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Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation

Nature Reviews Cancer volume 7, pages 270–280 (2007)Cite this article

Key Points

  • Human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that infects 20 million people worldwide, was the first retrovirus to be shown to be causal for a human cancer, adult T-cell leukaemia (ATL).

  • The infectivity of HTLV-1 is tightly cell-associated, and is mediated through a virological synapse. Cell-free virus is largely non-infectious.

  • HTLV-1 does not use viral capture of a cellular proto-oncogene for oncogenesis. Its viral oncoprotein, Tax, is needed to initiate but not maintain cellular transformation.

  • Tax transforms cells through various mechanisms, including the creation of chromosomal instability, the amplification of centrosomes, the abrogation of DNA repair, the activation of cyclin-dependant kinases and nuclear factor κB (NFκB) and Akt signalling, and the silencing of p53 and spindle-assembly checkpoints.

  • The maintenance of ATL transformation seems to require the function of a novel antisense protein and RNA, termed HTLV-1 basic leucine zipper factor (HBZ).

Abstract

It has been 30 years since a 'new' leukaemia termed adult T-cell leukaemia (ATL) was described in Japan, and more than 25 years since the isolation of the retrovirus, human T-cell leukaemia virus type 1 (HTLV-1), that causes this disease. We discuss HTLV-1 infectivity and how the HTLV-1 Tax oncoprotein initiates transformation by creating a cellular environment favouring aneuploidy and clastogenic DNA damage. We also explore the contribution of a newly discovered protein and RNA on the HTLV-1 minus strand, HTLV-1 basic leucine zipper factor (HBZ), to the maintenance of virus-induced leukaemia.

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Figure 1: The HTLV-1 proviral genome.
Figure 2: The natural history of HTLV-1 infection.
Figure 3: Cell–cell transmission of HTLV-1 occurs through a virological synapse.
Figure 4: The HTLV-1 oncoprotein Tax activates two survival pathways, NFκB and Akt, to promote cell survival and proliferation.
Figure 5: Aneuploidy and multipolar mitosis in HTLV-1-infected cells.
Figure 6: Tax affects many cellular factors that contribute to clastogenic DNA damage in HTLV-1-infected cells.
Figure 7: Schematic illustration of the expression and the activities of the HBZ RNA and protein in HTLV-1-infected cells.

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Acknowledgements

We thank L.-M. Huang for critical reading of this manuscript, and A. Pearl-Jacobvitz and J.-M. Peloponese for help with manuscript preparation. We apologize to investigators whose contributions could not be included owing to space limitations.

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Authors and Affiliations

  1. Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Japan

    Masao Matsuoka

  2. Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Bethesda, 20892-0460, Maryland, USA

    Kuan-Teh Jeang

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  1. Masao Matsuoka
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HTLV network

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Glossary

Deltaretrovirus

A genus of the retroviridae family, whose members include HTLV-1 and bovine leukaemia virus, amongst others.

Provirus

Usually represents the integrated DNA form of retroviruses.

Helper T cells

A subset of lymphocytes that activate the immune system. Helper cells enhance the functions of B cells, cytotoxic T cells and macrophages.

Regulatory T cells (TReg cells)

Also known as suppressor T cells. These cells function in establishing immune tolerance.

Parenteral

A route to introduce material into the body by injection or infusion.

Gag complex

Gag is a retroviral structural protein that wraps the retroviral RNA genome.

Long terminal repeat

A repeated sequence, several hundred base pairs long, found at the 5′ and the 3′ ends of the retroviral genome.

Memory T-cell subpopulation

A specialized population of T lymphocytes that recognizes foreign antigens. Memory T cells mount a faster and stronger T-cell response against antigens that they have been previously exposed to.

Human papillomavirus

A small DNA virus that causes cervical cancer.

PDZ domains

PDZ is an abbreviation using the first letters of three proteins — post synaptic density protein 95 (PSD95), Drosophila discs large 1 tumour suppressor (DLG1) and zona occludens 1 (ZO1). These three proteins were the first to be described as sharing a domain that specifies protein–protein association and the association of transmembrane proteins to the cytoskeleton of the cell.

Wnt

A protein family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis. Wnt protein functions have also been implicated in cancer development.

Frizzled

Frizzled proteins are seven-transmembrane molecules that act as receptors for Wnt proteins.

Hepatitis B virus

A virus that has been associated with hepatocellular cancers.

Epstein–Barr virus

A herpes virus that has been linked to Burkitt lymphoma and nasopharyngeal carcinoma.

Clastogenic

A term denoting a breakage in a chromosome.

Base excision repair

A cellular mechanism to repair bases in DNA that are mutated, for example by deamination or alkylation. Base excision repair removes and repairs the mutated base alone.

Nucleotide excision repair

This type of DNA repair is used by cells after UV irradiation. Nucleotide excision repair enzymes recognize bulky distortions in DNA and excise a short single-stranded DNA stretch that includes the bulky lesion. Defects in NER lead to diseases such as Xeroderma pigmentosum and Cockayne syndrome.

Mismatch repair

A repair system that removes the erroneous insertion, deletion and mis-incorporation of bases during DNA replication, usually on the newly synthesized strand.

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Matsuoka, M., Jeang, KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 7, 270–280 (2007). https://doi.org/10.1038/nrc2111

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