Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design

Novitsky, Vladimir; Rybak, Natasha; McLane, Mary Fran; Gilbert, Peter B.; Chigwedere, Pride; Klein, I.; Gaolekwe, Sarah; Chang, Sui‐Yuan; Peter, Trevor; Thior, Ibou; Ndung’u, Thumbi; Vannberg, Fredrik; Foley, Brian; Marlink, Richard; Lee, T. H.; Essex, Max

doi:10.1128/jvi.75.19.9210-9228.2001

Cited by 99 publications

(87 citation statements)

References 111 publications

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“…During natural infection, Tat also induces antigen-specific CD4+ [85,147,155] and CD8+ T cell responses [145,150,[156][157][158]. CTL responses to Tat are more frequent in patients controlling viremia [145,159] and correlate with early virus containment both in humans [156,160] and in monkeys [161,162].…”

Section: The Choice Of Tat As Vaccine Relevant Antigenmentioning

confidence: 99%

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Caputo

Gavioli

Bellino

et al. 2009

International Reviews of Immunology

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Section: The Choice Of Tat As Vaccine Relevant Antigenmentioning

confidence: 99%

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Caputo

Gavioli

Bellino

et al. 2009

International Reviews of Immunology

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“…Recombinant VV (rVV) carrying the LCMV glycoprotein (VV-G2) was obtained from Dr. D. Bishop (Institute of Virology, Oxford, U.K.) and rVV carrying the LCMV nucleoprotein (VV-YN4) was obtained from Dr. B. Moss (National Institutes of Health, Bethesda, MD). rVV expressing LCMV-derived gp [33][34][35][36][37][38][39][40][41] or NP 396 -404 as a minigene were described previously (12). For infection, mice were injected i.p.…”

Section: Virus Infection Of Mice and Measurement Of Virus Titersmentioning

confidence: 99%

Absence of CTL Responses to Early Viral Antigens Facilitates Viral Persistence

Schildknecht

Welti

Geuking

et al. 2008

The Journal of Immunology

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CD8+ T cells are crucial for the control of intracellular pathogens such as viruses and some bacteria. Using lymphocytic choriomeningitis virus (LCMV) infection of mice—the prototypic arenavirus evolutionarily closely related to human Lassa fever and South American hemorrhagic fever viruses, we have shown previously that the kinetics of Ag presentation determine immunodominance of the LCMV-specific CTL response due to progressive exhaustion of LCMV nucleoprotein (NP)-specific CTL upon increasing viral load. In this study, we provide evidence that CTL against early LCMV NP-derived epitopes are more important in virus control than those against late glycoprotein-derived epitopes. We show that mice that are tolerant to all NP-derived T cell epitopes are severely compromised in their ability to control larger inocula of LCMV, supporting our hypothesis that CD8+ T cells specific for early viral Ags play a major role in acute virus control. Thus, the kinetics with which virus-derived T cell epitopes are presented has a strong impact on the efficacy of the antiviral immunity. This aspect should be taken into consideration for the development of vaccines.

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“…Interestingly, Tat 41-55 overlaps the 31-50 [11] and 39-55 regions [12] and is close to the 30-37 sequence [15]. These regions are targeted by CD8 1 T-cells in multiple donors [11,12,15]. We therefore suggested that the long fragment 30-55 could elicit both CD4 1 and CD8 1 responses and hence constitute a potential candidate for epitope-based vaccine.…”

Section: Discussionmentioning

confidence: 90%

“…In one study, approximately one third of seropositive patients exhibited a Tat-specific CD4 + T-cell response, but the fine specificity of this response was not investigated [34]. Interestingly, Tat 41-55 overlaps the 31-50 [11] and 39-55 regions [12] and is close to the 30-37 sequence [15]. These regions are targeted by CD8 1 T-cells in multiple donors [11,12,15].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

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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Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design

Cited by 99 publications

References 111 publications

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Absence of CTL Responses to Early Viral Antigens Facilitates Viral Persistence

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

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Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design

Cited by 99 publications

References 111 publications

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Absence of CTL Responses to Early Viral Antigens Facilitates Viral Persistence

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

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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