Human T-Cell Lymphotropic Virus Type I

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Introduction

TEM image of both HIV and HTLV being produced within the same human lymphocyte. Provide by Cynthia Goldsmith through CDC [1].

Human T- lymphotropic virus type I, also known as human T-cell lymphotropic virus type I, human T-cell-leukemia-lymphoma virus, or HTLV-1 is an oncogenic retrovirus from a family of HTLV that can be sexually transmitted and has been associated with various diseases, including adult T-cell leukemia/lymphoma, as well as HTLV-associated myelopathy (also known as spastic paraparesis or HAM/TSP) [1] . Reported independently by Robert C. Gallo in 1980 and Yorio Hinuma in 1981 [2], it is the first human retrovirus discovered, preceding HIV 1 and 2. [3] The HTLV family is categorized into a larger group known as primate T-lymphotropic viruses (PTLVs) that include HTLVs, which infect humans, and Simian T-lymphotropic viruses (STLVs), which infects Old World monkeys. The HTLVs is also closely related to the bovine leukemia virus, a zoonotic infection that is widespread in domesticated cattle. There are currently 4 known types of HTLVs: HTLV-1, HTLV-2, HTLV-3, and HTLV-4. Strains HTLV-1 and HTLV-2 have been the most prevalent worldwide, while the effects of the latter two strains on human populations still remain unclear. The HTLVs most likely originated from cross-species transmission of the STLVs.

HTLVs target particularly T-cells, a lymphocyte that plays a crucial role in the human immune system. The HTLV-1 genome is diploidal, consisting of two copies of single-stranded RNA virus which are both turned into a double-stranded DNA form that is integrated into the genome of the host cell. After integration, HTLV uses components of the host cell to create more viral particles.

The majority of HTLV-infected individuals live asymptomatically and never face complications. It is not fully understood yet the progression of HTLV from asymptomatic to symptomatic state. [4] Japan, as well as the Caribbean islands, Central Africa, the Middle East, Central and South America, and Melanesia, are known endemic areas of HTLV. [5]

There are currently no antiretroviral therapy nor vaccinations available for HTLV-1. However, vaccine prospects are supported by the virus' demonstration of low antigen variability, natural human immunity, and a successful vaccination of the envelope antigen in animal models [6].



Discovery of the First Human Retrovirus

HTLV-1 was first detected and isolated by Robert C. Gallo from an analysis of a T cell line from a patient with Cutaneous T-cell Lymphoma. Positive results from a reverse transcriptase (RT) assay performed on the cells led to further testing. Electron microscopy performed on the cells found retrovirus particles present in the concentrated RT. To ensure that these particles are actually evidence of a human retrovirus and not from accidental laboratory contaminants like previous researches on the subject unfortunately found, Gallo had to prove that:

1) identical virus could be isolated from a primary tissue sample obtained from the same patient by using primary T cell with Interleukin-2, a particular cytokine secreted by lymphocytes in the human immune system,
2) the virus was new and not a form of any previously discover animal retroviruses,
3) the virus was capable of infecting human T cells in vitro,
4) there are specific antibodies to the virus present in the serum of the patient,
5) integration of proviral DNA in the DNA of the cell in which the virus was isolated
6) provide serological evidence that those specific antibodies

In March 1981, Gallo and Colleague presented their results in a meeting with several other Japanese scientists, including Takatsuki and his co-workers, hoping to address the prevalence of Adult T-cell Leukemia (ATL) in southern Japan. During this meeting, they reviewed several isolates of HTLV-1, along with reverse transcriptase proteins, evidence of HTLV-1 integration and linkage to T cell malignancies, and supporting serological results from Japanese ATL patients. Comparisons from this meeting were summarized and published in November 1981. [7]

Dr. Yorio Hinuma, a researcher who was personally infected with the retrovirus, also presented his research on ATL cells and established isolates which he called Adult T cell leukemia virus (ATLV) shortly after. [8] He objected to collaboration with American scientists due to “cultural reasons,” but a later comparative analysis of ATLV and HTLV isolates confirmed that these two isolates were indeed the same virus. [9]

Subsequent research shows that HTLV-1 infections are endemic in other regions, as well. Dr. Daniel Catovsky, a British hematologist, found an unusually high occurrence of ATL in immigrants from the Caribbean Islands to England. Following more highly specified research in the region, the endemicity was narrowed down to distinctive tribes in Africa as well as the Caribbean.

In 1981, Dr. Gallo and colleagues isolated another less pathogenic strain from the same family of viruses: HTLV-2. HTLV-2 was isolated from cancer resulting from B-cell abnormality also known as Hairy Cell Leukemia. [10] HTLV-2 may also be linked to Cutaneous T-Cell Lymphoma (CTCL), but more research is needed in order to confirm that a correlation exists [11] PCR amplification also identified HTLV-2 in a study using cultured lymphocytes from a patient suffering from Alibert-Bazin syndrome. [12]

In 2005, HTLV-3 and HTLV-4 were discovered in Cameroon [13]. The two new strains were results of cross-species transmission between monkeys and monkey hunters. HTLV-3 poses striking similarities with STLV-3 [14], a retrovirus from the same family that infects monkeys. While HTLV-4 is nearly identical to how STLV-4 infects gorillas. However, transmissions and diseases associated with HTLV-3 and HTLV-4 in humans still require further studies.

Currently, six human retroviruses, all of which targets T-cell, have been identified. Four of these are from the HTLV family; the other two are HIV 1 & 2.

Structure and Mechanism of HTLV-1

HTLV-1 is a tumor-forming RNA virus from the oncovirus subfamily (Oncovirnae) of the family (Retroviridae) of retroviruses and the genus Deltaretrovirus. The virus comprises a positive-sense RNA genome, functional protease, reverse transcriptase, and integrase, all of which are encased within an icosahedral capsid. [15] As a virion, it is protected by a proteolipid envelope bilayer. The inner cell membrane of this bilayer contains a matrix layer which plays an important role in viral assembly and organization of the viral components; the outermost layer is equipped with surface glycoproteins bounded by transmembrane proteins to the virus. [16] The entire virus is round-shaped and has a size of approximately 100nm in diameter. [17]

The ubiquitous vertebrate glucose transporter is proposed to be a host-cell receptor for HTLV-1. [18] After insertion into the DNA of a human host cell, the retrovirus becomes a provirus and causes a lifelong infection in the human host. [19] The precise mechanism in which HTLV-1 transforms T-cells is still not fully known. Similar to HIV, HTLV-1 most frequently infects CD4+ Helper cells both in vitro and in vivo, and less frequently the CD8+ T cells, through viral synapses. Cell-free infection in HTLV-1 is ineffectual.In the early stages of infection, HTLV-1 infection must be spread by direct cell contact until both CD4+ and CD8+ cells are affected. In the later stages in which equilibrium is achieved between viral replication and immune response, HTLV-1 then relies mainly upon mitotic processes of host cells for replication. [20]

HTLV-1 optimizes usages of its genome by protein mutations, typically through ribosomal frameshifts, and RNA splicing. [21] This allows for genetic variability, which is lost when HTLV-1 becomes a provirus after host genome integration and depends on cellular DNA polymerase, which efficiently proofreads, rather than its viral reverse transcriptase. By depending on cellular mitosis, however, HTLV elicits an advantageous response from the cytotoxic T-lymphocyte and the production of inflammatory cytokines of the immune system.

Seven genotypes of HTLV-1 have been identified --HTLV-1a to HTLV-1g. These subtypes are determined by the nucleotide diversity of the long terminal repeat (LTR) sequences. [22] Genotype A is the most predominant in infections. Genotypes B, D, E, F, and G have only been isolated from Central Africa; While, Genotype C has only been found in Asia. However, there is no change in the pathogenic potential between the subtypes. Thus, they present an inconsequential role in the epidemiological status of the virus. [23]

Transmission

HTLV-I can be transmitted through sexual intercourse [24], blood transfusions [25], contaminated needles, as well as mother-to-child relationships. [26]

HTLV-1 exhibits a low rate (<1%) of incident transmission through sexual intercourse.[27] It suggested that higher efficiency exists in male to female transmissions than female to male, with infections being twice as common in the female population.[28][29] The use of condoms demonstrated protection from HTLV-1 infections in clandestine female sex workers in Lima, Peru. [30]

Contaminated blood transfusions result in higher rates of transmission, demonstrated in seroconversion in more than 40% of.[31] However, screening of blood donors for HTLV-1 antibodies in many countries including Japan has proven effective at decreasing the number of new infections in the general population. Contaminated needles and syringes also perpetuate the spread of HTLV-1 infections, as demonstrated by higher rates of infections among injection-based drug users in Brazil and New York. [32]

The majority of mother-to-child transmissions occur through prolonged breastfeeding and are dependent on the proviral load, duration of breastfeeding, and the antibody titer of the maternal figure. [33] A study in Japan showed that breast-fed children of HTLV-1 infected mothers were 4x more likely to also contract HTLV-1 infections than bottle-fed children.[34]However, the majority of the mechanisms regarding the transmission of HTLV-1 through breastfeeding remains largely unclear.[35]

Epidemiology

Global map showing origin, spread, and prevalence of HTLV-[2].

HTLV-1 is present globally but has endemicity in the Caribbean islands, Central Africa, the Middle East, Central and South America, and Melanesia [36] [37] . In hyperendemic regions, almost 30% of adults present HTLV-1 infections. Based on MTC transmission of HTLV, clustering of infection is also common in families. [38]













Associated Diseases

The majority of people infected with HTLV-1 remain asymptomatic. The transition from an asymptomatic to symptomatic state is unclear but may be influenced by factors such as age and way of transmission. Severe diseases associated with HTLV-1 can be classified into three categories [39]:

Adult T-cell Leukemia/Lymphoma. A Wright's stain indicating abnormal lymphocytes by Isao Miyoshi on 5/28/2003 [3].

Neoplastic Diseases
- Adult T-Cell Leukemia-Lymphoma
- Cutaneous T-Cell Lymphoma

Inflammatory syndromes
- TSP/HAM
- Uveitis
- Arthropathy
- Sjögren’s syndrome
- Polymyositis
- Thyroiditis
- Pneumopathy
- T lymphocyte alveolitis

Opportunistic infections
- Crusted scabies
- Strongyloides stercoralis
- Infective dermatitis
- Tuberculosis
- Leprosy

The incident rate of developing Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM) is 0.3-4% among HTLV-1 infected persons. The risk of developing ATL is 1-5%. 1 in 10 people infected with HTLV will develop at least one of currently identified HTLV-1 associated diseases. [40]

Conclusion

HTLV-1 remains highly notable in not only was it the first established human retrovirus but also the only one to be directly linked to cancer. While the incidence rate of developing ATL, TSP/HAM, and other HTLV-1 related diseases remain relatively low, the severity of these diseases should not be overlooked. Fortunately, the contraction of this carcinogenic STI is highly preventative by safe sex and should encourage people to maintain healthy sexual practices, such as condom usage. Taking measures to prevent transmission is not only beneficial to the individual but aids public health. Furthermore, preventative measures should especially be taken in areas where transmission rates of HTLV-1 is high, such as blood banks, perinatal care settings, hospitals, and regions around the world in hyperendemicity.



References

  1. ↑ Marcus Tulius T. Silva, Ramza Cabral Harab, Ana Cláudia Leite, Doris Schor, Abelardo Araújo, Maria José Andrada-Serpa, Human T Lymphotropic Virus Type 1 (HTLV-1) Proviral Load in Asymptomatic Carriers, HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis, and Other Neurological Abnormalities Associated with HTLV-1 Infection, Clinical Infectious Diseases, Volume 44, Issue 5, 1 March 2007, Pages 689–692,https://doi.org/10.1086/510679
  2. ↑ Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2.Retrovirology. 2005;2:17. Published 2005 Mar 2. doi:10.1186/1742-4690-2-17
  3. ↑ Human retroviruses. Retrieved December 10, 2020, from http://www.virology.uct.ac.za/vir/teaching/mbchb/human-retroviruses
  4. ↑ Marcus Tulius T. Silva, Ramza Cabral Harab, Ana Cláudia Leite, Doris Schor, Abelardo Araújo, Maria José Andrada-Serpa, Human T Lymphotropic Virus Type 1 (HTLV-1) Proviral Load in Asymptomatic Carriers, HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis, and Other Neurological Abnormalities Associated with HTLV-1 Infection, Clinical Infectious Diseases, Volume 44, Issue 5, 1 March 2007, Pages 689–692,https://doi.org/10.1086/510679
  5. ↑ Denise Utsch Gonçalves, Fernando Augusto Proietti, João Gabriel Ramos Ribas, Marcelo Grossi Araújo, Sônia Regina Pinheiro, Antônio Carlos Guedes, Anna Bárbara F. Carneiro-Proietti Clinical Microbiology Reviews Jul 2010, 23 (3) 577-589; DOI: 10.1128/CMR.00063-0 https://cmr.asm.org/content/23/3/577#:~:text=Japan%20is%20the%20most%20important,%2C%20and%20Okinawa%20(103)
  6. ↑ de Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses. 1993 May;9(5):381-6. doi: 10.1089/aid.1993.9.381. PMID: 8318266.
  7. ↑ Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, et al. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981;294:770–771. doi: 10.1038/294770a0.
  8. ↑ Gallo, Robert C., B. Guy, and Yohei Ito. "Kyoto workshop on some specific recent advances in human tumor virology." (1981): 4738-4739.
  9. ↑ Gallo RC, Blattner WA, Reitz MS, Jr, Ito Y. HTLV: the virus of adult T-cell leukaemia in Japan and elsewhere. Lancet. 1982;1:683.
  10. ↑ Takatsuki K. Discovery of adult T-cell leukemia. Retrovirology. 2:16. doi: 10.1186/1742-4690-2-16.
  11. ↑ Mirvish, Ezra D.; Pomerantz, Rebecca G.; Geskin, Larisa J. (2011). "Infectious agents in cutaneous T-cell lymphoma". Journal of the American Academy of Dermatology. 64 (2): 423–431. doi:10.1016/j.jaad.2009.11.692. PMC 3954537. PMID 20692726.
  12. ↑ Mirvish, Ezra D.; Pomerantz, Rebecca G.; Geskin, Larisa J. (2011). "Infectious agents in cutaneous T-cell lymphoma". Journal of the American Academy of Dermatology. 64 (2): 423–431. doi:10.1016/j.jaad.2009.11.692. PMC 3954537. PMID 20692726.
  13. ↑ Mahieux, R.; Gessain, Antoine (2009). "The human HTLV-3 and HTLV-4 retroviruses: New members of the HTLV family". Pathologie Biologie. 57 (2): 161–6. doi:10.1016/j.patbio.2008.02.015. PMID 18456423.
  14. ↑ Murphey-Corb. "Isolation of an HTLV-III-Related Retrovirus from Macaques with Simian AIDS and its Possible Origin in Asymptomatic Mangabeys." Nature (London), vol. 321, no. 6068, 05/01/1986, pp. 435-437,
  15. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  16. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  17. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  18. ↑ Manel N, Kim FJ, Kinet S, Taylor N, Sitbon M, Battini JL. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell. 2003 Nov 14;115(4):449-59. doi: 10.1016/s0092-8674(03)00881-x. PMID: 14622599.
  19. ↑ Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2.Retrovirology. 2005;2:17. Published 2005 Mar 2. doi:10.1186/1742-4690-2-17
  20. ↑ anaka G, Okayama A, Watanabe T, Aizawa S, Stuver S, Mueller N, Hsieh CC, Tsubouchi H. The clonal expansion of human T lymphotropic virus type 1-infected T cells: a comparison between seroconverters and long-term carriers. J Infect Dis. 2005 Apr 1;191(7):1140-7. doi: 10.1086/428625. Epub 2005 Mar 1. PMID: 15747250.
  21. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  22. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  23. ↑ Marcus Tulius T. Silva, Ramza Cabral Harab, Ana Cláudia Leite, Doris Schor, Abelardo Araújo, Maria José Andrada-Serpa, Human T Lymphotropic Virus Type 1 (HTLV-1) Proviral Load in Asymptomatic Carriers, HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis, and Other Neurological Abnormalities Associated with HTLV-1 Infection, Clinical Infectious Diseases, Volume 44, Issue 5, 1 March 2007, Pages 689–692,https://doi.org/10.1086/510679
  24. ↑ Tajima K, Tominaga S, Suchi T, et al. Epidemiological analysis of the distribution of antibody to adult T-cell leukemia virus-associated antigen: possible horizontal transmission of adult T-cell leukemia virus. Jpn J Cancer Res (Gann) 1982;73:893-901.
  25. ↑ Okochi K, Sato H, Hinuma Y. A retrospective study on transmission of adult T cell leukemia virus by blood transfusion: seroconversion in recipients. Vox Sang 1984;46:245-53.
  26. ↑ Percher F, Jeannin P, Martin-Latil S, et al. Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission. Viruses. 2016;8(2):40. Published 2016 Feb 3. doi:10.3390/v8020040
  27. ↑ Trujillo L, Muñoz D, Gotuzzo E, Yi A, Watts DM. Sexual practices and prevalence of HIV, HTLV-I/II, and Treponema pallidum among clandestine female sex workers in Lima, Peru. Sex Transm Dis. 1999 Feb;26(2):115-8. doi: 10.1097/00007435-199902000-00010. PMID: 10029987.
  28. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  29. ↑ Human retroviruses. (n.d.). Retrieved December 10, 2020, from http://www.virology.uct.ac.za/vir/teaching/mbchb/human-retroviruses
  30. ↑ Trujillo L, Muñoz D, Gotuzzo E, Yi A, Watts DM. Sexual practices and prevalence of HIV, HTLV-I/II, and Treponema pallidum among clandestine female sex workers in Lima, Peru. Sex Transm Dis. 1999 Feb;26(2):115-8. doi: 10.1097/00007435-199902000-00010. PMID: 10029987.
  31. ↑ Manns A, Wilks RJ, Murphy EL, et al. A prospective study of transmission by transfusion of HTLV-I and risk factors associated with seroconversion.
  32. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  33. ↑ Percher F, Jeannin P, Martin-Latil S, et al. Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission. Viruses. 2016;8(2):40. Published 2016 Feb 3. doi:10.3390/v8020040
  34. ↑ Hino S., Katamine S., Miyata H., Tsuji Y., Yamabe T., Miyamoto T. Primary prevention of HTLV-I in Japan. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 1996
  35. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  36. ↑ Denise Utsch Gonçalves, Fernando Augusto Proietti, João Gabriel Ramos Ribas, Marcelo Grossi Araújo, Sônia Regina Pinheiro, Antônio Carlos Guedes, Anna Bárbara F. Carneiro-Proietti Clinical Microbiology Reviews Jul 2010, 23 (3) 577-589; DOI: 10.1128/CMR.00063-0 https://cmr.asm.org/content/23/3/577#:~:text=Japan%20is%20the%20most%20important,%2C%20and%20Okinawa%20(103)
  37. ↑ Human retroviruses. (n.d.). Retrieved December 10, 2020, from http://www.virology.uct.ac.za/vir/teaching/mbchb/human-retroviruses
  38. ↑ Human retroviruses. (n.d.). Retrieved December 10, 2020, from http://www.virology.uct.ac.za/vir/teaching/mbchb/human-retroviruses
  39. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/
  40. ↑ Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7:266–81. https://pubmed.ncbi.nlm.nih.gov/17376384/


Edited by Rachel Chen, student of Joan Slonczewski for BIOL 116 Information in Living Systems, 2020, Kenyon College.

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