The human leukemia virus HTLV-1 alters the structure and transcription of host chromatin in cis

Melamed, Anat; Yaguchi, Hiroko; Miura, Michi; Witkover, Aviva; Fitzgerald, Tomas; Birney, Ewan; Bangham, Charles R. M.

doi:10.7554/elife.36245

Cited by 69 publications

(74 citation statements)

References 55 publications

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“…It has been reported that antisense proviral transcription is constitutively active, whereas sense transcription is frequently suppressed or expressed only intermittently. Previous studies also reported that transcription is regulated by genetic and epigenetic mechanisms [47–50]; however, the findings of the current study indicate that there is another regulatory mechanism controlling proviral transcription at the post-transcriptional level.…”

Section: Discussioncontrasting

confidence: 76%

HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP

et al. 2019

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BackgroundHuman T cell leukaemia virus type 1 (HTLV-1) is a retrovirus associated with human diseases such as adult T-cell leukaemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. In contrast to another human retrovirus, human immunodeficiency virus type 1 (HIV-1), HTLV-1 persists in the host not via vigorous virus production but mainly via proliferation and/or long-term survival in the form of silent proviruses in infected host cells. As a result, HTLV-1-infected cells rarely produce virus particles in vivo even without anti-retroviral treatment. That should be an advantage for the virus to escape from the host immune surveillance by minimizing the expression of viral antigens in host cells. However, why HIV-1 and HTLV-1 behave so differently during natural infection is not fully understood.ResultsWe performed cap analysis of gene expression (CAGE) using total RNAs and nascent, chromatin-associated, RNAs in the nucleus and found that HTLV-1 RNAs were processed post-transcriptionally in infected cells. RNA processing was evident for the sense viral transcripts but not the anti-sense ones. We also found a higher proportion of CG di-nucleotides in proviral sequences of HTLV-1-infected cells, when compared to the HIV-1 genomic sequence. It has been reported recently that CG dinucleotide content of viral sequence is associated with susceptibility to the antiviral ZC3HAV1 (ZAP), suggesting the involvement of this protein in the regulation of HTLV-1 transcripts. To analyse the effect of ZAP on HTLV-1 transcripts, we over-expressed it in HTLV-1-infected cells. We found there was a dose-dependent reduction in virus production with ZAP expression. We further knocked down endogenous ZAP with two independent targeting siRNAs and observed a significant increase in virus production in the culture supernatant. Other delta-type retroviruses such as simian T-cell leukaemia virus and bovine leukaemia virus, also contain high CG-dinucleotide contents in their viral genomes, suggesting that ZAP-mediated suppression of viral transcripts might be a common feature of delta-type retroviruses, which cause minimal viremia in their natural hosts.ConclusionsThe post-transcriptional regulatory mechanism involving ZAP might allow HTLV-1 to maintain a delicate balance required for prolonged survival in infected individuals.

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Section: Discussioncontrasting

confidence: 76%

HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP

et al. 2019

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“…showed that integration of HTLV-1 and BLV preferentially occurs near cancer drivers and that insertional mutagenesis appears to drive the clonal persistence and expansion of transformed T cells 112 . All of these findings were supported by another recent publication 113 . In addition, Satou and Bangham et al .…”

Section: Pathogenic Mechanism Of Htlv-1 Diseasessupporting

confidence: 80%

40 years of the human T-cell leukemia virus: past, present, and future

2019

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It has been nearly 40 years since human T-cell leukemia virus-1 (HTLV-1), the first oncogenic retrovirus in humans and the first demonstrable cause of cancer by an infectious agent, was discovered. Studies indicate that HTLV-1 is arguably one of the most carcinogenic agents to humans. In addition, HTLV-1 causes a diverse array of diseases, including myelopathy and immunodeficiency, which cause morbidity and mortality to many people in the world, including the indigenous population in Australia, a fact that was emphasized only recently. HTLV-1 can be transmitted by infected lymphocytes, from mother to child via breast feeding, by sex, by blood transfusion, and by organ transplant. Therefore, the prevention of HTLV-1 infection is possible but such action has been taken in only a limited part of the world. However, until now it has not been listed by the World Health Organization as a sexually transmitted organism nor, oddly, recognized as an oncogenic virus by the recent list of the National Cancer Institute/National Institutes of Health. Such underestimation of HTLV-1 by health agencies has led to a remarkable lack of funding supporting research and development of treatments and vaccines, causing HTLV-1 to remain a global threat. Nonetheless, there are emerging novel therapeutic and prevention strategies which will help people who have diseases caused by HTLV-1. In this review, we present a brief historic overview of the key events in HTLV-1 research, including its pivotal role in generating ideas of a retrovirus cause of AIDS and in several essential technologies applicable to the discovery of HIV and the unraveling of its genes and their function. This is followed by the status of HTLV-1 research and the preventive and therapeutic developments of today. We also discuss pending issues and remaining challenges to enable the eradication of HTLV-1 in the future.

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“…For human T cell leukemia virus-1 (HTLV-1), long-range interactions between target gene promoters and viral enhancers are facilitated through chromatin looping utilizing the host zinc finger binding protein CTCF [62,63]. The HTLV-1 provirus contains a CTCF nucleotide-binding motif that has been shown to mediate clone-specific deregulation of host transcription from distances up to 300 kb [62], and CTCFmediated cis contacts within the host genome can be as far as 1.4 Mb [62,63]. Although M-MLV does not encode a known CTCF binding motif, CTCF binding sites have been identified at the promoter region of Rasgrp1 and~10 kb downstream from the integration site (ENCODE reference ENCFF310MUQ).…”

Section: Mechanisms Of Retroviral Enhancer Activationmentioning

confidence: 99%

Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model

et al. 2019

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Murine leukemia virus (MLV) integrase (IN) lacking the C-terminal tail peptide (TP) loses its interaction with the host bromodomain and extraterminal (BET) proteins and displays decreased integration at promoter/enhancers and transcriptional start sites/CpG islands. MLV lacking the IN TP via an altered open reading frame was used to infect tumorigenesis mouse model (MYC/Runx2) animals to observe integration patterns and phenotypic effects, but viral passage resulted in the restoration of the IN TP through small deletions. Mice subsequently infected with an MLV IN lacking the TP coding sequence (TP -) showed an improved median survival by 15 days compared to wild type (WT) MLV infection. Recombination with polytropic endogenous retrovirus (ERV), Pmv20, was identified in seven mice displaying both fast and slow tumorigenesis, highlighting the strong selection within the mouse to maintain the full-length IN protein. Mapping the genomic locations of MLV in tumors from an infected mouse with no observed recombination with ERVs, TP -16, showed fewer integrations at TSS and CpG islands, compared to integrations observed in WT tumors. However, this mouse succumbed to the tumor in relatively rapid fashion (34 days). Analysis of the top copy number integrants in the TP -16 tumor revealed their proximity to known MLV common insertion site genes while maintaining the MLV IN TPgenotype. Furthermore, integration mapping in K562 cells revealed an insertion preference of MLV IN TPwithin chromatin profile states associated with weakly transcribed heterochromatin with PLOS Pathogens | https://doi.fewer integrations at histone marks associated with BET proteins (H3K4me1/2/3, and H3K27Ac). While MLV IN TPshowed a decreased overall rate of tumorigenesis compared to WT virus in the MYC/Runx2 model, MLV integration still occurred at regions associated with oncogenic driver genes independently from the influence of BET proteins, either stochastically or through trans-complementation by functional endogenous Gag-Pol protein. Author summaryMany different retroviruses, including murine leukemia virus (MLV), are used as vectors for human gene therapy and cancer immunotherapies (CAR-T) because of their stable and efficient delivery of genetic material into the host DNA. However, this process can result in activation and/or disruption of cellular genes, which has resulted in the outgrowth of tumors in previous clinical trials. Of critical importance is the preferred location within the host genome at which the retrovirus integrates. Our study presents a modified MLV virus that has lost the ability to bind to the host BET proteins, the drivers of insertion at promoter/enhancer regions of highly activated genes. This is the first direct study within an animal model to examine whether infection with this type of modified MLV virus affects tumor progression. We found that the modified virus improved the survival of the well-characterized MYC/Runx2 mouse compared to infections with the wild-type MLV. Most modified viral integrants mapped into less...

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The human leukemia virus HTLV-1 alters the structure and transcription of host chromatin in cis

Cited by 69 publications

References 55 publications

HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP

HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP

40 years of the human T-cell leukemia virus: past, present, and future

Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model

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