eMedicine Specialties > Infectious Diseases > Viral Infections

Human T-Cell Lymphotrophic Viruses

Author: Ewa Maria Szczypinska, MD, Fellow, Department of Infectious Diseases, Orlando Health
Coauthor(s): Mark R Wallace, MD, FACP, FIDSA, Clinical Professor of Medicine, Florida State University College of Medicine; Infectious Disease Fellowship Director, Orlando Regional Medical Center; Booth Wainscoat, DO, Assistant Director, Division of Infectious Disease, Hartford Hospital; Christopher Mark Salas, MD, Resident Physician, Department of Internal Medicine, Maine Medical Center; Josiah D Rich, MD, MPH, Associate Professor, Department of Internal Medicine, Division of Infectious Disease, Brown University School of Medicine
Contributor Information and Disclosures

Updated: Nov 19, 2009

Introduction

Background

Human T-cell lymphotropic virus (HTLV) was the first human retrovirus discovered. HTLV belongs to the Retroviridae family in the genus Deltaretrovirus. Retroviruses are RNA viruses that use an enzyme called reverse transcriptase to produce DNA from RNA. The DNA is subsequently incorporated into the host’s genome. HTLV predominantly affects T lymphocytes.

Prior to 1979, the isolation of retroviruses was possible only in nonhuman primates; in fact, it was believed that human retroviruses did not exist. In 2005 in Retrovirology, Gallo reflected about earlier concepts that supported this belief. First, if human retroviruses did in fact exist, then why had they not yet been discovered? Second, the virus was easily detected in animals, and therefore should have also been easily detectable in humans. Third, technical difficulties hampered efforts to grow primary human cells in the laboratory. Finally, it was shown that the human complement lyses animal retroviruses in vitro, suggesting erroneously that humans were intrinsically protected from these viruses.1

In 1979, T-cell lymphotropic virus was isolated in a patient with cutaneous T-cell lymphoma.2 This led to the discovery of the first HTLV and marked the beginning of the human retrovirus era. Two years later, HTLV-2 was documented in a patient who had been diagnosed with hairy cell leukemia,3 although subsequent studies showed no affiliation between the two processes.

In 1983, the third and most important retrovirus was discovered. At the time of its discovery, this virus was classified in the HTLV genus. However, upon further research, it was reclassified into the Lentivirus genus and given the name human immunodeficiency virus (HIV). In 2005, two novel viruses, HTLV-3 and HTLV-4, were discovered. Little is known about these viruses, as only a few cases have been reported.

Now, 30 years later after the initial discovery, 4 HTLVs are well established. HTLV-1 and HTLV-2 are both involved in actively spreading epidemics, affecting 15-20 million people worldwide.4 HTLV-1 is the more clinically significant of the two, as it has been proven to be the etiologic agent of multiple disorders. At least 500,000 of the individuals infected with HTLV-1 eventually develop an often rapidly fatal leukemia, while others will develop a debilitative myelopathy, and yet others will experience uveitis, infectious dermatitis, or another inflammatory disorder. HTLV-2 is associated with milder neurologic disorders and chronic pulmonary infections. The novel HTLV-3 and HTLV-4 have been isolated only in a few cases; no specific illnesses have yet been associated with these viruses.

Pathophysiology

HTLVs are intracellular proviruses that pass through formation of a "virological synapse", allowing the viral genome to be passed from one cell to another. Once infection has occurred, little replication takes place. Infection affects the expression of T-lymphocyte gene expression, leading to increased proliferation of affected T lymphocytes. HTLV primarily affects T lymphocytes: specifically, HTLV-1 predominantly affects CD4 lymphocytes, while HTLV-2 predominantly affects CD8 lymphocytes. In vitro, HTLV-1 is also capable of infecting other cell types, possibly accounting for the diverse pathogenesis of HTLV-1. Recently, GLUT-1, a ubiquitous glucose transporter, has been identified as a receptor for HTLV-15 ; this may explain its ability to infect various cell types.

Acute HTLV infection is rarely seen or diagnosed, as most infections are latent and asymptomatic. Infection might be diagnosed after an attempted blood donation or through workup of a disease caused by the virus. For example, HTLV-1 is associated primarily with two diseases, adult T-cell leukemia (ATL) and HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP).

HTLV-1 and HTLV-2 have similar transmission patterns, although the transmission efficiency of HTLV-2 is uncertain because of a lack of unbiased data gathering. Both can be transmitted via breast milk, sexual contact, and intravenous drug use, and both can be introduced directly into the vascular system. HTLV-3 and HTLV-4 seem to be transmitted through direct human contact with primates (eg, through hunting, butchering, keeping them as pets), but data are lacking.6

On the molecular level, as with all retroviruses, HTLV has a gag-pol-env motif with flanking long terminal repeat sequences. Unique to the Deltraviruses, however, it includes a fourth sequence named Px, which participates in open-reading–frame transcription, in turn encoding for regulatory proteins Tax, Rex, p12, p13, and p30. All these proteins are important for the infectivity of cells, as well as in stimulating replication. In ATL, the main pathogenic protein, Tax, leads to leukogenesis and immortalization of T lymphocytes in vitro.7 This is achieved by stimulation of interleukin-15 (IL-15) and interleukin-2 (IL-2), in turn leading to T-cell growth and transformation. Research on this subject is ongoing, and the expression of this gene is not always found in ATL cells.8 Furthermore, Tax is inherent to both HTLV-1 and HTLV-2, although HTLV-1 is more pathogenic.9

Recently, the HTLV-1 basic zipper factor gene (HBZ) has been found to be consistently expressed in ATL cells, suggesting a role in cellular transformation and leukemogenesis. This might correlate with the increased pathogenesis of HTLV-1.10 The expression of the HBZ gene also correlates with the provirus load of HTLV-1.

Epidemiology

Because of the low replicating nature of HTLV, the virus develops little genetic sequence variation.4 Therefore, most epidemiologic data are based on serologic studies rather than on molecular typing. Variations exist in the env gene for each HTLV; they define the HTLV subtypes. The distribution of HTLV-1 and HTLV-2 subtypes is quite distinct and can probably be explained by differing evolutionary trends.4 HTLV-1 subtypes are associated with specific regions of the globe, while HTLV-2 subtypes are related to highly specific subpopulations (eg, Brazilian Indians) and behaviors such as injection drug use.

Transmission of HTLV-1 and HTLV-2

  • Breastfeeding
    • HTLV-infected T cells in breast milk pass from mother to child. The risk of HTLV-1 transmission reaches 20% and is affected by the duration of breastfeeding, the proviral load, and the quantity of maternal antibodies. Intrauterine infection is less common, about 5%.11,12,13
    • For HTLV-2, the quantitative risk remains uncertain for both breastfeeding and intrauterine transmission.
  • Sexual: Increased exposure and increased proviral load increase the risk of sexual transmission of both HTLV-1 and HTLV-2.14
  • Transfusion: The risk of seroconversion due to contaminated blood transfusion has been reported to be 40%-60% and increases in immunosuppressed recipients.15
  • Transplant: Reports have documented kidney, liver, and lung transplant transmission of HTLV-1.16
  • Intravenous drug use: This mode of transmission is mostly linked to HTLV-2. The prevalence of HTLV-2 infection in North American injection drug users ranges from 8%-17%.17

HTLV-1

Six different HTLV-1 subclasses exist, and each subtype is endemic to a particular region.4

  • Subtype A (cosmopolitan subtype) - Japan
  • Subtypes B, D, and F - Central Africa
  • Subtype C - Melanesia
  • Subtype E - South and Central Africa

HTLV-1 is associated with the below diseases. Note that ATL and HAM/TSP are generally mutually exclusive, and only a few cases with both disorders have been described.18,19

  • ATL develops in 2%-4% of individuals with HTLV-1 infection.20 Four clinical subtypes of ATL have been described.21
    • The acute form comprises 55%-75% of all ATL cases. It is characterized by a significantly increased white blood cell count that is mostly made up of leukemic T cells. It also features generalized lymphadenopathy.
    • The chronic form is characterized by absolute lymphocytosis (4 × 109/L or more), with T lymphocytosis comprising more than 3.5 × 109/L. These laboratory findings persist for months to years in most patients with chronic ATL. The lymphatic system may become involved.
    • Smoldering ATL is characterized by 5% or more abnormal T lymphocytes in peripheral blood, with a normal total lymphocyte count.
    • The lymphoma type involves generalized lymphadenopathy and an absence of peripheral blood involvement.
  • HAM/TSP develops in 1%-2% of individuals with HTLV-1 infection.20
    • The pathophysiology of HAM/TSP remains unclear, but, clinically, it can be defined as a slowly progressive degenerative disease that primarily affects the corticospinal tracts of the thoracic cord.
    • Major pathologic findings of HAM/TSP may include inflammatory perivascular and parenchymal infiltration by T-lymphocyte cells, leading to degeneration and fibrosis in the spinal cord. The degree of infiltration is less than in other retroviral infections (eg, HIV infection), perhaps because of the slow pathogenesis of the virus.22
    • Immunologic mechanisms may be involved in the development of HAM/TSP. This is likely mediated through autoimmune processes or cytotoxic attack on the HTLV-1–infected cells.
    • A higher provirus load increases not only the overall risk of HAM/TSP but also the likelihood that the disease will progress more quickly.23
    • HTLV-1 is also associated with a broader spectrum of neurologic abnormalities that are not as severe as HAM/TSP. It is not clearly established if individuals with the other neurologic abnormalities will eventually develop HAM/TSP or will remain stable.24
  • HTLV-1–associated uveitis25
    • This is defined as the presence of HTLV viral sequences and HTLV-infected lymphocytes in the vitreous fluid.
    • Additional ocular manifestations in individuals with HTLV-1 infection include retinal vasculitis, choroidopathy, and keratopathy.
  • HTLV-1–associated infective dermatitis
    • HTLV-1–associated infective dermatitis (IDH) is a chronic and severe dermatitis that mainly affects children who have been infected with HTLV via vertical transmission.
    • There is an association between IDH and onset of HAM/TSP; 30% of Brazilian children with IDH develop HAM/TSP in adolescence.23
    • Patients with IDH have a higher proviral load than asymptomatic carriers of HTLV-1. Primo et al (2009) reported that the proviral load was not associated with age, duration of infection, duration of breastfeeding, or severity of skin infection.23
    • Other diseases associated with HTLV-1 include Sjögren syndrome, polymyositis, and chronic inflammatory arthropathy.26,20

HTLV-2

HTLV-2 is classified into 4 molecular subtypes. Each has a characteristic geographic association.

  • Subtypes A and B - Present throughout Western Hemisphere and Europe; sporadic distribution in Asia and Africa
  • Subtype C - Kayapo indigenous people of the Amazon and urban Brazilian populations
  • Subtype D - Discovered in an African pygmy tribe

To date, no conclusive evidence has proven that HTLV-2 is an etiologic agent in any specific disease. However, the following links have been suggested:

  • HTLV-2 infection may result in neurologic manifestations similar to the non-HAM complications of HTLV-1 infection. Recent data suggest that HTLV-1 and HTLV-2 carry similar risks in terms of resulting in non-HAM neurological illness.27,24
  • Case reports have linked HTLV-2 infection with pneumonia, bronchitis, arthritis, asthma, and dermatitis.17

HTLV-3 and HTLV-4

These HTLV subtypes were first isolated in 2005. HTLV-3 was initially isolated from a 62-year-old male pygmy in southern Cameroon.28 Now, with the aid of advancing laboratory technology, new strains are quickly being identified. Individuals infected with HTLV-3 have all been asymptomatic, with a low proviral load. HTLV-4 has been described in African bush meat hunters.

Neither HTLV-3 nor HTLV-4 has been associated with specific diseases thus far, and further research is ongoing. Given the ongoing discovery of subtypes and strains, it is not surprising that 28% of certain populations in central Africa have been reported to have indeterminate HTLV serology results.6

The HTLV-3 label was initially applied to the virus that causes AIDS. However, further research found that the pathogenesis and genetic makeup of the AIDS virus differed from HTLV-1 and HTLV-2. Subsequently, the name was formally changed to HIV.

Frequency

United States

  • HTLV-14  
    • Based on transfusion screening data, the seroprevalence of HTLV-1 infection is 0.01%-0.03%.
    • HTLV-1 infection is primarily limited to immigrants, children of immigrants, sex workers, and injection drug users.
  • HTLV-217  
    • In the United States, HTLV-2 infection predominantly affects Native American Indians. Some tribes have seroprevalence rates as high as 13%.
    • Intravenous drug users, in whom the seroprevalence is estimated to be about 20%, with a disproportionate share occurring in African American injection drug users.

International

  • Areas and small population clusters with high concentrations of HTLV-1 include the following:4  
    • Southwest Japan: Japan has both low and high endemic microregions, with an estimated total 1.2 million HTLV-1 carriers.
    • Caribbean basin (Jamaica and Trinidad): This region has a prevalence of up to 6%.
    • Sub-Saharan African countries (Benin, Cameroon, Guinea-Bissau): These countries have a prevalence of up to 5%.
    • South America
    • The Mashadi Jewish people of northern Iran and various immigrant populations from endemic areas
  • Areas and populations with high concentrations of HTLV-2 include the following: 
    • Central and South America
    • North America and Europe, mainly among intravenous drug users

Mortality/Morbidity

Mortality and morbidity due to HTLV infections are primarily associated with diseases caused by HTLV-1, namely ATL or HAM/TSP.

  • Infected individuals have a cumulative lifetime risk of 1%-4% of developing ATL or HAM/TSP.4 The latency period for ATL is typically 30-50 years. ATL is usually rapidly progressive and fatal, with a median survival time of 2 years.29
  • HAM/TSP can occur as early as 3 months after blood transfusion–related HTLV-1 infection. Three years of latency is more typical, and 20-30 years is possible.
  • Biswas et al (2009) found that patients infected with HTLV - 2 missed more work days than patients with HTLV-1, possibly because of isolated neurological manifestations and the increased rate of upper respiratory infections and arthritis associated with HTLV-2.24

Sex

  • In endemic areas, HTLV-1 seropositivity is clustered in families, especially among women, suggesting that transmission occurs more easily from men to women than from women to children. Determining the sexual predominance of HTLV-2 infection is complicated by intravenous drug use in the study population.
  • Recent findings suggest that vertical transmission has a male predisposition, accounting for the predominance of male HTLV-1 seropositivity in childhood. This, in turn, may explain the increased prevalence of ATL in males because of a longer carrier state.30
  • HAM/TSP disproportionately affects females (with a female-to-male ratio as high as 2:1).4

Age

The prevalence of HTLV-1 and HTLV-2 infections increases with advancing age. The onset of ATL or HAM/TSP is often delayed until later in life because of the prolonged latency state; vertical transmission is associated with an elevated risk of ATL or HAM/TSP.

Clinical

History

Acute human T-cell lymphotropic virus (HTLV) infection is rarely suspected or diagnosed.

Because of the low viral replication of HTLV, there are usually no clinical symptoms. Diagnosis may stem from blood donation, testing performed because of a familial history of the infection, or a workup of adult T-cell leukemia (ATL) or HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) in patients with consistent clinical manifestations. Suspected cases may prompt investigation for a history of a recent blood-product transfusion or a nursing mother from an endemic area.

In considering HTLV infection, the most important historical information pertains to risk assessment. Because detecting accurate seroprevalence in low-endemic populations is inherently problematic, it is important to stratify a patient's risk. Screening enzyme immunoassays (EIAs) yield false-positive results in more than 50% of cases in areas of low prevalence. Therefore, a high-risk individual is anyone who has any of the following characteristics:

  • Has lived or lives in an endemic area (ie, Japan, the Caribbean, Central or West Africa, South America)
  • Is a Native American Indian
  • Has parents or sexual partners from an endemic area
  • Received blood-product transfusions in the United States before 1988
  • Has received blood transfusions anywhere that lacks active blood-bank screening
  • Has a history of injection drug use
  • Has sexual partners with a history of injection drug use
  • Has multiple sexual partners and does not use barrier protection
  • Has strongyloidiasis hyperinfection

The sequelae of latent HTLV infection generally occur decades after the initial infection, with the one exception being the reports of HAM/TSP occurring within a few months of HTLV-1–contaminated blood transfusion.31

Patients with HAM/TSP may present with weakness and stiffness in the lower limbs (first presenting symptom in 60% of cases32 ), urinary incontinence, and/or severe lower back pain radiating to the legs. In some cases, urinary frequency, urgency, incontinence, or retention precedes the paraparesis by many years. Infected patients may also have symptoms of autonomic dysfunction leading to constipation, and, in some cases, sexual dysfunction.

Symptoms of ATL are clinically broad and can manifest as fatigue, overt lymphadenopathy, thirst (due to hypercalcemia), nausea, vomiting, fever, or abdominal pain.

Physical

There are no strict criteria established in terms of physical findings of HAM/TSP; however, the following constellation of physical findings are typical and progressively worsen:24

  • Motor and sensory changes in the lower extremities
  • Clonus (may be evident); involuntary muscular contractions upon stretching of the muscles
  • Spastic gait in combination with weakness of the lower limbs
  • Detrusor insufficiency leading to bladder dysfunction
  • Preserved cognitive and upper-extremity neurological functions

The following isolated neurological symptoms have been also described in patients affected with HTLV-1 or HTLV-2:24

  • Sensory neuropathies
  • Gait abnormalities
  • Bladder dysfunction
  • Erectile dysfunction
  • Mild cognitive defects
  • Motor abnormalities

ATL has the following 4 distinct types and clinical characteristics:

  • Acute ATL
    • Short and aggressive clinical course
    • Hypercalcemia, lytic bone lesions, pulmonary involvement, and lymphocytosis
    • Hepatosplenomegaly
    • Cutaneous lesions (indolent, nodular, indurated, exfoliative, or erythrodermal)
  • Smoldering ATL
    • Abnormal lymphocytes of 5% or less
    • Malignant cells with monoclonal proviral integration
    • Skin lesions
    • Pulmonary involvement (occasional)
    • No hypercalcemia, lymphadenopathy, or other visceral involvement
    • Possible elevation of the serum lactase dehydrogenase level
  • Chronic ATL
    • No hypercalcemia, ascites, or pleural effusion
    • No CNS, bone, or GI involvement
    • Possible lymphadenopathy, hepatomegaly, splenomegaly, skin or pulmonary involvement
    • A serum lactate dehydrogenase level that may be twice the reference range
    • Abnormal T-cell lymphocytes, greater than 3.5 X 109/L
    • Absolute lymphocytosis, greater than 4.0 X 109/L
  • Lymphomatous ATL
    • Lymphadenopathy in the absence of lymphocytosis
    • Histologic evidence of lymph node involvement required
    • Skin lesions clinically indistinguishable from cutaneous T-cell lymphomas

Causes

HTLV-1 and HTLV-2 are transmitted vertically from mother to child via breastfeeding or childbirth, from person to person through sexual contact, and through blood contact, either by transfusion or by reuse of injection equipment.

Blood transfusion is very effective at transmitting HTLV-1 and HTLV-2. Screening is standard policy in the United States and in many other countries. The United States has been screening donated blood since 1988.

More on Human T-Cell Lymphotrophic Viruses

Overview: Human T-Cell Lymphotrophic Viruses
Differential Diagnoses & Workup: Human T-Cell Lymphotrophic Viruses
Treatment & Medication: Human T-Cell Lymphotrophic Viruses
Follow-up: Human T-Cell Lymphotrophic Viruses
References
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Further Reading

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Keywords

human T-cell lymphotrophic viruses, HTLV, lymphotropic virus, HTLV-1, HTLV-2, HTLV-3, HTLV-4, human T-cell leukemia/lymphoma virus, adult T-cell leukemia virus, ATLV, adult T-cell leukemia, ATL, HTLV-1–associated myelopathy, HAM, tropical spastic paraparesis, TSP, HTLV I/II, gibbon ape leukemia virus, gibbon ape leukemic virus, GALV, bovine leukemic virus, bovine leukemia virus, BLV

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Contributor Information and Disclosures

Author

Ewa Maria Szczypinska, MD, Fellow, Department of Infectious Diseases, Orlando Health
Ewa Maria Szczypinska, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Mark R Wallace, MD, FACP, FIDSA, Clinical Professor of Medicine, Florida State University College of Medicine; Infectious Disease Fellowship Director, Orlando Regional Medical Center
Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Tropical Medicine and Hygiene, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Booth Wainscoat, DO, Assistant Director, Division of Infectious Disease, Hartford Hospital
Booth Wainscoat, DO is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Merck Honoraria Speaking and teaching

Christopher Mark Salas, MD, Resident Physician, Department of Internal Medicine, Maine Medical Center
Disclosure: Nothing to disclose.

Josiah D Rich, MD, MPH, Associate Professor, Department of Internal Medicine, Division of Infectious Disease, Brown University School of Medicine
Josiah D Rich, MD, MPH is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Medical Association, American Public Health Association, Infectious Diseases Society of America, Massachusetts Medical Society, and Rhode Island Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Joseph Richard Masci, MD, Chief of Infectious Diseases, Associate Director, Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, Elmhurst Hospital Center, Mount Sinai School of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: BioMerieux Honoraria Review panel membership; Cubist Honoraria Review panel membership; Pfizer Honoraria Speaking and teaching; Merck Stock dividends stock holdings

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

 
 
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