Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element

Lim, Chun Shen; Brown, Chris M.

doi:10.1080/15476286.2016.1166330

Cited by 18 publications

(15 citation statements)

References 36 publications

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“…TCR construction was in the vector PRRL (29) further modified by introducing six point mutations into the start codon and putative promoter region of the woodchuck hepatitis virus X protein as described (30), with the TCR beta gene preceding the TCR alpha gene separated by a P2A translational skip sequence. Cysteine residues were introduced to facilitate pairing of introduced TCR chains as described (31).…”

Section: T-cell Receptor Vector Constructionmentioning

confidence: 99%

Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent OncogenicKRASandERBB2(Her2) Driver Mutations

Veatch

Jesernig

Kargl

et al. 2019

Cancer Immunology Research

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T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8 þ T cells by class I MHC. However, CD4 þ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8 þ or CD4 þ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non-small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations.However, CD4 þ T cells that recognized the recurrent KRAS G12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. Two different T-cell receptors (TCR) specific for KRAS G12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITDspecific TCR in the tumor but not nonadjacent lung. Our results showed that CD4 þ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4 þ neoantigen-specific T cells and elucidate their role in human antitumor immunity.

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Section: T-cell Receptor Vector Constructionmentioning

confidence: 99%

Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent OncogenicKRASandERBB2(Her2) Driver Mutations

Veatch

Jesernig

Kargl

et al. 2019

Cancer Immunology Research

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“…The HBV transcripts are made of a number of functional entities embedded inside the RNA sequence. These include the encapsidation signal necessary for pgRNA packaging [29,30], the PRE regulating the nuclear export of the HBV transcripts [2,3,31], the RNA region involved in destabilizing HBV RNA in response to cytokines treatments [32,33] and the ERE described here. It is therefore possible that with the minimization of the HBV genome, some of the essential activities have become adapted to be executed by the viral RNA and therefore the emergence of multitasking HBV RNA is an important evolutionary step in establishing the hepadnavirus family.…”

Section: Discussionmentioning

confidence: 99%

“…The HBV genome harbors enhancers and promoters regulating the transcription of a number of positive strand transcripts. The generated RNA species are nuclear exported by a unique mechanism that is not entirely understood but requires a RNA region shared by all the viral mRNAs called PRE (posttranscriptional regulatory element) [2,3]. An exceptional RNA species is the longest viral transcript that accumulates in the nucleus [4].…”

Section: Introductionmentioning

confidence: 99%

A short HBV RNA region induces RNR-R2 expression in non-cycling cells and in primary human hepatocytes

Ricardo-Lax

Broennimann

Adler

et al. 2018

Preprint

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25 Hepatitis B virus infects non-dividing cells in which dNTPs are scarce. HBV replication 26 requires dNTPs. To cope with this constraint the virus induces the DNA damage response 27 (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR 28 holoenzyme, the key regulator of dNTP levels. Previously we reported that the HBx open 29 reading frame (ORF) triggers this pathway. Unexpectedly however, we report here that 30 the production of HBx protein is not essential. We found that a small region of 125 bases 31 within the HBx transcript is sufficient to induce RNR-R2 expression in growth arrested 32 HepG2 cells and in primary human hepatocytes (PHH). The observed HBx embedded 33 regulatory element is named ERE. We demonstrate that ERE is functional as a positive 34 strand RNA polymerase-II transcript. Remarkably, ERE is sufficient to induce the Chk1-35 E2F1-RNR-R2 DDR pathway, previously reported to be activated by HBV. Furthermore, 36 we found that ERE activates ATR but not ATM in eliciting this DDR pathway in 37 upregulating RNR-R2. These findings demonstrate the multitasking role of HBV 38 transcripts in mediating virus-host cell interaction, a mechanism that explains how such a 39 small genome effectively serves such a pervasive virus. 40 41 Author summary 42 The hepatitis B virus (HBV) infects the human liver and over 250 million people 43 worldwide are chronically infected with HBV and at risk for cirrhosis and liver cancer.44 HBV has a very small DNA genome with only four genes, much fewer than other 45 viruses. For propagation the virus consumes dNTPs, the building blocks of DNA, in 46 much higher amounts than the infected cells provide. To cope with this constraint, the 3 47 virus manipulates the cells to increase the production of dNTPs. We found that the virus 48 activates the cellular response to DNA damage upon which the cells increase the 49 production of dNTPs, but instead of repairing cellular DNA, the virus uses them for 50 production of its own DNA. Usually viruses manipulate host cells with one or more of 51 their unique proteins, however the small HBV genome cannot afford having such a 52 unique gene and protein. Instead, we found that here the virus relies on RNA to 53 manipulate the host cells. Our findings highlight the unprecedented principle of a 54 multitasking viral RNA that is not only designed to be translated into proteins but also 55 harbors an independent role in activating the cellular DNA damage response. 56 57 Introduction 58 Hepatitis B virus (HBV) is a non-cytopathic enveloped virus containing a small circular 59 partially double-stranded DNA genome. Upon entering the cell the genome is converted 60 into a covalently closed circular DNA (cccDNA), the viral transcription template [1]. The 61 HBV genome harbors enhancers and promoters regulating the transcription of a number 62 of positive strand transcripts. The generated RNA species are nuclear exported by a 63 unique mechanism that is not entirely understood but requires a RNA region shared by all 64 t...

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“…In addition, AID has been shown to interact with HBV pol and RNA processing exosome to degrade HBV RNA (Liang et al, 2015a). Lastly, the nuclear export of HBV RNA is regulated by PRE and involves a cellular factor TAP/NXF1 (Tip-associated protein/nuclear export factor-1) (Li et al, 2010; Lim and Brown, 2016; Yang et al, 2014). …”

Section: Transcription Of Cccdna and Transport Of Rna Out Of The Nucleusmentioning

confidence: 99%

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

et al. 2018

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Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus’ life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions.

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Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element

Cited by 18 publications

References 36 publications

Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent OncogenicKRASandERBB2(Her2) Driver Mutations

Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent OncogenicKRASandERBB2(Her2) Driver Mutations

A short HBV RNA region induces RNR-R2 expression in non-cycling cells and in primary human hepatocytes

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

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