsupporting

confidence: 90%

“…In the Vpr protein (Table 2), multiple peptides exhibited binding activity comparable to that of the reference peptides. Vpr peptides (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79) were retained for further investigations because they bound to at least three molecules and encompassed different peptide regions. Selected Tat and Vpr peptides were then investigated for their capacity to prime in vitro a CD4 1 T-cell response.…”

Section: Multiple Tat and Vpr Peptides Bound To Multiple Hla-dr Molecmentioning

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: 90%

Section: Multiple Tat and Vpr Peptides Bound To Multiple Hla-dr Molecmentioning

confidence: 99%

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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“…Individual peptides inducing IFN-␥ responses in at least one donor were considered candidate T cell epitopes and were analyzed further by ICS assays using PBMCs, TCLs expanded with HHV-6 viral preparations, and TCLs expanded with candidate peptides and also by competition binding to purified HLA-DR1. Similar approaches have been used recently to identify CD4 ϩ T cell epitopes in other large-genome pathogens, including Plasmodium falciparum, Mycobacterium tuberculosis, HIV, and vaccinia virus (11,22,26,54).…”

Section: Resultsmentioning

confidence: 99%

Human CD4⁺T Cell Response to Human Herpesvirus 6

Nastke

Becerra

Yin

et al. 2012

J Virol

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Following primary infection, human herpesvirus 6 (HHV-6) establishes a persistent infection for life. HHV-6 reactivation has been associated with transplant rejection, delayed engraftment, encephalitis, muscular dystrophy, and drug-induced hypersensitivity syndrome. The poor understanding of the targets and outcome of the cellular immune response to HHV-6 makes it difficult to outline the role of HHV-6 in human disease. To fill in this gap, we characterized CD4 T cell responses to HHV-6 using peripheral blood mononuclear cell (PBMC) and T cell lines generated from healthy donors. CD4؉ T cells responding to HHV-6 in peripheral blood were observed at frequencies below 0.1% of total T cells but could be expanded easily in vitro. Analysis of cytokines in supernatants of PBMC and T cell cultures challenged with HHV-6 preparations indicated that gamma interferon (IFN-␥) and interleukin-10 (IL-10) were appropriate markers of the HHV-6 cellular response. Eleven CD4 ؉ T cell epitopes, all but one derived from abundant virion components, were identified. The response was highly cross-reactive between HHV-6A and HHV-6B variants. Seven of the CD4 ؉ T cell epitopes do not share significant homologies with other known human pathogens, including the closely related human viruses human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). Major histocompatibility complex (MHC) tetramers generated with these epitopes were able to detect HHV-6-specific T cell populations. These findings provide a window into the immune response to HHV-6 and provide a basis for tracking HHV-6 cellular immune responses.

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“…This assay requires peptides that are known to bind to certain MHC class II molecules. Peptides identified in the current assay were linked to biological activity: some peptides, previously shown to be functional HIV-specific CD4 ϩ T-cell epitopes (10,15,39), showed good binding to soluble MHC class II molecules employed in the current assay (see Table S1 in the supplemental material), and newly identified MHC class II-binding peptide epitopes resided in "immunogenic regions" of HIV-1B Nef (see Fig. 5) or gp160 and showed the capacity to expand MHC class II-restricted and peptide-specific CD4 ϩ T cells defined by cytokine production.…”

Section: Cd4mentioning

confidence: 99%

Major Histocompatibility Complex Class II Molecule-Human Immunodeficiency Virus Peptide Analysis Using a Microarray Chip

Gaseitsiwe

Valentini

Ahmed

et al. 2009

Clin Vaccine Immunol

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Major histocompatibility complex (MHC) class II alleles, cell surface glycoproteins with a high degree of allelic polymorphism (8), are constitutively expressed on professional antigen-presenting cells. The peptide repertoire presented by MHC class II molecules to CD4 ϩ T cells is edited by intracellular, nonclassical MHC molecules, i.e., HLA-DM and -DO (43). MHC class II alleles exhibit four major pockets (13) to accommodate and present a broad peptide repertoire to CD4 ϩ

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Identification of novel consensus CD4 T-cell epitopes from clade B HIV-1 whole genome that are frequently recognized by HIV-1 infected patients

Cited by 52 publications

References 42 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

Human CD4⁺T Cell Response to Human Herpesvirus 6

Major Histocompatibility Complex Class II Molecule-Human Immunodeficiency Virus Peptide Analysis Using a Microarray Chip

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Identification of novel consensus CD4 T-cell epitopes from clade B HIV-1 whole genome that are frequently recognized by HIV-1 infected patients

Cited by 52 publications

References 42 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

Human CD4+T Cell Response to Human Herpesvirus 6

Major Histocompatibility Complex Class II Molecule-Human Immunodeficiency Virus Peptide Analysis Using a Microarray Chip

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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

Human CD4⁺T Cell Response to Human Herpesvirus 6