Induction of Broadly Cross-Reactive Cytotoxic T Cells Recognizing an HIV-1 Envelope Determinant

Takahashi, Hidemi; Nakagawa, Yohko; Pendleton, C. David; Houghten, Richard A.; Yokomuro, Kozo; Germain, Ronald N.; Berzofsky, Jay A.

doi:10.1126/science.1372448

Cited by 133 publications

(99 citation statements)

References 25 publications

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“…In this report we compared the structures of a 15-residue peptide from the HIV-1IIIB V3 loop and a glycosylated analogue with N-acetylgalactosamine (NAG) c~-linked to the threonine four residues to the C-terminal side of the so-called immunodominant tip [18,19] (sequence -GPGR-) of the loop. As this peptide is also an immunodominant epitope for CTL recognition [20][21][22][23], we have also tested these peptides for their ability to be recognized by class I-MHC molecule-restricted CTL as measured by lysis of a tumor cell line incubated with the peptides.…”

Section: Introductionmentioning

confidence: 99%

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue

et al. 1996

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As part of a program to study the effect of glycosylation on the three-dimensional structures of HIV-ImB V3 peptide constructs, we have examined the solution structures of a 15 residue peptide (RIQRGPGRAFVTIGK, P18ms), originally mapped as an epitope recognized by CD8 + D u class I MHC-restricted murine cytotoxic T-lymphocytes (CTL), and an analogue (P18mB-g), O-glycosylated with an t~-galactosamine on Thr-12, using NMR, circular dichroism and molecular modeling methods. Our studies show that the peptides sample mainly random conformations in aqueous solution near 25°C and become more ordered by the addition of trifluoroethanol. Upon decreasing the temperature to 5°C, a reverse turn is formed around the immunodominant tip (GS-RS). Glycosylation on T Iz 'tightens' the turn slightly as suggested by NOE and CD analysis. In addition, the sugar has a defined conformation with respect to the peptide backbone and influences the local peptide conformation. These data suggest that simple glycosylation may influence the conformational equilibrium of a V3 peptide which contains a domain critical for antibody recognition and virus neutralization. We also show that the ability of cytotoxic Tlymphocytes (CTL) to lyse tumor cells presenting P18ttm was completely abrogated by threonine glycosylation.

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Section: Introductionmentioning

confidence: 99%

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue

et al. 1996

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“…sequence of the HXB2 gp120 protein [28]. We first explored the potential adjuvant effects of PEI-DNA complexes delivered by the intramuscular route.…”

Section: Pei Polymers Enhance Immunogenicity Of Dna and Increase Antimentioning

confidence: 99%

“…We performed these studies using plasmid DNA encoding the HIV-1 gp120 protein as the immunogen. In BALB/c mice, CD8 + T cells recognize the immunodominant 10-amino acid p18sequence of the HXB2 gp120 protein [28]. We first explored the potential adjuvant effects of PEI-DNA complexes delivered by the intramuscular route.…”

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confidence: 99%

Enhancement of plasmid DNA immunogenicity with linear polyethylenimine

et al. 2012

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The utility of plasmid DNA as an immunogen has been limited by its weak immunogenicity. In the present study, we evaluated the ability of a family of linear polyethylenimine (PEI) polymers, complexed to plasmid DNA, to augment DNA expression in vivo and to enhance antigen-specific adaptive immune responses. We showed that four of five structurally different PEIs that we evaluated increased in vivo DNA expression 20-to 400-fold, and enhanced DNA-induced epitope-specific CD8 IntroductionDNA vaccine constructs have been evaluated and are being tested in a number of human clinical trials for generating immunity to many types of diseases, including infectious, cancer, allergic, and autoimmune diseases [1,2]. In addition, the use of DNA vaccinesCorrespondence: Dr. Evita V. Grant e-mail: evita.grant@gmail.com has proven effective in some current veterinary products such as a vaccine against infectious hematopoietic necrosis virus for salmon [3], melanoma immunotherapeutic vaccine for dogs [4] and a vaccine against the West Nile Virus for horses [5]. Unfortunately, the immunogenicity of plasmid DNA in humans has proven to be modest in comparison with the immunogenicity observed in other species of microbial expression vectors. Consequently, efforts are being made to increase the immunogenicity of DNA vaccine constructs. Strategies have been developed to increase plasmid DNA expression via codon modification [6], the use of enhanced promoters [7] and the use of microbial transcriptional C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2938 Evita V. Grant et al. Eur. J. Immunol. 2012. 42: 2937-2948 control elements [8]. Since plasmid DNA has poor in vivo transfection efficiency, a number of formulations of plasmid DNA have been evaluated to protect DNA from degradation and to enhance transfection efficiency [9][10][11]. The "gene gun" technology [12] was developed to enhance DNA delivery and immunogenicity. Furthermore, immunomodulation strategies have been evaluated for their ability to enhance DNA immunogenicity [13][14][15]. The synthetic polycationic polymer polyethylenimine (PEI), consisting of chains of ethylenimine units-CH 2 CH 2 NH-, has become the gold standard for enhancing the in vivo expression of administered genes [16,17]. PEI is superior to other nonmicrobial transfection agents because of its ability to protect DNA from degradation [18], to escape intracellular endosomal lysis [19] and to efficiently deliver DNA into the nucleus of cells [20]. Formulation with PEI polymers has been employed in DNA-and siRNAbased immunotherapy against cancer [21,22] and in vaccination studies targeting different infectious agents [10,23,24].In the present study, we have evaluated the physicochemical characteristics of a series of PEI polymers and have assessed associations between particular characteristics of these polymers and their ability to facilitate in vivo DNA expression and enhanced adaptive immune responses. Moreover, we have examined plasmid DNA constructs formulated with these various PEI...

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“…Groups of naive recipient mice (n ϭ 4/group) received 500 l of purified IgG by tail vein injection before immunization with 10 8 vp of rAd5-Env. Env-specific CD8 ϩ T lymphocyte responses against the dominant P18 epitope (RGPGRAFVTI) (26) were assessed by D d /P18 tetramer binding assays (27,28). As shown in Fig.…”

Section: Suppressive Effects Of Low Titers Of Ad-specific Nabsmentioning

confidence: 99%

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Sumida

Truitt

Lemckert

et al. 2005

The Journal of Immunology

320

276

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The utility of recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 and other pathogens will likely be limited by the high prevalence of pre-existing Ad5-specific neutralizing Abs (NAbs) in human populations. However, the immunodominant targets of Ad5-specific NAbs in humans remain poorly characterized. In this study, we assess the titers and primary determinants of Ad5-specific NAbs in individuals from both the United States and the developing world. Importantly, median Ad5-specific NAb titers were >10-fold higher in sub-Saharan Africa compared with the United States. Moreover, hexon-specific NAb titers were 4- to 10-fold higher than fiber-specific NAb titers in these cohorts by virus neutralization assays using capsid chimeric viruses. We next performed adoptive transfer studies in mice to evaluate the functional capacity of hexon- and fiber-specific NAbs to suppress the immunogenicity of a prototype rAd5-Env vaccine. Hexon-specific NAbs were remarkably efficient at suppressing Env-specific immune responses elicited by the rAd5 vaccine. In contrast, fiber-specific NAbs exerted only minimal suppressive effects on rAd5 vaccine immunogenicity. These data demonstrate that functionally significant Ad5-specific NAbs are directed primarily against the Ad5 hexon protein in both humans and mice. These studies suggest a potential strategy for engineering novel Ad5 vectors to evade dominant Ad5-specific NAbs.

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Induction of Broadly Cross-Reactive Cytotoxic T Cells Recognizing an HIV-1 Envelope Determinant

Cited by 133 publications

References 25 publications

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue

Enhancement of plasmid DNA immunogenicity with linear polyethylenimine

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

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Induction of Broadly Cross-Reactive Cytotoxic T Cells Recognizing an HIV-1 Envelope Determinant

Cited by 133 publications

References 25 publications

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1IIIb and an O‐glycosylated analogue

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1IIIb and an O‐glycosylated analogue

Enhancement of plasmid DNA immunogenicity with linear polyethylenimine

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Contact Info

Product

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Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue

Structural comparison of a 15 residue peptide from the V3 loop of HIV‐1_IIIb and an O‐glycosylated analogue