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Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.

ABSTRACT: The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis and literature precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 open reading frame 2 induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human LINE-1 open reading frame 2 (96% identity with macaque), as well as simian endogenous retrovirus-K Gag and Env, induced polyfunctional T cell responses to all Ags, and Ab responses to simian endogenous retrovirus-K Env. There were no adverse safety or pathological findings related to vaccination. These studies provide the first evidence, to our knowledge, that immune responses can be induced safely against this class of self-antigens and pave the way for investigation of them as HIV- or tumor-associated targets.

SUBMITTER: Sacha JB

PROVIDER: S-EPMC3401319 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.

Sacha Jonah B JB Kim In-Jeong IJ Chen Lianchun L Ullah Jakir H JH Goodwin David A DA Simmons Heather A HA Schenkman Daniel I DI von Pelchrzim Frederike F Gifford Robert J RJ Nimityongskul Francesca A FA Newman Laura P LP Wildeboer Samantha S Lappin Patrick B PB Hammond Daisy D Castrovinci Philip P Piaskowski Shari M SM Reed Jason S JS Beheler Kerry A KA Tharmanathan Tharsika T Zhang Ningli N Muscat-King Sophie S Rieger Melanie M Fernandes Carla C Rumpel Klaus K Gardner Joseph P JP Gebhard Douglas H DH Janies Juliann J Shoieb Ahmed A Pierce Brian G BG Trajkovic Dusko D Rakasz Eva E Rong Sing S McCluskie Michael M Christy Clare C Merson James R JR Jones R Brad RB Nixon Douglas F DF Ostrowski Mario A MA Loudon Peter T PT Pruimboom-Brees Ingrid M IM Sheppard Neil C NC

Journal of immunology (Baltimore, Md. : 1950) 20120627 3

The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis a ...[more]

PMID: 22745376

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Project description:BACKGROUND:The therapeutic HIV-1 Tat protein vaccine is in advanced clinical development. Tuberculosis, the main AIDS co-infection, is highly endemic in areas where AIDS prevention through vaccination is needed. However, safety and immunogenicity of Tat vaccination in the course of Mycobacterium tuberculosis (Mtb) infection is still unknown and it prevents the possibility to administer the vaccine to Mtb-infected individuals. We addressed the interplay and effects of Tat vaccination on Mtb infection in immunocompetent mice. METHODS:C57BL/6 mice were vaccinated or not with Bacillus Calmette-Guerin (BCG), the current tuberculosis vaccine, and after 5 weeks were infected with Mtb by intravenous route. The Tat protein was injected intradermally at 1, 2 and 4 weeks after Mtb challenge. Eight weeks after Mtb infection, all mice were sacrificed, and both the degree of pathology and immune responses to Mtb and Tat were evaluated. As additional control, some mice were either vaccinated or not with BCG, were not challenged with Mtb, but received the Tat protein. Statistical significances were evaluated by one-way or two-way ANOVA and Tukey's multiple comparisons post-test. RESULTS:In the lungs of Mtb-infected mice, Tat-vaccine did not favour Mtb replication and indeed reduced both area of cellular infiltration and protein levels of Interferon-?, Chemokine (C-C motif) ligand-4 and Interleukin-1?, pathological events triggered by Mtb-infection. Moreover, the protection against Mtb infection conferred by BCG remained good after Tat protein treatment. In spleen cells of Mtb-infected mice, Tat vaccination enhanced Mtb-specific Interferon-? and Interleukin-17 responses, which may have a protective role. Of note, Mtb infection reduced, but did not suppress, the development of anti-Tat antibodies, required for Tat vaccine efficacy and the titer of anti-Tat IgG was potentiated by BCG vaccination in Mtb-free mice. In general, Tat treatment was well tolerated in both Mtb-infected and Mtb-free mice. CONCLUSIONS:Tat protein vaccine, administered in Mtb-infected mice with a protocol resembling that used in the clinical trials, was safe, immunogenic, limited the lung Mtb-associated immunopathology and did not abrogate the protective efficacy of BCG. These data provide preliminary evidence for a safe use of Tat vaccine in people vaccinated with BCG and/or suffering from tuberculosis.

Project description:BackgroundTransposable elements (TEs) have the potential to produce broad changes in the genomes of their hosts, acting as a type of evolutionary toolbox and generating a collection of new regulatory and coding sequences. Several TE classes have been studied in Neotropical cichlids; however, the information gained from these studies is restricted to the physical chromosome mapping, whereas the genetic diversity of the TEs remains unknown. Therefore, the genomic organization of the non-LTR retrotransposons Rex1, Rex3, and Rex6 in five Amazonian cichlid species was evaluated using physical chromosome mapping and DNA sequencing to provide information about the role of TEs in the evolution of cichlid genomes.ResultsPhysical mapping revealed abundant TE clusters dispersed throughout the chromosomes. Furthermore, several species showed conspicuous clusters accumulation in the centromeric and terminal portions of the chromosomes. These TE chromosomal sites are associated with both heterochromatic and euchromatic regions. A higher number of Rex1 clusters were observed among the derived species. The Rex1 and Rex3 nucleotide sequences were more conserved in the basal species than in the derived species; however, this pattern was not observed in Rex6. In addition, it was possible to observe conserved blocks corresponding to the reverse transcriptase fragment of the Rex1 and Rex3 clones and to the endonuclease of Rex6.ConclusionOur data showed no congruence between the Bayesian trees generated for Rex1, Rex3 and Rex6 of cichlid species and phylogenetic hypothesis described for the group. Rex1 and Rex3 nucleotide sequences were more conserved in the basal species whereas Rex6 exhibited high substitution rates in both basal and derived species. The distribution of Rex elements in cichlid genomes suggests that such elements are under the action of evolutionary mechanisms that lead to their accumulation in particular chromosome regions, mostly in heterochromatins.

Dataset Information

Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.

Publications

Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.

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