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Chapter 33 : Human Lymphotropic Viruses: HTLV-1 and HTLV-2

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Human Lymphotropic Viruses: HTLV-1 and HTLV-2, Page 1 of 2

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Abstract:

Human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) and the more recently recognized HTLV-3 and HTLV-4 are human retroviruses of the genus originally derived from closely related simian viruses. Proviral DNA is integrated in the host genome and propagated by lymphocytic division with only a minimal production of infectious virus. A small viral genome encodes several structural and regulatory proteins that in concert with the host cellular immune response control the burden of infection, as measured by the proportion of lymphocytes harboring HTLV proviral DNA. Most chronically infected humans are asymptomatic, but 2% to 4% of HTLV-1 carriers develop a mature T-cell malignancy called adult T-cell lymphoma (ATL). HTLV-2 infection does not cause malignant disease. Another 1% to 2% of HTLV-1 and HTLV-2 carriers develop a spinal cord disease known as HTLV- associated myelopathy (HAM) characterized by a progressive weakness and spasticity of the lower extremities as well as a hyperactive bladder. Various inflammatory conditions have been associated with infection, and long-term mortality may be increased. HTLV-1 and HTLV-2 are transmitted from mother to child via breast-feeding, by sexual intercourse, and parenterally by the infusion of infected blood or injection drug use. From its presumed origins in Central Africa and Melanesia, HTLV-1 has spread globally along with human migrations and the historical slave trade. HTLV-2, endemic in Amerindian and African pygmy populations, has had a more limited geographic distribution except for hyperendemic spread among injection drug users (IDUs) in the United States and Europe.

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Figures

Image of FIGURE 1
FIGURE 1

Phylogenetic relationships of HTLV-1, HTLV-2, HTLV-3, and HTLV-4 inferred using Bayesian analysis and a relaxed molecular clock. Topology inferred using the first and second codon positions of concatenated , , and sequences (3,490-bp). Posterior probabilities greater than 0.7 are provided at branch nodes. (We are grateful to Dr. William Switzer for his development of and permission to use this figure.)

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 2
FIGURE 2

Genomic structures of HTLV-1 and HTLV-2. A. HTLV-1. B. HTLV-2. LTR, long terminal repeat; , group-specific antigen whose products form the skeleton of the virion (matrix, capsid, nucleocapsid, nucleic acid binding protein); , gene for protease; , gene for reverse transcriptase and integrase; , envelope gene; , viral regulatory gene involved in promoting genomic RNA production; , transactivator gene; HBZ, antisense transcribed HTLV-I basic zipper gene involved in cell proliferation; and APH-2, antisense transcribed Antisense Protein of HTLV-2 gene involved in transcription regulation.

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 3
FIGURE 3

Geographic distributions of HTLV-1 (panel A) and HTLV-2 (panel B). Viral subtypes are indicated by lower case letters, red font indicates an endemic region for the virus, and blue font indicates imported or immigrant infections.

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 4
FIGURE 4

Seroprevalence of HTLV-1 (panels A and B) and HTLV-2 (panels C and D), illustrating age and sex dependence of HTLV-1 among endemic Jamaicans and US blood donors. For HTLV-2, a similar age and sex dependence is seen for endemic Kayapo Indians, but a likely birth-cohort effect is seen for US blood donors. (Adapted from references .)

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 5
FIGURE 5

HTLV lymphomagenesis: progression of T lymphocytes from immortalization and clonal expansion to transformation. Various changes in the cell during the different stages are listed in the shaded boxes. As shown, virus-infected cells can also go into apoptosis. (Adapted from reference ( ) with permission of Macmillan Publishers Ltd.)

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 6
FIGURE 6

Model of CD8 CTL-mediated control of HTLV-1 infection. HTLV-1 infects CD4 T lymphocytes, with expansion of infection primarily via cell replication. As HTLV-1-specific antigens, particularly Tax, are expressed, a robust CD8 CTL response is generated that results in the killing of CD4-infected cells expressing Tax. Anti-HBZ CTL response is weak but associated with a reduction of PVL. The inability of some persons to control HTLV-1 expansion is thought to contribute to disease pathogenesis. In this model, the dynamic equilibrium between viral replication and immune destruction is mediated through Tax overexpression, causing CD4 target cell proliferation and a robust cell-mediated response to the antigen in particular, thereby leading to CTL-mediated lysis of these HTLV-1-infected CD4 cells. (Adapted from references ( .) As a consequence of ongoing Tax and/or HBZ expression, there is a cell-associated expansion of HTLV-1 genome-containing CD4 cells and a compensatory expansion of CD8 CTL. As the number of CD4 cells containing integrated HTLV-1 provirus expands, HTLV-1 antigens are expressed on the cell surface and become targets for CD8-mediated cytotoxic killing.

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 7
FIGURE 7

Examples of assay results for HTLV-1 and HTLV-2. (A) Modified HTLV-1 and HTLV-2 Western blot including recombinant type-specific peptides MTA-1 for HTLV-1 and K55 for HTLV-2, in addition to other viral antigens. Lane 1 shows an HTLV-1-positive serum, lane 2 shows an HTLV-2-positive serum, and lane 3 shows a negative control serum. Modified from reference ( ). B) HTLV-1 and HTLV-2 line immunoassay, including type-specific HTLV-1 GAG p19, HTLV-1 ENV gp46, and HTLV-2 ENV gp46 antigens, in addition to shared GAG p19, GAG p24, ENV gp46, and ENV gp21 antigens. Lane 1 shows an HTLV-1-positive serum, lane 2 shows an HTLV-2-positive serum, lane 3 shows a negative control serum, and lane 4 shows an HTLV-3-positive serum from an African pygmy. (Modified from reference .)

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 8
FIGURE 8

Photomicrographs of typical peripheral blood leukemic cells from patients with acute ATL (A), chronic ATL (B), smoldering ATL (C), and cutaneous manifestations (D). Details of the features are discussed in the text.

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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Image of FIGURE 9
FIGURE 9

Survival patterns of patients with different ATL subtypes after polychemotherapy. Patients with acute and lymphoma-type ATL have the poorest prognosis after chemotherapy. (Adapted from reference .)

Citation: Bruhn R, Mahieux R, Murphy E. 2017. Human Lymphotropic Viruses: HTLV-1 and HTLV-2, p 771-794. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch33
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