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Vol. 25. Issue 3.
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Vol. 25. Issue 3.
(May - June 2021)
Review Article
Open Access
Pathogenesis of HTLV-1 infection and progression biomarkers: An overview
Carlos Britesa, Maria Fernanda Grassib, Juarez Antônio Simões Quaresmac, Ricardo Ishakd, Antonio Carlos Rosário Vallinotod,
Corresponding author

Corresponding author.
a Federal University of Bahia (UFBA), Professor Edgard Santos University Hospital Complex, Laboratory of Infectious Diseases Research, Salvador, BA, Brazil
b Oswaldo Cruz Foundation, Advanced Laboratory of Public Health, Salvador, BA, Brazil
c Federal University of Pará (UFPA), Nucleus of Tropical Medicine, Belém, PA, Brazil
d Federal University of Pará (UFPA), Institute of Biological Sciences, Laboratory of Virology, Belém, PA, Brazil
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Infection by human T-cell lymphotropic virus type 1 (HTLV-1) occurs in lymphocytes, which travel throughout the body, thus affecting several target organs and causing varied clinical outcomes, particularly in populations that are underserved and do not have access to healthcare. However, the mechanism of pathogenesis is not yet fully understood. The TAX and HTLV-1 basic leucine zipper factor (HBZ) proteins maintain viral persistence and affect pathogenesis through cell proliferation and immune and inflammatory responses that accompany each clinical manifestation. TAX expression leads to inhibition of transcription error control, OX40 overexpression, and cell proliferation in adult T-cell leukemia (ATL). OX40 levels are elevated in the central nervous system (CNS), and the expression of TAX in the CNS causes neuronal damage and loss of immune reactivity among patients with HTLV-1-associated myelopathy (HAM). HBZ reduces viral replication and suppresses the immune response. Its cell compartmentalization has been associated with the pathogenesis of HAM (cytoplasmic localization) and ATL (nuclear localization). TAX and HBZ seem to act antagonistically in immune responses, affecting the pathogenesis of HTLV-1 infection. The progression from HTLV-1 infection to disease is a consequence of HTLV-1 replication in CD4+ T and CD8+ T lymphocytes and the imbalance between proinflammatory and anti-inflammatory cytokines. The compartmentalization of HBZ suggests that this protein may be an additional tool for assessing immune and inflammatory responses, in addition to those already recognized as potential biomarkers associated with progression from infection to disease (including human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), interleukin (IL)-6, IL-10, IL-28, Fas, Fas ligand, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and mannose-binding lectin).

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Human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus described in lymphocytes from a patient with cutaneous T-cell lymphoma [1,2], followed by the identification of human T-cell lymphotropic virus type 2 (HTLV-2) in a patient with hairy cell leukemia and/or hairy cell tricholeukemia [3]. HTLV-3 and HTLV-4 have also been described in isolated areas of forests in the Republic of Cameroon [4,5]; however, to date, they have not been found in other geographic areas or related to clinical manifestations [6,7]. There are at least six HTLV-1 molecular subtypes (a, b, c, d, e, f) [8–10] and four HTLV-2 molecular subtypes (a, b, c, d) [11–13].

HTLV-1/2 are classified in the family Retroviridae and genus Deltaretrovirus. The viral particle is spherical and enveloped, measuring between 100 and 120 nm [14,15] (Fig. 1). The glycoproteins gp21 and gp46 are located in the viral envelope and are important for viral binding to the cell receptor and for envelope fusion with the cell membrane [11,16–19]. The protein capsid (formed by p15, p19, and p24) contains the viral genome, composed of two RNA molecules (single-stranded, positive polarity, and identical) [19-21], protease, reverse transcriptase (RT), integrase, and RNAse H, enzymes that facilitate viral replication [19,21,22]. RT is responsible for the transcription of single-stranded RNA into a double-stranded DNA molecule, which integrates into the genome of the host cell, becoming proviral DNA [19,21,23].

Fig. 1.

Schematic representation of the morphological components of HTLV-1/2. The nucleocapsid is composed of capsid proteins (p24 – genome protection), viral genomic RNA (ssRNA+ - genetic code), reverse transcriptase (p55 – RNA reverse transcription), protease (p10 - hydrolysis of viral peptides), and integrase (p32 – DNA proviral integration). The viral matrix is composed of the p19 protein and surrounds the nucleocapsid. The viral envelope is externally composed of a lipid bilayer plus the viral glycoproteins gp21 and gp46.


HTLV-1/2 share molecular and biological characteristics [11,21,24], and the integration of viral nucleic acids into the cellular genome establishes viral persistence and maintains and transmits the virus, which determines the various outcomes of infection [21].

HTLV-1/2 infect lymphocytes that are found in various body fluids, including blood, semen, vaginal secretions, and breast milk. The virus, which affects several target organs, is transmitted by blood and blood component transfusion, use of injectable drugs, organ transplantation, and unprotected sex [25–30]. There is therefore great variability in clinical manifestations associated with infection [31].

The mechanism of HTLV-1 pathogenesis is not yet fully understood. Among all of the regulatory proteins encoded by proviral DNA, the proteins TAX and HTLV-1 basic leucine zipper factor (HBZ) are essential for maintaining viral persistence and pathogenesis, possibly by inducing cell proliferation associated with the induction of immune responses [32].

HTLV-1 is a viral infectious agent with unique biological characteristics and diverse clinical manifestations. Because it still goes unnoticed in human populations, it is important to recognize the disease mechanisms previously associated with infection that result in the various known clinical manifestations.

The present review describes the main aspects of the immunopathogenesis of diseases associated with HTLV-1; it highlights the role of the viral proteins TAX and HBZ in the control of cell proliferation and activation of immune and inflammatory responses, and describes the multifactorial nature of diseases related to infection associated with the presence of immunogenic biomarkers in the host.

The role of HBZ and TAX in HTLV-1 infection

Two HTLV-1 genes, TAX and HBZ, are extremely important in determining the infectivity of HTLV-1 and the leukemogenic process through regulation of the growth and survival of tumor cells [33–35]. TAX is an immunodominant HTLV-1 antigen with transformation and transactivation activities and is associated with dysregulation of immune responses in patients with HTLV-1-associated myelopathy (HAM), which leads to the main immunological changes observed in these patients [36–37]. TAX expression leads to persistent cell proliferation characterized by abnormal expansion of infected cells, generating DNA lesions characteristic of adult T-cell leukemia/lymphoma (ATLL) [38–41]. Inhibition of cell checkpoint activity to control transcription errors allows the proliferation of infected cells with damaged DNA [32].

TAX is involved in the overexpression of OX40, a member of the TNF receptor costimulation family capable of promoting proliferation and survival of effector and memory T cells and suppressing differentiation and activity of T regulatory cells (Tregs) [42]. Elevated levels of soluble OX40 have been detected in the central nervous system (CNS) of patients with HAM [43]. Expression of TAX in the CNS of patients with HAM can lead to direct or indirect neuronal damage through the loss of cells capable of activating and generating a specific immune response against TAX [44].

An association between a higher frequency of TAX-specific CD8+ T cells in the CNS of patients with HAM has been described, suggesting the active participation of these cells in the pathogenesis of the disease [45,46]. The presence of intrathecal antibodies against HTLV-1 has been associated with protective and pathogenic effects. Although the levels of intrathecal antibodies specific for HTLV-1 are inversely correlated with the proviral load, antibodies against TAX and Gag may cross-react with CNS tissues and lead to neurological damage [47–49].

Similar to TAX, HBZ is an immunogenic protein recognized by specific cytotoxic cell clones [50,51]. Expression of the HBZ protein induces a reduction in viral replication and suppression of immune responses [52–54]. HBZ is present in cells infected with HTLV-1, in both asymptomatic carriers and patients with HAM or ATL, and promotes the growth and survival of leukemic cells [55]. HBZ expression increases HTLV-1 infectivity, cell proliferation, and lymphoma [54,56]. Localization of HBZ in the nucleus suggests that HTLV-1 may increase viral persistence by reducing the translation of HBZ so that infected cells escape the immune response directed to this protein [57]. In turn, localization of HBZ in the cytoplasm of peripheral blood mononuclear cells (PBMCs) of patients with HAM occurs almost exclusively in CD4+ T cells and is independent of coexpression of CD25 [58]. These findings suggest that HBZ expression can be compartmentalized or co-occur with TAX expression, facilitating evasion of the virus from the host immune system and contributing to the pathogenesis of HAM.

The role of HBZ associated with its nuclear or cytoplasmic localization is related to the increased risk of developing HAM or ATLL. The intensity of the immune response and HBZ activation define the type of behavior of HTLV-1 infection [58]. The correlation between the intracellular compartmentation of the HBZ protein and the clinical outcomes of infection was reported, and it was proposed that the cytoplasmic presence of HBZ in leukocytes of patients with HAM is a biomarker of progression from infection to disease [39,58].

The available data suggest a crucial role of TAX and HBZ in the immune changes found in patients with HAM; however, the mechanism involved in the expression and regulation of these genes is still poorly understood. The most recent evidence indicates that TAX and HBZ exhibit antagonistic behaviors [59], with the action of HBZ being central in the pathogenesis of HTLV-1 infection; through its pleiotropic functions, HBZ initiates a viral strategy to increase the effectiveness of cell-to-cell transmission.


HTLV-1 infects different cell types (dendritic cells, macrophages, monocytes, CD8+ T lymphocytes) but mainly CD4+ T lymphocytes, which act as reservoirs for the virus [60]. In CD4+ T lymphocytes, HTLV-1 can remain latent for a long period [61] by maintaining a low rate of replication, which can cause genetic changes, induce cell proliferation, or even damage the CNS as the result of an inflammatory immune response [62–64].

Infection of CD4+ T and CD8+ T lymphocytes plays an important role in the immunopathogenesis of HAM [46,65] because it induces the production of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β, IL-12, and IL-6, which are involved in the mediation of inflammatory immune responses observed in infection [66,67,68]. Inflammatory chemokines, such as CXCL9 and CXCL-10, are also involved in the pathogenesis of HAM [69].

According to Hӧllsberg (1997), the pathophysiology of HAM is explained by three main mechanisms [70]: direct toxicity, autoimmunity, and surrounding damage. In the direct or cytotoxic toxicity theory, glial cells infected by HTLV-1 express surface viral antigens, and specific cytotoxic CD8+ T cells cross the blood-brain barrier to destroy infected glial cells through direct cytotoxic activity or the release of cytokines [71,72]. In turn, the autoimmunity theory suggests that a host antigen mimics an HTLV-1 antigen and triggers an autoimmune inflammatory process, resulting in neural injury [73,74]. The surrounding damage theory suggests that anti-HTLV-1-specific CD4+ T and CD8+ T lymphocytes migrate through the blood-brain barrier, reaching the CNS, where glial cells undergo cell damage because of the release of cytokines in response to lymphocytes infected by HTLV-1 [46,75–78].

TNF-α and INF-γ, which are secreted by CD4+ T lymphocytes (Th1 subpopulation), are the cytokines with the highest concentration in the cerebrospinal fluid (CSF) of patients with HAM [79]. Furthermore, other studies have shown that in addition to the predominance of Th1 cytokines (TNF-α, IFN-γ, IL-12), Th2 cytokines (IL-4, IL-10) are decreased in patients with neurological disease [66,80]. Patients with HAM show increased number of CD4+ T lymphocytes (Th1 subpopulation), with a higher proportion of IFN-γ- and TNF-α-producing cells than IL-10-producing cells [81]. This increase is also observed for CD8+ T lymphocytes that express the same cytokine pattern. A classification of disease activity in patients with HAM was proposed based on the concentration of CXCL10 and neopterin in the CSF. Patients with high levels of these cytokines have greater disease activity and appear to benefit most from the use of anti-inflammatory treatment [82–84]. Asymptomatic HTLV-1 carriers have an immunoregulatory mechanism characterized by increased IL-10 cytokine levels as a way to counteract the effects of TNF-α [65,81].

Asymptomatic patients with a high proviral load, as well as those with HAM, have higher IFN-γ expression than IL-10 expression [85,86], whereas asymptomatic patients with a low proviral load have similar levels of IFN-γ and IL-10 expression. This finding suggests that the imbalance between proinflammatory and anti-inflammatory cytokines is related to the development of HAM; that is, the pattern of the immune response in the host cell to HTLV-1 infection, combined with a high proviral load, may be important for the development of this severe neurological disease [65,87]. Recently, it was reported that the increased expression of adhesion molecules, such as CD49d, in T lymphocytes may contribute to the pathogenesis of HTLV-1-associated neurological disease in both asymptomatic and oligosymptomatic individuals [88].

Immunogenic profile of the host

The interaction mechanisms of HTLV-1 with host responses and immunogenetic characteristics are important factors in the pathogenesis of HAM, ATLL, and other clinical manifestations associated with HTLV-1. It is still unknown why some individuals develop severe HAM or ATLL, others have moderate disease, and many others are asymptomatic. HTLV-1 is a genetically stable virus, and the same viral strain can generate various clinical outcomes. Numerous data on host genetic variations associated with immune responses to HTLV-1 infection, including human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), IL-6, IL-10, IL-28, Fas, Fas ligand, IFN-γ, TNF-α, and mannose-binding lectin, have been described as potential biomarkers associated with progression from infection to disease [89-91].

Recently, one study reported an association between polymorphisms in the TREX and SAMHD1 genes and increased proviral load of HTLV-1 among people with HAM [92,93]; similar results had also been described previously [88,94–96]. These data reinforce the need for further epidemiological genetic studies involving a larger number of people infected with HTLV-1 to better understand the effect of these markers on the pathogenesis and natural history of HAM.

There is also evidence of an association between genetic biomarkers and ATLL; that is, the genetic profile of the host can contribute to prognosis and can be an important additional tool in the management of affected individuals if properly implemented in endemic areas [97–101]. This finding demonstrates the importance of implementing these approaches in our environment.

HTLV-1 has a wide variety of interactions with the host and is associated with clinical manifestations that may involve the CNS, blood, eyes, skin, lungs, joints, intestine, bladder, thyroid, and heart, among other organs and systems [31]. The clinical complexity of the infection requires multidisciplinary care of the infected patient. Although the frequency of unfavorable clinical outcomes of HTLV-1 infections is considered low (5-10%), HTLV-1 infection may be associated with other clinical processes that need to be better defined. [102–104]. The increased frequency of reports of diseases associated with HTLV-2 [3,94,105–111] requires attention to rule out the participation of HTLV-2 in clinical outcomes, especially in areas endemic for this virus [112].

Summary and perspectives

HTLV-1 induces a persistent chronic infection. The development of associated diseases, such as HAM and ATLL, is multifactorial, involving factors related to the virus and to the immune and inflammatory responses of the host. The virus induces genetic changes in infected cells, cell proliferation, and even CNS injury from inflammatory immune responses. The genetic profile of the host is clearly associated with the balance between inflammatory and regulatory responses, predisposing or protecting against inflammatory diseases, such as HAM, caused by the virus. The development of ATLL is also related to the immunogenetic profile of individuals. Identification of prognostic markers in HTLV-1 infection is essential for predicting clinical outcomes and developing strategies for their prevention and management. In this sense, genome-wide association studies (GWAS) should be performed to screen possible new biomarkers.

A high HTLV-1 proviral load, HBZ, and some inflammatory cytokines are potential biomarkers for the development of diseases associated with HTLV-1.


We thank the Health Surveillance Secretariat from the Department of Diseases of Chronic Conditions and Sexually Transmitted Infections of the Ministry of Health of Brazil, the National Council for Scientific and Technological Development (CNPQ - Grant #301869/2017-0 ACRV; #312979/2018-5 RI; #304811/2017-3 MFRG), and the National Foundation for the Development of Private Higher Education – FUNADESP (, grant #9600140 MFRG.

BJ Poiesz, FW Ruscetti, AF Gazdar, 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 U S A, 77 (1980), pp. 7415-7419
BJ Poiesz, FW Ruscetti, MS Reitz, et al.
Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia.
Nature, 294 (1981), pp. 268-271
VS Kalyanaraman, MG Sarngadharan, M Robert-Guroff, et al.
A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia.
Science, 218 (1982), pp. 571-573
S Calattini, SA Chevalier, R Duprez, et al.
Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa.
Retrovirology, 2 (2005), pp. 30
ND Wolfe, W Heneine, JK Carr, et al.
Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters.
Proc Natl Acad Sci U S A, 102 (2005), pp. 7994-7999
YT Duong, H Jia, JA Lust, et al.
Short communication: absence of evidence of HTLV-3 and HTLV-4 in patients with large granular lymphocyte (LGL) leukemia.
AIDS Res Hum Retroviruses, 24 (2008), pp. 1503-1505
R Perzova, P Benz, L Abbott, et al.
Short communication: no evidence of HTLV-3 and HTLV-4 infection in New York State subjects at risk for retroviral infection.
AIDS Res Hum Retroviruses, 26 (2010), pp. 1229-1231
T Miura, T Fukunaga, T Igarashi, et al.
Phylogenetic subtypes of human T-lymphotropic virus type I and their relations to the anthropological background.
Proc Natl Acad Sci U S A, 91 (1994), pp. 1124-1127
A Talarmin, B Vion, A Ureta-Vidal, et al.
First seroepidemiological study and phylogenetic characterization of human T-cell lymphotropic virus type I and II infection among Amerindians in French Guiana.
J Gen Virol, 80 (1999), pp. 3083-3088
S Van Dooren, M Salemi, AM. Vandamme.
Dating the origin of the African human T-cell lymphotropic virus type-i (HTLV-I) subtypes.
WW Hall, R Ishak, SW Zhu, et al.
Human T lymphotropic virus type II (HTLV-II): epidemiology, molecular properties, and clinical features of infection.
J Acquir Immune Defic Syndr Hum Retrovirol, 13 (1996), pp. S204-S214
R Ishak, WJ Harrington Jr, VN Azevedo, et al.
Identification of human T cell lymphotropic virus type iia infection in the Kayapo, an indigenous population of Brazil.
AIDS Res Hum Retroviruses, 11 (1995), pp. 813-821
AM Vandamme, M Salemi, M Van Brussel, et al.
African origin of human T-lymphotropic virus type 2 (HTLV-2) supported by a potential new HTLV-2d subtype in Congolese Bambuti Efe Pygmies.
International Committee on Taxonomy of Viruses (ICTV). <⁣tv_id=19911434>. Accessed 3 October, 2020.
MS Barski, JJ Minnell, Z Hodakova, et al.
Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit b56γ.
Nat Commun, 11 (2020), pp. 5043
MS Reitz Jr, L Hall, M Robert-Guroff, et al.
Viral variability and serum antibody response in a laboratory worker infected with HIV type 1 (HTLV type IIIB).
AIDS Res Hum Retroviruses, 10 (1994), pp. 1143-1155
S Cao, JO Maldonado, IF Grigsby, et al.
Analysis of human T-cell leukemia virus type 1 particles by using cryo-electron tomography.
J Virol, 89 (2015), pp. 2430-2435
AK Coskun, RE. Sutton.
Expression of glucose transporter 1 confers susceptibility to human T-cell leukemia virus envelope-mediated fusion.
KH Fogarty, W Zhang, IF Grigsby, et al.
New insights into HTLV-1 particle structure, assembly, and Gag-Gag interactions in living cells.
Viruses, 3 (2011), pp. 770-793
F. Tangy.
Molecular Biology of HTLV-I.
HTLV, truths and questions, Cali, Feriva Editores, (1996), pp. 1-13
MP Martinez, J Al-Saleem, PL. Green.
Comparative virology of HTLV-1 and HTLV-2.
Retrovirology, 16 (2019), pp. 21
V.M. Vogt.
Retroviral virions and genomes.
Retroviruses, Cold Spring Harbor Laboratory Press, (1997),
M Seiki, S Hattori, Y Hirayama, et al.
Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA.
Proc Natl Acad Sci U S A, 80 (1983), pp. 3618-3622
LJ Seigel, WG Nash, BJ Poiesz, et al.
Dynamic and nonspecific dispersal of human T-cell leukemia/lymphoma virus type-I integration in cultured lymphoma cells.
A Manns, RJ Wilks, EL Murphy, et al.
A prospective study of transmission by transfusion of HTLV-I and risk factors associated with seroconversion.
Int J Cancer, 51 (1992), pp. 886-891
M Moriuchi, H. Moriuchi.
Seminal fluid enhances replication of human T-cell leukemia virus type 1: implications for sexual transmission.
LB Cook, A Melamed, MA Demontis, et al.
Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients.
Retrovirology, 13 (2016), pp. 3
C de Mendoza, L Roc, R Benito, et al.
HTLV-1 infection in solid organ transplant donors and recipients in Spain.
BMC Infect Dis, 19 (2019), pp. 706
MD Lairmore, R Anupam, N Bowden, et al.
Molecular determinants of human T-lymphotropic virus type 1 transmission and spread.
Viruses, 3 (2011), pp. 1131-1165
C Rosadas, GP. Taylor.
Mother-to-Child HTLV-1 transmission: unmet research needs.
Front Microbiol, 10 (2019), pp. 999
M Boxus, L. Willems.
Mechanisms of HTLV-1 persistence and transformation.
Br J Cancer, 101 (2009), pp. 1497-1501
G Schierhout, S Mcgregor, A Gessain, et al.
Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies.
Lancet Infect Dis, 20 (2020), pp. 133-143
Y Enose-Akahata, A Vellucci, S. Jacobson.
Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP.
Front Microbiol, 8 (2017), pp. 2563
S Mohanty, EW. Harhaj.
Mechanisms of oncogenesis by HTLV-1 Tax.
Pathogens, 9 (2020), pp. 543
K Yamada, H Miyoshi, N Yoshida, et al.
Human T-cell lymphotropic virus HBZ and tax mrna expression are associated with specific clinicopathological features in adult T-cell leukemia/lymphoma.
Mod Pathol, 34 (2021), pp. 314-326
S Jacobson, H Shida, DE Mcfarlin, et al.
Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I px in patients with HTLV-I associated neurological disease.
Nature, 348 (1990), pp. 245-248
V Ciminale, F Rende, U Bertazzoni, et al.
HTLV-1 and HTLV-2: highly similar viruses with distinct oncogenic properties.
Front Microbiol, 5 (2014), pp. 398
Y Yamano, M Nagai, M Brennan, et al.
Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mrna with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP).
R. Harrod.
Silencers of HTLV-1 and HTLV-2: the px-encoded latency-maintenance factors.
Retrovirology, 16 (2019), pp. 25
H Kinosada, JI Yasunaga, K Shimura, et al.
Correction: HTLV-1 bzip Factor Enhances T-cell proliferation by impeding the suppressive signaling of co-inhibitory receptors.
S Fochi, V Ciminale, E Trabetti, et al.
NF-κb and microrna Deregulation Mediated by HTLV-1 Tax and HBZ.
Pathogens, 8 (2019), pp. 290
M Croft, T So, W Duan, et al.
The significance of OX40 and OX40L to T-cell biology and immune disease.
Immunol Rev, 22 (2009), pp. 173-191
M Saito, R Tanaka, S Arishima, et al.
Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.
Retrovirology, 10 (2013), pp. 51
F Medina, S Quintremil, C Alberti, et al.
Tax posttranslational modifications and interaction with calreticulin in MT-2 cells and human peripheral blood mononuclear cells of human T cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.
AIDS Res Hum Retroviruses, 30 (2014), pp. 370-379
TF Greten, JE Slansky, R Kubota, et al.
Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients.
Proc Natl Acad Sci U S A, 95 (1998), pp. 7568-7573
M Nagai, R Kubota, TF Greten, et al.
Increased activated human T cell lymphotropic virus type I (HTLV-I) Tax11-19-specific memory and effector CD8+ cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with HTLV-I provirus load.
J Infect Dis, 183 (2001), pp. 197-205
M Puccioni-Sohler, M Rios, C Bianco, SW Zhu, et al.
An inverse correlation of HTLV-I viral load in CSF and intrathecal synthesis of HTLV-I antibodies in TSP/HAM.
Neurology, 3 (1999), pp. 1335-1339
MC Levin, SM Lee, F Kalume, et al.
Autoimmunity due to molecular mimicry as a cause of neurological disease.
Nat Med, 8 (2002), pp. 509-513
S Lee, Y Shin, J Marler, et al.
Post-translational glycosylation of target proteins implicate molecular mimicry in the pathogenesis of HTLV-1 associated neurological disease.
J Neuroimmunol, 204 (2008), pp. 140-148
A Macnamara, A Rowan, S Hilburn, et al.
HLA class I binding of HBZ determines outcome in HTLV-1 infection.
Y Higuchi, JI Yasunaga, Y Mitagami, et al.
HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling.
Proc Natl Acad Sci U S A, 117 (2020), pp. 13740-13749
Y Satou, J Yasunaga, M Yoshida, et al.
HTLV-I basic leucine zipper factor gene mrna supports proliferation of adult T cell leukemia cells.
Proc Natl Acad Sci U S A., 103 (2006), pp. 720-725
M Saito, T Matsuzaki, Y Satou, et al.
In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP).
Retrovirology, 6 (2009), pp. 19
Y Satou, M. Matsuoka.
Molecular and Cellular Mechanism of Leukemogenesis of ATL: Emergent Evidence of a Significant Role for HBZ in HTLV-1-Induced Pathogenesis.
Leuk Res Treatment, 2012 (2012),
T Usui, K Yanagihara, K Tsukasaki, et al.
Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells.
Retrovirology, 5 (2008), pp. 34
J Arnold, B Zimmerman, M Li, et al.
Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation.
Blood, 112 (2008), pp. 3788-3797
F Rende, I Cavallari, A Corradin, et al.
Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mrnas.
Blood, 117 (2011), pp. 4855-4859
M Baratella, G Forlani, GU Raval, et al.
Cytoplasmic Localization of HTLV-1 HBZ Protein: A Biomarker of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).
A Akkouche, S Moodad, R Hleihel, et al.
In vivo antagonistic role of the human T-cell leukemia virus type 1 regulatory proteins Tax and HBZ.
Y Koyanagi, Y Itoyama, N Nakamura, et al.
In vivo infection of human T-cell leukemia virus type I in non-T cells.
Virology, 196 (1993), pp. 25-33
AQ Araujo, MT. Silva.
The HTLV-1 neurological complex.
Lancet Neurol, 5 (2006), pp. 1068-1076
K Etoh, S Tamiya, K Yamaguchi, et al.
Persistent clonal proliferation of human T-lymphotropic virus type i-infected cells in vivo.
Cancer Research, 57 (1997), pp. 4862-4867
L. Farre.
Patogênese da Leucemia/Linfoma de células T do Adulto (ATL).
Gazeta Médica da Bahia, 79 (2009), pp. 18-24
I Olah, LM Fukumori, P Montanheiro, et al.
Patterns of in vitro lymphoproliferative responses among HTLV-1-infected subjects: upregulation by HTLV-1 during HIV-1 co-infection.
Scand J Immunol, 65 (2007), pp. 577-580
DU Goncalves, FA Proietti, EF Barbosa-Stancioli, et al.
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) inflammatory network.
Inflamm Allergy Drug Targets, 7 (2008), pp. 98-107
J Ahuja, V Lepoutre, B Wigdahl, et al.
Induction of pro-inflammatory cytokines by human T-cell leukemia virus type-1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells.
Biomed Pharmacother, 61 (2007), pp. 201-208
P Montanheiro, MP Vergara, J Smid, et al.
High production of RANTES and MIP-1alpha in the tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM).
J Neuroimmunol, 188 (2007), pp. 138-142
PA Montanheiro, AC Penalva de Oliveira, J Smid, et al.
The elevated interferon gamma production is an important immunological marker in HAM/TSP pathogenesis.
Scand J Immunol, 70 (2009), pp. 403-407
M Guerra, T Luna, A Souza, et al.
Local and systemic production of proinflammatory chemokines in the pathogenesis of HAM/TSP.
Cell Immunol, 334 (2018), pp. 70-77
P. Höllsberg.
Pathogenesis of chronic progressive myelopathy associated with human T-cell lymphotropic virus type I.
Acta Neurol Scand Suppl, 169 (1997), pp. 86-93
S Ijichi, M. Osame.
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP): recent perspectives.
Intern Med, 34 (1995), pp. 713-721
MC Levin, S. Jacobson.
HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP): a chronic progressive neurologic disease associated with immunologically mediated damage to the central nervous system.
J Neurovirol, 3 (1997), pp. 126-140
T Furuya, T Nakamura, H Goto, et al.
HTLV-I-associated myelopathy associated with multi-organ inflammatory disease: a case report.
J Neurol Sci, 157 (1998), pp. 109-112
SM Lee, Y Morcos, H Jang, et al.
HTLV-1 induced molecular mimicry in neurological disease.
Curr Top Microbiol Immunol, 296 (2005), pp. 125-136
K Endo, T. Tsukamoto.
Experimental bystander encephalitis induced by immunization with HTLV-I-producing T cells in mice.
Acta Neurol Scand, 96 (1997), pp. 106-113
PK Goon, T Igakura, E Hanon, et al.
High circulating frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4+ T cells in patients with HTLV-1-associated neurological disease.
R Kubota, Y Furukawa, S Izumo, et al.
Degenerate specificity of HTLV-1-specific CD8+ T cells during viral replication in patients with HTLV-1-associated myelopathy (HAM/TSP).
Blood, 101 (2003), pp. 3074-3081
M. Osame.
Pathological mechanisms of human T-cell lymphotropic virus type I-associated myelopathy (HAM/TSP).
J Neurovirol, 8 (2002), pp. 359-364
I Best, G López, K Verdonck, et al.
IFN-gamma production in response to Tax 161-233, and frequency of CD4+ Foxp3+ and Lin HLA-drhigh CD123+ cells, discriminate HAM/TSP patients from asymptomatic HTLV-1-carriers in a Peruvian population.
Immunology, 128 (2009), pp. e777-e786
Y Yamano, N Araya, T Sato, et al.
Abnormally high levels of virus-infected IFN-gamma+ CCR4+ CD4+ CD25+ T cells in a retrovirus-associated neuroinflammatory disorder.
GE Brito-Melo, V Peruhype-Magalhães, A Teixeira-Carvalho, et al.
IL-10 produced by CD4+ and CD8+ T cells emerge as a putative immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha and guarantee asymptomatic clinical status during chronic HTLV-I infection.
Clin Exp Immunol, 147 (2007), pp. 35-44
T Sato, A Coler-Reilly, A Utsunomiya, et al.
CSF CXCL10, CXCL9, and neopterin as candidate prognostic biomarkers for HTLV-1-associated myelopathy/tropical spastic paraparesis.
Plos Negl Trop Dis, 7 (2013), pp. e2479
K Tamaki, T Sato, J Tsugawa, et al.
Cerebrospinal fluid CXCL10 as a candidate surrogate marker for HTLV-1-associated myelopathy/tropical spastic paraparesis.
Front Microbiol, 10 (2019), pp. 2110
J Yamauchi, T Sato, N Yagishita, et al.
Use of cerebrospinal fluid CXCL10 and neopterin as biomarkers in HTLV-1-associated myelopathy/tropical spastic paraparesis treated with steroids.
J Neurol Neurosurg Psychiatry, 91 (2020), pp. 321-323
OM Espíndola, LC Oliveira, PM Ferreira, et al.
High IFN-γ/IL-10 expression ratio and increased frequency of persistent human T-cell lymphotropic virus type 1-infected clones are associated with human T-cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis development.
Intervirology, 58 (2015), pp. 106-114
HR Bidkhori, MR Hedayati-Moghaddam, A Mosavat, et al.
The IL-18, IL-12, and IFN-γ expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, HTLV-1 carriers, and healthy subjects.
J Neurovirol, 26 (2020), pp. 338-346
MF Grassi, VN Olavarria, A Kruschewsky R de, et al.
Human T cell lymphotropic virus type 1 (HTLV-1) proviral load of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients according to new diagnostic criteria of HAM/TSP.
J Med Virol, 83 (2011), pp. 1269-1274
LTA Janahú, CA Da Costa, ACR Vallinoto, et al.
CD49d is upregulated in circulating T lymphocytes from HTLV-1-infected patients.
Neuroimmunomodulation, 27 (2020), pp. 113-122
T Assone, FV de Souza, KO Gaester, et al.
IL28B gene polymorphism SNP rs8099917 genotype GG is associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 carriers.
Plos Negl Trop Dis, 8 (2014), pp. e3199
T Assone, FM Malta, S Bakkour, et al.
Polymorphisms in HLA-C and KIR alleles are not associated with HAM/TSP risk in HTLV-1-infected subjects.
ACR Vallinoto, I Cayres-Vallinoto, MA Freitas Queiroz, et al.
Influence of immunogenetic biomarkers in the clinical outcome of HTLV-1 infected persons.
Viruses, 11 (2019), pp. 974
MAF Queiroz, EDSG Amoras, TCF Moura, et al.
The SAMHD1 rs6029941 (A/G) Polymorphism Seems to Influence the HTLV-1 Proviral Load and IFN-Alpha Levels.
Front Cell Infect Microbiol, 10 (2020), pp. 246
DC Silva, EDSG Amoras, TCF Moura, et al.
TREX1 531C>T Polymorphism is Associated with High Proviral Load Levels in HTLV-1-Infected Persons.
Viruses, 12 (2019), pp. 7
MC Rocha-Júnior, R Haddad, DC Cilião Alves, et al.
Interleukin-18 and interferon-gamma polymorphisms are implicated on proviral load and susceptibility to human T-lymphotropic virus type 1 infection.
Tissue Antigens, 80 (2012), pp. 143-150
J Rosado, S Morales, G López, et al.
The FAS-670 AA genotype is associated with high proviral load in peruvian HAM/TSP patients.
J Med Virol, 89 (2017), pp. 726-731
D Schor, LC Porto, EH Roma, et al.
Lack of association between single-nucleotide polymorphisms of pro- and anti-inflammatory cytokines and HTLV-1-associated myelopathy /tropical spastic paraparesis development in patients from Rio de Janeiro, Brazil.
BMC Infect Dis, 18 (2018), pp. 593
Y Kogure, K. Kataoka.
Genetic analysis and its clinical implication in adult T-cell leukemia/lymphoma.
Rinsho Ketsueki, 59 (2018), pp. 2127-2135
CM Lin, YL Zeng, M Xiao, et al.
The Relationship Between MMP-2 -1306C>T and MMP-9 -1562C>T Polymorphisms and the Risk and Prognosis of T-Cell Acute Lymphoblastic Leukemia in a Chinese Population: A Case-Control Study.
Cell Physiol Biochem, 42 (2017), pp. 1458-1468
M Nagasaka, M Yamagishi, N Yagishita, et al.
Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.
Proc Natl Acad Sci U S A, 117 (2020), pp. 11685-11691
K Kataoka, J. Koya.
Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma.
J Clin Exp Hematop, 60 (2020), pp. 66-72
The T- and B-cell Malignancy Study Group.
The third nation-wide study on adult T-cell leukemia/lymphoma (ATL) in Japan: characteristic patterns of HLA antigen and HTLV-I infection in ATL patients and their relatives.
Int J Cancer, 41 (1988), pp. 505-512
AQC Araujo, D. Wedemann.
HTLV-1 associated neurological complex. What is hidden below the water?.
AIDS Rev, 21 (2019), pp. 211-217
D Tanajura, N Castro, P Oliveira, et al.
Neurological manifestations in human T-cell lymphotropic virus type 1 (HTLV-1)-infected individuals without HTLV-1-associated myelopathy/tropical spastic paraparesis: a longitudinal cohort study.
Clin Infect Dis, 61 (2015), pp. 49-56
ME Haziot, MR Gascon, T Assone, et al.
Detection of clinical and neurological signs in apparently asymptomatic HTLV-1 infected carriers: association with high proviral load.
D Zucker-Franklin, WC Hooper, BL. Evatt.
Human lymphotropic retroviruses associated with mycosis fungoides: evidence that human T-cell lymphotropic virus type II (HTLV-II) as well as HTLV-I may play a role in the disease.
Blood, 80 (1992), pp. 1537-1545
J Maytal, S Horowitz, S Lipper, et al.
Progressive nemaline rod myopathy in a woman coinfected with HIV-1 and HTLV-2.
Mt Sinai J Med., 60 (1993), pp. 242-246
B Hjelle, O Appenzeller, R Mills, et al.
Chronic neurodegenerative disease associated with HTLV-II infection.
D Zucker-Franklin, BA. Pancake.
The role of human T-cell lymphotropic viruses (HTLV-I and II) in cutaneous T-cell lymphomas.
Semin Dermatol, 13 (1994), pp. 160-165
AA Peters, JJ Oger, MB Coulthart, et al.
An apparent case of human T-cell lymphotropic virus type II (HTLV-II)-associated neurological disease: a clinical, molecular, and phylogenetic characterisation.
J Clin Virol, 14 (1999), pp. 37-50
A Araujo, WW. Hall.
Human T-lymphotropic virus type II and neurological disease.
Ann Neurol, 56 (2004), pp. 10-19
C Rosadas, AC Vicente, L Zanella, et al.
Human T-lymphotropic virus type 2 subtype b in a patient with chronic neurological disorder.
J Neurovirol, 20 (2014), pp. 636-639
R Ishak, M de Oliveira Guimarães Ishak, ACR. Vallinoto.
The challenge of describing the epidemiology of HTLV in the Amazon region of Brazil.
Retrovirology, 17 (2020), pp. 4
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