Animal Models Utilized in HTLV-1 Research

Panfil, Amanda R.; Al-Saleem, Jacob; Green, Patrick L.

doi:10.4137/vrt.s12140

Cited by 21 publications

(23 citation statements)

References 144 publications

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“…Of the animal models of HTLV-1 infection, the rabbit model is perhaps the most amenable to experimentation, although none of the human diseases associated with HTLV-1 infection have been recapitulated therein [ 64 , 65 ]. With this system, Li et al have shown that the tax/rex mRNA levels in PBMCs peak one week after inoculation of rabbits with γ-irradiated HTLV-1-produing cells [ 66 ].…”

Section: Htlv-1 Infection and Its Outcomesmentioning

confidence: 99%

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

Giam

Semmes

2016

Viruses

125

116

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HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

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Section: Htlv-1 Infection and Its Outcomesmentioning

confidence: 99%

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

Giam

Semmes

2016

Viruses

125

116

View full text Add to dashboard Cite

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“…Previously, rabbits and transgenic mice were used to productively study viral persistence/immune responses and importance/function of viral genes, respectively [83]. However, none of these animal models has offered the ability to study HTLV-1 viral infection and leukemia/lymphoma development.…”

Section: ‘Humanized’ Mouse Modelmentioning

confidence: 99%

Human T-cell leukemia virus-associated malignancy

Panfil

Martinez

Ratner

et al. 2016

Current Opinion in Virology

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Human T-cell leukemia virus type 1 (HTLV-1) is a tumorigenic delta retrovirus and the causative infectious agent of a non-Hodgkin’s peripheral T-cell malignancy called adult T-cell leukemia/lymphoma (ATL). ATL develops in approximately 5% of infected individuals after a significant clinical latency period of several decades. Clinical classifications of ATL include smoldering, chronic, lymphoma, and acute subtypes, with varying median survival ranges of a few months to several years. Depending on the ATL subtype and disease symptoms, treatment options include ‘watchful waiting’, chemotherapy, antiviral therapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and targeted therapies. Herein we review the characteristics and development of ATL, as well as current and future treatment options and perspectives.

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“…Mouse models have traditionally been cost-effective and easy to develop and maintain: however, HTLV-1 transmission in mice using usual methods of infection does not produce reliable infection and virus expression due to the inefficient fusion of HTLV-1 envelope with murine cells (Hajj et al 2012; Lairmore et al 2005). Hence, mice have been manipulated to establish HTLV-1 infection through the generation of transgenic and humanized mice models (Dodon 2014; Panfil et al 2013). The first humanized mouse model was generated by introducing the SCID mutation that impaired the development of mature B and T cells thus improving engraftment efficiency.…”

Section: Introductionmentioning

confidence: 99%

HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice

Ginwala

Caruso

Khan

et al. 2017

J Neuroimmune Pharmacol

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To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1−/−γc−/− or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34+ hematopoietic stem cells. Flow cytometry and histological analyses confirmed reconstitution of Rag1 and BLT mice with human immune cells. Following HTLV-1 infection, proviral load (PVL) was detected in the blood of Rag-1 and BLT hu-mice as early as 2 weeks post-infection (wpi) with sustained elevation in the subsequent weeks followed by Tax expression. Additionally, infection was compared between adult and neonatal Rag1 mice with both PVL and Tax expression considerably higher in the adult Rag1 mice as compared to the neonates. Establishment of peripheral infection led to lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption within the central nervous system of infected mice. In addition, up-regulation in the expression of several immune checkpoint mediators such as programmed cell death-1 (PD-1), T-cell Ig and ITIM domain (TIGIT), and T cell Ig and mucin domain-3 protein (Tim-3) were observed on CD8+ T cells in various organs including the CNS of infected hu-mice. Collectively, these studies represent the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice as potential novel tools for understanding HTLV-1 neuropathogenesis and testing of novel therapies such as immune checkpoint blockade in the amelioration of chronic HTLV-1 infection.

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Animal Models Utilized in HTLV-1 Research

Cited by 21 publications

References 144 publications

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

Human T-cell leukemia virus-associated malignancy

HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice

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