Cross-Subtype T-Cell Immune Responses Induced by a Human Immunodeficiency Virus Type 1 Group M Consensus Env Immunogen

Weaver, Eric A.; Lu, Zuneng; Camacho, Zenaido T.; Moukdar, Fatiha; Liao, Hua Xin; Jiang, Ben; Muldoon, Mark; Theiler, James; Nabel, Gary J.; Letvin, Norman L.; Korber, Bette T.; Hahn, Beatrice H.; Haynes, Barton F.; Gao, Feng

doi:10.1128/jvi.02484-05

Cited by 66 publications

(69 citation statements)

References 35 publications

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“…Helper T-cell epitopes in gp120 have been mapped to exposed [27], but relatively conserved [34] regions of the protein. Epitopes in the outer domain were found to be an average of eight residues C-terminal to flexible regions of the protein [25].…”

Section: Discussionmentioning

confidence: 99%

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

2008

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The development of an effective vaccine against HIV/AIDS has been hampered, in part, by a poor understanding of the rules governing helper T-cell epitope immunodominance. Studies in mice have shown that antigen structure modulates epitope immunodominance by affecting the processing and subsequent presentation of helper T-cell epitopes. Previous epitope mapping studies showed that the immunodominant helper T-cell epitopes in mice immunized with gp120 were found flanking flexible loops of the protein. In this report, we show that helper T-cell epitopes against gp120 in humans infected with HIV are also found flanking flexible loops. Immunodominant epitopes were found to be located primarily in the outer domain, an average of 12 residues C-terminal to flexible loops. In the less immunogenic inner domain, epitopes were found an average of five residues N-terminal to conserved regions of the protein, once again placing the epitopes C-terminal to flexible loops. These results show that antigen structure plays a significant role in the shaping of the helper T-cell response against HIV gp120 in humans. This relationship between antigen structure and helper T-cell epitope immunodominance may prove to be useful in the development of rationally designed vaccines against pathogens such as HIV.Key words: Antigen processing Á Helper T lymphocyte Á HIV envelope protein gp120 Á MHC class II Á Protein structure IntroductionOver the past 25 years, great strides have been made in the area of HIV/AIDS research. Much is now known about the biology and pathogenesis of the virus. In spite of this, HIV/AIDS continues to be a major health problem worldwide. In 2006, there were approximately 4.3 million new HIV cases, 400 000 more cases than in 2004, bringing the global total of people living with HIV to 39.5 million [1]. This number reflects the increase of HIV cases in every region of the world, suggesting that the epidemic is far from declining. In order to reverse this trend, an effective vaccine against HIV must be developed.Studies in humans and non-human primates have shown that the CD8 + cytotoxic T lymphocyte (CTL) response is essential to the control of viremia [2][3][4][5][6]. Neutralizing antibody has also been shown to aid in the maintenance of low viral loads, presumably through the prevention of viral transmission from cell to cell [7][8][9]. CD4 + helper T cells are required for the induction and maintenance of both of these effector mechanisms [10][11][12][13][14][15][16][17][18]. Therefore, the ideal vaccine against HIV must be able to activate these three arms of the immune response in order to confer protection against infection and disease progression. Helper T-cell activation begins when an immature CD4 + T cell encounters an antigen-presenting cell (APC) displaying a peptide bound to an MHC class II molecule (pMHCII). This contact between the CD4 + T cell and the pMHCII complex initiates a signaling cascade that leads to the maturation of the helper T cell. Although every sequence within a protein antigen can poten...

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Section: Discussionmentioning

confidence: 99%

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

2008

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“…Our lab and others have previously published work on consensus DNA immunogens [16][17][18][19]. These constructs have been shown to not only induce strong CD8+ and CD4+ T cell responses, but that these responses are in fact more cross-reactive than their individual component constructs.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Laddy

Yan

Corbitt

et al. 2007

Vaccine

107

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The frequency of H5N1 avian influenza outbreaks in China and Eastern Europe has raised concern in the world health community regarding the potential for an influenza pandemic. Efforts to monitor the disease will only provide minimal warning in a global society, and steps must be taken to prevent the morbidity and mortality associated with past pandemics. The current stockpiling of antibody-inducing "bird flu" vaccines assumes the strain that emerges will be the same as strains currently circulating. We propose a novel consensus-based approach to vaccine development, employing a DNA vaccine strategy that can provide more highly cross-reactive cellular immunity against lethal influenza infection. We show such constructs can induce strong cellular immunity against H5 influenza antigens.

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“…However, future studies are needed to test the ability of this A20 inhibition approach, together with use of the conservative, but subdominant protective HIV epitopes or antigens (57)(58)(59)(60)(61)(62)(63), in a prophylactic or therapeutic vaccination setting to induce immune responses and protection in animal models of SIV/HIV infections. (44) and then immunized twice with gp120-pulsed (100 μg/ml), Ad-transfected DCs matured with LPS at a weekly interval, followed by in vivo stimulation with poly(I:C) (i.p., 50 μg/mouse) daily for 3 consecutive days.…”

Section: Figurementioning

confidence: 99%

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Hong

Song²,

Rollins³

et al. 2011

J. Clin. Invest.

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Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20 -an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs -restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

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Cross-Subtype T-Cell Immune Responses Induced by a Human Immunodeficiency Virus Type 1 Group M Consensus Env Immunogen

Abstract: The genetic diversity among globally circulating human immunodeficiency virus type 1 (HIV-1) strains is a serious challenge for HIV-1 vaccine design. We have generated a synthetic group M consensus env gene (

Cited by 66 publications

References 35 publications

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

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