Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Miura, Michi; Dey, Supravat; Ramanayake, Saumya; Singh, Abhyudai; Rueda, David; Bangham, Charles R. M.

doi:10.1371/journal.ppat.1008164

Cited by 34 publications

(42 citation statements)

References 45 publications

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“…These studies also found the minus-strand (i.e. Hbz) is transcribed at lower, more constant levels and is silent in a proportion of cells at given times (Miura et al, 2019). This data supports the observation of persistently activated cytotoxic T lymphocytes (CTLs) directed against plus strand viral antigens.…”

Section: Htlv-1 Infection Persistence and Diseasesupporting

confidence: 77%

CRISPR Genome Editing Applied to the Pathogenic Retrovirus HTLV-1

Panfil

Green

Yoder

2020

Front. Cell. Infect. Microbiol.

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CRISPR editing of retroviral proviruses has been limited to HIV-1. We propose human T-cell leukemia virus type 1 (HTLV-1) as an excellent model to advance CRISPR/Cas9 genome editing technologies against actively expressing and latent retroviral proviruses. HTLV-1 is a tumorigenic human retrovirus responsible for the development of both leukemia/lymphoma (ATL) and a neurological disease (HAM/TSP). The virus immortalizes and persists in CD4+ T lymphocytes that survive for the lifetime of the host. The most important drivers of HTLV-1-mediated transformation and proliferation are the tax and hbz viral genes. Tax, transcribed from the plus-sense or genome strand, is essential for de novo infection and cellular immortalization. Hbz, transcribed from the minus-strand, supports proliferation and survival of infected cells in both its protein and mRNA forms. Abrogating the function or expression of tax and/or hbz by genome editing and mutagenic double-strand break repair may disable HTLV-1-infected cell growth/survival and prevent immune modulatory effects and ultimately HTLV-1-associated disease. In addition, the HTLV-1 viral genome is highly conserved with remarkable sequence homogeneity, both within the same host and even among different HTLV isolates. This offers more focused guide RNA targeting. In addition, there are several well-established animal models for studying HTLV-1 infection in vivo as well as cell immortalization in vitro. Therefore, studies with HTLV-1 may provide a better basis to assess and advance in vivo genome editing against retroviral infections.

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Section: Htlv-1 Infection Persistence and Diseasesupporting

confidence: 77%

CRISPR Genome Editing Applied to the Pathogenic Retrovirus HTLV-1

Panfil

Green

Yoder

2020

Front. Cell. Infect. Microbiol.

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“…It is assumed that AHR ligands in peripheral blood are ordinarily kept at a relatively stable level due to the excretory system, whereas in cell culture dish the ligands should accumulate with incubation, contributing to background AHR signaling. The different ligand dynamics in vivo versus in vitro might provide a reasonable explanation for a strange phenomenon—the spontaneous transcriptional activation of HTLV-1 in freshly isolated PBMCs of infected individuals, as one common characteristic of this activation is that the isolated PBMCs generally require incubation in vitro for hours [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

et al. 2020

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Establishing latent infection but retaining the capability to reactivate in certain circumstance is an ingenious tactic for retroviruses to persist in vivo while evading host immune surveillance. Many evidences indicate that Human T-cell leukemia virus type 1 (HTLV-1) is not completely silent in vivo . However, signals that trigger HTLV-1 latency-reactivation switching remain poorly understood. Here, we show that aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a critical role in HTLV-1 plus-strand expression. Importantly, HTLV-1 reactivation could be tunably manipulated by modulating the level of AHR ligands. Mechanistically, activated AHR binds to HTLV-1 LTR dioxin response element (DRE) site (CACGCATAT) and drives plus-strand transcription. On the other hand, persistent activation of nuclear factor kappa B (NF-κB) pathway constitutes one key prerequisite for AHR overexpression in HTLV-1 infected T-cells, setting the stage for the advent of AHR signaling. Our findings suggest that HTLV-1 might achieve its reactivation in vivo when encountering environmental, dietary, microbial and metabolic cues that induce sufficient AHR signaling.

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“… 6 Several recent studies reported that Tax is expressed in short, self-terminating bursts in a minor fraction of ATL cells, leading to persistent infection and leukemogenesis. 10 , 11 Therefore, ATL cells may exploit these host and viral mechanisms to activate the NF-κB pathway required for their maintenance and progression. Furthermore, other T-cell-related signaling pathways, including the JAK/STAT ( STAT3 ) and NOTCH ( NOTCH1 ) pathways, are frequently altered in ATL.…”

Section: Distinct Features Of Genetic Alterations In Atlmentioning

confidence: 99%

Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma

Kataoka¹,

Koya²

2020

J Clin Exp Hematopathol

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Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell malignancy with a markedly poor prognosis. The low prevalence of ATL among human T-cell leukemia virus type-1 (HTLV-1) carriers and the long latency period before ATL onset suggest that additional genetic lesions are required for ATL leukemogenesis. Recently, a large-scale genetic analysis clarified the entire picture of genetic alterations, identified a number of novel driver genes, and delineated their characteristics. Frequent alterations are observed in the molecules belonging to T-cell receptor/NF-κB signaling and other T-cell-related pathways. A notable feature of the ATL genome is the predominance of gain-of-function alterations, including activating mutations in PLCG1 , PRKCB , and CARD11 . As many as one-fourth of all ATL cases harbor structural variations disrupting the 3′-untranslated region of the PD-L1 gene, leading to immune evasion of tumor cells. The frequency and pattern of these somatic alterations differ among clinical subtypes. Aggressive subtypes are associated with an increased burden of genetic alterations, and higher frequencies of TP53 and IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions than indolent subtypes. In contrast, STAT3 mutations are more characteristic of indolent ATL. Furthermore, these subtypes are further classified into molecularly distinct subsets with a different prognosis by genetic alterations. We present an overview of the current understanding of somatic alterations in ATL, with specific focus on their utility in clinical settings. Furthermore, we highlight their genetic features by exploring their similarities and differences among peripheral T-cell lymphomas.

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Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Cited by 34 publications

References 45 publications

CRISPR Genome Editing Applied to the Pathogenic Retrovirus HTLV-1

CRISPR Genome Editing Applied to the Pathogenic Retrovirus HTLV-1

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma

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