Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Ferrari, Guido; Neal, Wesley A.; Ottinger, Janet; Jones, A.; Edwards, Bradley H.; Goepfert, Paul; Betts, Michael R.; Koup, Richard A.; Buchbinder, Susan; McElrath, M. Juliana; Tartaglia, Jim; Weinhold, Kent J.

doi:10.4049/jimmunol.173.3.2126

Cited by 24 publications

(21 citation statements)

References 66 publications

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“…A different pattern of changing epitopic usage over time is illustrated by responses to the immunodominant HLA-A2-restricted Gag 77-85 ( 77 SLYNTV ATL 85 [SL9]) epitope in p17 Gag. SL9 is recognized by the majority of chronically infected individuals but not by most acutely infected individuals (4,10,16,18,21,24,37). This temporal relationship for CTL recognition of virus proteins/ epitopes is also supported by observations that the HIV-1-Nef protein is recognized before other proteins (2,5,9,28) and, in mouse models, by constantly evolving CTL immunodominance (7,(42)(43)(44).…”

supporting

confidence: 52%

Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

Karlsson

Chapman

Heiken

et al. 2007

J Virol

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supporting

confidence: 52%

Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

Karlsson

Chapman

Heiken

et al. 2007

J Virol

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“…In particular, the HLA-A2-restricted CD8 ϩ T-cell epitope SLYNTVATL in HIV-1 p17 Gag is rarely targeted in acute HIV-1 infection but is the immunodominant HLA-A2-restricted CD8 ϩ T-cell epitope in chronic HIV-1 infection in persons expressing HLA-A2 (13). Similarly, this epitope is not targeted in Gag CTL-positive, HIV-1-uninfected vaccine recipients expressing the HLA-A2 allele (10).…”

Section: Resultsmentioning

confidence: 99%

“…The most frequently targeted HLA-A2-restricted CD8 ϩ Tcell epitopes in chronic infection were the p17 Gag epitope SLYNTVATL (p17 77-85 ), the p1 Gag epitope FLGKIWPSYK (p1 [1][2][3][4][5][6][7][8][9][10], and the RT epitope ILKEPVHGV (RT 309-317 ), which were targeted in 62, 54, and 45% of the chronically infected individuals expressing HLA-A2, respectively. These three epitopes were significantly less frequently recognized in individuals identified during primary infection (SLYNTVATL, 1 of 14 [P Ͻ 0.001]; ILKEPVHGV, 1 of 14 [P Ͻ 0.01]; FLG KIWPSYK, 0 of 14 [P Ͻ 0.001]) (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design

Altfeld

Allen

Kalife

et al. 2005

J Virol

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Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr 59-67 ) that is targeted by acute-phase HIV-1-specific CD8 ؉ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I 60 L variant all developed these responses. The I 60 L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic Tlymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.The human immunodeficiency virus type 1 (HIV-1) epidemic is characterized by a high genetic diversity within the viral population that results from high replication and mutation rates in the presence of immunological selection pressure (29). Viral strains from the same HIV-1 clade can differ by 25% at the amino acid level, depending on the particular HIV-1 protein under consideration (29). This substantial sequence diversity poses a major challenge to the design of vaccines capable of inducing cross-reactive CD8 ϩ T-cell responses. As a consequence, the use of clade-specific consensus sequences has been recently proposed for vaccine design (12). Clade consensus sequences have the advantage of being most similar to currently circulating strains of interest, with each amino acid corresponding to the most commonly found amino acid at that position within the overall viral population.A number of studies have demonstrated that HIV-1 can rapidly escape from CD8 ϩ T-cell-mediated immune pressure by sequence variation within or flanking targeted epitopes (1,6,11,14,15,18,20,(23)(24)(25). The accumulation of escape variants within epitopes presented by the HLA class I alleles expressed in an infected individual can result in "HLA footprints" on the viral sequence (21,22,30). Recent data demonstrate that these cytotoxic T-lymphocyte (CTL) escape variants can be transmitted and impair the generation of otherwise immunodominant immune responses during primary infection in a new host (1,14,20). The rate at which these sequence mutations within epitopes may accumulate in the viral population largely depends on ...

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“…CD107a and CD107b are lysosomal-associated membrane glycoproteins that surround the core of the lytic granules in cytotoxic T cells (40,46). Upon TCR engagement and stimulation by Ags in association with MHC molecules, CD107a/b are exposed on the cell membrane of cytotoxic T cells.…”

Section: Gd Epitope-primed Cd8mentioning

confidence: 99%

HLA-A*0201-Restricted CD8+ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D

Chentoufi

Zhang

Lamberth³

et al. 2008

The Journal of Immunology

140

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Evidence obtained from both animal models and humans suggests that T cells specific for HSV-1 and HSV-2 glycoprotein D (gD) contribute to protective immunity against herpes infection. However, knowledge of gD-specific human T cell responses is limited to CD4+ T cell epitopes, with no CD8+ T cell epitopes identified to date. In this study, we screened the HSV-1 gD amino acid sequence for HLA-A*0201-restricted epitopes using several predictive computational algorithms and identified 10 high probability CD8+ T cell epitopes. Synthetic peptides corresponding to four of these epitopes, each nine to 10 amino acids in length, exhibited high-affinity binding in vitro to purified human HLA-A*0201 molecules. Three of these four peptide epitopes, gD53–61, gD70–78, and gD278–286, significantly stabilized HLA-A*0201 molecules on T2 cell lines and are highly conserved among and between HSV-1 and HSV-2 strains. Consistent with this, in 33 sequentially studied HLA-A*0201-positive, HSV-1-seropositive, and/or HSV-2-seropositive healthy individuals, the most frequent and robust CD8+ T cell responses, assessed by IFN-γ ELISPOT, CD107a/b cytotoxic degranulation, and tetramer assays, were directed mainly against gD53–61, gD70–78, and gD278–286 epitopes. In addition, CD8+ T cell lines generated by gD53–61, gD70–78, and gD278–286 peptides recognized infected target cells expressing native gD. Lastly, CD8+ T cell responses specific to gD53–61, gD70–78, and gD278–286 epitopes were induced in HLA-A*0201 transgenic mice following ocular or genital infection with either HSV-1 or HSV-2. The functional gD CD8+ T cell epitopes described herein are potentially important components of clinical immunotherapeutic and immunoprophylactic herpes vaccines.

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Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Cited by 24 publications

References 66 publications

Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design

HLA-A*0201-Restricted CD8+ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D

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