HTLV-1: ancient virus, new challenges

Document Type: Review

Authors

1 Department of Infectious Diseases, Imam Reza Hospital, Mashhad University of Medical Science, Mashhad, Iran.

2 Department of infectious diseases, Imam reza hospital, Mashhad university of Medical science, Mashhad, Iran.

3 Department of immunology, Ghaem hospital, Mashhad university of Medical science, Mashhad, Iran

4 Department of Cardiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Human T-lymphotropic virus (HTLV-1)  is an ancient pathogen for human being but arising and recognized recently. The routes of transmission are vertical (mainly by breastfeeding), unsafe sexual contacts and through contaminated blood components specially in whom need frequent and repeated blood transfusions such as permanent anemia due to blood loss in hemophilia and major thalassemia. Patients who should undergo hemodialysis in their lifelong are another instance for increased risk of HTLV-1 exposure. The main HTLV-1-associated diseases are tropical spastic tetraparesis (HAM/TSP), an inflammatory myelopathy and adult T-cell leukemia (ATL). Although HTLV-1 is scattered around the world, only in endemic areas where prevalence rate is more than 1%, viral burden of infection have accumulated. Japan, Southern and Central parts of Africa, Caribbean basin and Iran are examples of endemic areas of HTLV-1. In this article, a rapid and brief review of HTLV-1 virology, immunology and pathogenesis have emerged. In addition, a short debate has driven about current statues of HTLV-1 in Iran.

Keywords


Introduction
The human T-lymphotropic virus (HTLV-1) was recognized about 30 years ago in a case of adult T-cell leukemia for the first time. This isolated virus confirms the hypothesis that human retroviruses can participate as a contributor for developing cancer (1,2). About 10 to 20 million people are infected with HTLV-1 around the world (3). A vast majority of infected individuals remain asymptomatic but about 3-5% of them display diseases due to this virus. These disorders include malignancies such as adult T-cell leukemia and lymphoma, inflammatory diseases such as myelopathy/tropical spastic paraparesis (HAM/TSP) and opportunistic infections such as Strongyloides stercoralis (4,5). The critical pathogenesis of these diseases is pertained to lymphocytic dysfunction infected by HTLV-1. It is remarkable that these disorders do not appear in majority of carriers, which is probably due to influence of other factors other than etiological role of HTLV-1 (6).
HTLV-1, a type C virus, is a member of Deltaretrovirus genus in Retroviridae family. Other members of this oncovirus family include HTLV-2, bovine leukemia virus (BLV), simian T-cell leukemia (STLV), HTLV-3 and HTLV-4 (7).
The main structure of virus consists of a double layer proteolipid membrane. Enveloping inner contains include capsids, reverse transcriptase, polymerase and other protease enzymes. The main virion, consisting of a single strand RNA, is surrounded by an icosahedral capsid. The viral diameter is about 100 nm (8).
To capture the entire human cell as a host, viral genome should insert to host cell DNA. This purpose is achieved when single strand RNA converts to double strand DNA and then arrives to host genome DNA. This arrival viral DNA is called provirus (2). All retroviruses produce permanent infection including HTLV-1. The same as HIV, the most interested cell for HTLV-1 is CD4+ T cell, but CD8+ T cells also could be selected as alternative host cell.
HTLV-1 has a double genetic structure, encompasses of two similar strands with a length of 9032 base pairs for each one. The genomic structure, similar to other retroviruses, contains of two ending long terminal repeat (LTR) series in both side named gag, pol and env genes (2,8). In addition, HTLV-1 has particular segment namely pX between env and 3`LTR, responsible for encoding of regulatory important proteins such as p40 tax (TAX), p27rex, p12, p13 and p30. Moreover, pX region is responsible for encoding of HTLV-1 basic leucine zipper factor (HBZ), a gene that is involved in pathogenesis of virus (9).
Spreading of HTLV-1, in contrast to HIV, occurs directly through cell to cell contact rather than free plasma a particle, resulted in low and undetectable plasma virus. Further way for spreading is transmission from dendritic cells to CD4+ T cell. In this way, infection of both dendritic and T cells perform by means of glucose transporter that plays as a receptor for HTLV-1 envelope glycoprotein (10-13). After arriving at host cell, RNA strand undergo a reverse transcription to produce double strand DNA named provirus to insert it to host DNA randomly. After insertion whenever a mitotic division occurs for host cell, HTLV-1 genome replication occurs. By this way, HTLV-1 replication is completely dependent on host cell and not viral DNA polymerase, a way in which viral genome transcription is guaranteed accurately and causes high stability for HTLV-1 genome (14). When provirus is installed in host genome, permanent infection of cell establishes and the host cell undergoes a plenty of changes under influence of viral production. These changes are not harmful for host cell. Whether the infected person become a healthy appearance carrier or a severe case of spastic tetraparesis is partially dependent to the degree of peripheral blood mononuclear cells (PBMCs) loading of provirus.  Loading of 0.1 to 1% causes only a healthy carrier and loading rates up to 30% results in a HAM/TSP victim (15). Proviral loading is not correlated with sex or age but varies with duration of infection (16). Host factors including MHC class 1 variations and subsequent antigen presentation to CD8 T cells are more important for determination of proviral loading rather than HTLV-1 (17, 18). In opposite to HIV-1, HTLV-1 causes a low number of viruses in plasma due to lower rate of viral replication but with high loyalty in replication which results in high stability for HTLV-1 (19). Furthermore, HTLV-1 not only does not cause host cell death, but also it facilitates cell proliferation and transformation (20). ALT and HAM/TSP that caused by HTLV-1 are different in pathogenesis and route of transmission.  ALT is a malignant disorder of T cells transmitted via breastfeeding while HAM/TSP, which has an inflammatory foundation, is broadcast through blood transfusion. HTLV-1 can result in cellular transformation followed by ontogenetic alterations by means of viral products, which interact with host proteins mainly transcription factors and deviates their functions. The most critical molecule for pathogenesis of HTLV-1 and cell transformation is TAX, a phosphoprotein with 40 Kda weight (21-24).
Immunologic response to HTLV-1 is displayed in both cellular and humoral levels. Antibodies to gag, env and tax are manufactured in order of time respectively (25). TAX antibody seems to play an important role in HAM/TSP pathogenesis and there is a linear relation between higher TAX antibody and elevated proviral load and subsequently developing HAM/TSP (26). In cellular level, HTLV-specific cytotoxic T-lymphocytes (CTLs), which are found both in carriers and in associated-HTLV-1 ALT and HAM/TSP diseases, is essentially stimulated by TAX protein epitopes (27,28). It has been assumed that tha virus is able to escape from CTL killing duty by mutation in its TAX (29). Malfunction of CTLs in both diseases have been described (30-32).
The most common way of HTLV-1 transmission is breastfeeding followed by blood transfusion, needle sharing and high risk sexual behaviors. Vertical transmission causes clustering spreading of disease in defined geographical areas and special familial groups. HTLV-1 is endemic in many areas of the world including Southern Japan, Caribbean, South America, and Middle East, Southern and Central parts of Africa.  HTLV-1 prevalence is under 1% in non-endemic areas and ranges from 5% to more than 30% in endemic sites. Parallel to increased age, the prevalence increases as well especially in women, with twice as likely to be infected as men, probably due to ability for sexual transmission from men to women (33).
There is a low variability in viral genome among patients and even among viruses founded in diverse geographical areas (14). Higher common similarity in HLA class 1 type between mother and child increases the likelihood of vertical transmission (34).
The prevalence estimation of HTLV-1 is essentially according to seropositivity of volunteer of blood donation and particular population groups such as pregnant women,  IV drug  abusers, patients who need frequent blood transfusions such as hemophilia, thalassemia and patients who need hemodialysis. Different diagnostic tests and variable criteria for test result interpretation causes significant variation in estimation of HTLV-1 prevalence between different studies. A worldwide spreading of HTLV-1 is assumed to originate from Africa, where phylogenetic studies have approved its central parts as the cradle of all different primate T-lymphotrophic viruses including HTLV-1 (35, 36). It is assumed that broadcasting of these primitive viruses has happened 27300 years ago and derivation of HTLV-1 has occurred 21100 to 5300 years ago (37). The scattering of HTLV-1 in Asia is focused on Japan with more than 10% prevalence of general population in some areas of its southern parts (38,39) and Iran, Fujian, Taiwan and some parts of Chine with prevalence of 0.1% to 10% (40-42).
 
Current status of HTLV-1 in Iran
Eastern North of Iran is known as an endemic area for HTLV-1 since 1996 (43). Many studies have conducted to evaluate the HTLV-1 prevalence in general and in selected groups of population by different authors. Mashhad, Sabzevar and Neyshabour are studied for evaluation of HTLV-1 prevalence. In the first study published in 1996, Safai et al. reported 3% prevalence for HTLV-1 in Mashhad city in a population size of 696 people (13 subjects of lymphoma) (43). In the second study driven in 1999, the prevalence rate was 0.77% among 28926 healthy blood donors (42). Another study, in 2009 (published in 2011), confirmed Mashhad as an endemic area for HTLV-1 with a prevalence rate of 2.12% (44). Variability in the obtained results in these studies may be in part correlated with different applied diagnostic tests.
Sabzevar and Neyshabour, two other cities in Khorasan Razavi province neighbor to Mashhad, were studied for evaluating of HTLV-1 prevalence. Reported results in 2010 and 2012 showed 7.2% and 1.66% prevalence rate of HTLV-1 for Neyshabour and Sabzevar, respectively (45,46). The important parameters of these studies are presented in Table 1.
 Among demographic characters, the role of age and sex seems to be more important in these studies.
 According to Abedi et al. survey, the most important risk factor for HTLV-1 infection was medical injection medication such as dental procedure (85.7%) in Iran, followed by tattoo (10.1%), unsafe sexual behavior (7.9%) and transfusion of blood products (8.7%) (47). Repeated need to blood component transfusion put the patients in exposure of elevated risk to be infected by blood borne pathogens including HTLV-1 including hematologic patients and end-stage kidney disease patients that experience frequent hemodialysis in his or her lifelong. Increased risk groups such as patients with hemophilia, major thalassemia and hemodialysis-undergoing patients have been investigated for HTLV-1 prevalence in Iran. The characters of these studies are showed in Table 2.
As HTLV-1 displays an intracellular function necessarily, it seems cell-free blood products such as cryoprecipitate, fresh frozen plasma and coagulation factor concentrates remain intact and safe in blood transfusion (48,49).

Conclusion
HTLV-1 as a worldwide health problem has not recognized sufficiently up till now. There are no essential treatment for its main associated disorders except for symptomatic relief management and the lack of a substitute marker to follow up remains a challenge for clinical practitioners. Chronicity inherence of HTLV-1 infection in association with asymptomatic carriers who consist the majority of patients contribute to silent spreading of infection, particularly in frequent implication with blood transfusion, make its control hard if not impossible. Although there is not a precise drug to treat, meticulous blood screening protocols and recognizing infected nursing mothers remain the fundamental prophylactic implementation to control broadcasting of infection.

Acknowledgement
We would like to thank Clinical Research Development Center of Ghaem Hospital for their assistant in this manuscript. This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences for the research project as a medical student thesis with approval number of 911018.

Conflict of Interest
The authors declare no conflict of interest.

  1. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci. 1980;77:7415–7419.
  2. Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2.  Retrovirology. 2005;2-17.
  3. de The G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses. 1993;9:381–386.
  4. Takatsuki K. Discovery of adult T-cell leukemia. Retrovirology. 2005;2-16.
  5. Gessain A, Barin F, Vernant JC, et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985;2:407–410.
  6. Bangham CR. The immune control and cell-to-cell spread of human T-lymphotropic virus type 1. J Gen Virol. 2003;84:3177–3189.
  7. Mahieux R, Gessain A. The human HTLV-3 and HTLV-4 retroviruses: new members of the HTLV family. Pathol Biol. 2009;57:161-166.
  8. Ohtsuki Y, Akagi T, Takahashi K, et al. Ultrastructural study on type C virus particles in a human cord T-cell line established by co-cultivation with adult T-cell leukemia cells. Arch Virol. 1982;73:69–73.
  9. Gaudray G, Gachon F, Basbous J, et al. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76:12813-12822.
  10. Ghez D, Lepelletier Y, Lambert S, et al. Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol. 2006;80:6844-6854.
  11. Jones KS, Petrow-Sadowski C, Huang YK, et al. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med. 2008;14:429-436.
  12. Coskun AK, Sutton RE. Expression of glucose transporter 1 confers susceptibility to human T-cell leukemia virus envelope-mediated fusion. J Virol. 2005;79:4150-4158.
  13. Manel N, Kim FJ, Kinet S, et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell. 2003;115:449-459.
  14. Kakuda K, Ikematsu H, Chong WL, et al. Molecular epidemiology of human T lymphotropic virus type 1 transmission in Okinawa, Japan. Am J Trop Med Hyg. 2002; 66:404-408.
  15. Taylor GP, Tosswill JH, Matutes E, et al. Prospective study of HTLV-I infection in an initially asymptomatic cohort. J Acquir Immune Defic Syndr. 1999;22:92-100.
  16. Etoh K, Yamaguchi K, Tokudome S, et al. Rapid quantification of HTLV-I provirus load: detection of monoclonal proliferation of HTLV-I-infected cells among blood donors. Int J Cancer. 1999;81:859-864.
  17. Iga M, Okayama A, Stuver S, et al. Genetic evidence of transmission of human T cell lymphotropic virus type 1 between spouses. J Infect Dis. 2002;185:691-695.
  18. Jeffery KJ, Siddiqui AA, Bunce M, et al. The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol. 2000;165:7278-7284.
  19. Jeang KT, Widen SG, Semmes OJ 4th, et al. HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene. Science. 1990;247:1082-1084.
  20. Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998;93:81-91.
  21. Grassman R, Dengler C, Muller-Fleckenstein I, et al. Transformation to continuous growth of primary human T lymphocytes by human T cell leukemia virus type 1 X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci USA. 1989;87:3351-3355.
  22. Grassmann R, Berchtold S, Radant I, et al. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture. J Virol. 1992;66:4570-4575.
  23. Smith MR, Greene WC. Type I human T cell leukemia virus tax protein transforms rat fibroblasts through the cyclic adenosine monophosphate response element binding protein/activating transcription factor pathway. J Clin Invest. 1991;88:1038-1042.
  24. Tanaka A, Takahashi C, Yamaoka S, et al. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci USA. 1990;87:1071-1075.
  25. Manns A, Murphy EL, Wilks R, et al. Detection of early human T-cell lymphotropic virus type I antibody patterns during seroconversion among transfusion recipients. Blood. 1991;77:896-905.
  26. Kamihira S, Toriya K, Amagasaki T, et al. Antibodies against p40tax gene product of human T-lymphotropic virus type-I (HTLV-I) under various conditions of HTLV-I infection. Jpn J Cancer Res. 1989;80:1066-1071.
  27. Kannagi M, Harada S, Maruyama I, et al. Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. Int Immunol. 1991;3:761-767.
  28. Parker CE, Nightingale S, Taylor GP, et al. Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously. J Virol. 1994;68:2860-2866.
  29. Niewiesk S, Daenke S, Parker CE, et al. Naturally occurring variants of human T-cell leukemia virus type I Tax protein impair its recognition by cytotoxic T lymphocytes and the transactivation function of Tax. J Virol. 1995;69:2649-2654.
  30. Arnulf B, Thorel M, Poirot Y, et al. Loss of the ex vivo but not the reinducible CD8+ T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma. Leukemia. 2004;18:126-132.
  31. Wodarz D, Hall SE, Usuku K, et al. Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1. Proc Biol Sci. 2001;268:1215-1221.
  32. Sabouri AH, Usuku K, Hayashi D, et al. Impaired function of human T-lymphotropic virus type 1 (HTLV-1)-specific CD8+ T cells in HTLV-1-associated neurologic disease. Blood. 2008;112:2411-2420.
  33. Manns A, Hisada M, La Grenade L. Human T-lymphotropic virus type I infection. Lancet. 1999;353:1951-1958.
  34. Biggar RJ, Ng J, Kim N, et al. Human leukocyte antigen concordance and the transmission risk via breast-feeding of human T cell lymphotropic virus type I. J Infect Dis. 2006;193:277-282.
  35. Vandamme AM, Salemi M, Desmyter J. The simian origins of the pathogenic human T-cell lymphotropic virus type I. Trends Microbiol. 1998;6:477-483.
  36. Van Dooren S. Central Africa: cradle of divergent PTLV types.  AIDS Reviews. 2005;7:126-127.
  37. Holmgren B, da Silva Z, Larsen O, et al. Dual infections with HIV-1, HIV-2 and HTLV-I are more common in older women than in men in Guinea-Bissau. AIDS. 2003;17:241-253.
  38. Matsuzaki T, Otose H, Hashimoto K, et al. Diseases among men living in human T-lymphotropic virus type I endemic areas in Japan. Intern Med. 1993;32:623–628.
  39. Kishihara Y, Furusyo N, Kashiwagi K, et al. Human T lymphotropic virus type 1 infection infl uences hepatitis C virus clearance. J Infect Dis.2001;184:1114–1119.
  40. Lu SC, Chen BH. Seroindeterminate HTLV-1 prevalence and characteristics in blood donors in Taiwan. Int J Hematol. 2003;77:412–413.
  41. Wang Y, Li X, Song A, et al. Prevalence and partial sequence analysis of human T cell lymphotropic virus type I in China. J Med Virol. 2005;76:613-618.
  42. Abbaszadegan MR, Gholamin M, Tabatabaee A, et al. Prevalence of human T-lymphotropic virus type 1 among blood donors from Mashhad, Iran. J Clin Microbiol. 2003;41:2593-2595.
  43. Safai B, Huang JL, Boeri E, et al. Prevalence of HTLV type I infection in Iran: a serological and genetic study. AIDS Res Hum Retroviruses. 1996;12:1185-1190.
  44. Rafatpanah H, Hedayati-Moghaddam MR, Fathimoghadam F, et al. High prevalence of HTLV-I infection in Mashhad, Northeast Iran: a population-based seroepidemiology survey. J Clin Virol. 2011;52:172-176.
  45. Hedayati-Moghaddam MR, Fathimoghadam F,  Eftekharzadeh Mashhadi I, et al. Epidemiology of HTLV-1 in Neyshabour, Northeast of Iran. Iran Red Crescent Med J. 2011;13:424-427.
  46. Azarpazhooh MR, Hasanpour K, Ghanbari M, et al. Human T-lymphotropic virus type 1 prevalence in northeastern Iran, Sabzevar: an epidemiologic-based study and phylogenetic analysis. AIDS Res Hum Retroviruses. 2012;28:1095-1101.
  47. Abedi F, Hamidipour S. What the major disorder in Iranian HTLV-I infected patients in compare with other HTLV-1 infected patients? 2010.
  48. Hjelle B, Mills R, Mertz G, et al. Transmission of HTLV-1 via blood transfusion. Vox Sang. 1990;59:119–122.
  49. 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;46:245-253.
  50. Abedi F, Hamidipour S. Predominant Epidemiologic Patterns of HTLV-I in Endemic Area of Iran, The First International Congress on HTLV-I and Associated Diseases in Iran,2009,winter.     
  51. Abedi F, Shakibzade A, Khalvati B, et al. Phylogeny and molecular epidemiology of HTLV in Hormozgan province. 2009.
  52. Abedi F, Yavarian M, Shakibzade A, et al. A seroepidemiologic study of HTLV in hemophilia and thalassemic patients and hemodialysis undergoing patients in Hormozgan province. Hormozgan Med jor. 2009;13:75-80.
  53. Karimi A, Nafici MR, Imani R. Comparison of human T- cell leukemia virus type-1(HTLV-1) seroprevalence in high risk patients (thalassemia and hemodialysis) and healthy individuals from Charmahal - Bakhtiari Province, Iran. Kuwait Med J. 2007,39:259-261.
  54. Khameneh ZR, Baradaran M, Sepehrvand N. Survey of the seroprovalence of HTLV I/II in hemodialysis patients and blood donors in Urmia. Saudi J Kidney Dis Transpl. 2008;19:838-841.
  55. Ghadiri K, Hashemian AH, Rezaei M, et al. serologic prevalence of human T-lymphotrophic virus (HTLV) among major thalassemic patients in Kermanshah 2010. Int J Hem Onc Stem cell Res. 2011;5:14-17.
  56. Mortezaie Z, Bouzari M, Roghanian R. Evaluating the frequency of HTLV-Ι/II infection among blood donors, major thalassemic patients and individuals infected with hepatitis B and C viruses in Isfahan, Iran. IJBC. 2012;1:169-175.
  57. Ghaffari J, Kowsarian M, Mahdavi MR, et al. Prevalence of HTLV-1infection in patients with thalassemia major in Mazandaran, north of Iran. Jundishapur J Microbiol. 2013;6:57-60.
  58. Ghaffari J, Ebrahimi M, Makhlough A. Seroepidemiology of human T-cell lymphotropic virus 1infection in hemodialysis patients, should we be concerned about it? IJKD. 2013;7:187-190.