Human T-Cell Lymphotropic Viruses (HTLV) 

Updated: Aug 20, 2019
Author: Joseph M Yabes, Jr, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 

Overview

Background

In 1979, human T-cell lymphotropic virus (HTLV) was isolated in a patient with adult cutaneous T-cell lymphoma (ATL).[1] This led to the discovery of the first HTLV, designated HTLV-1, and marked the beginning of the human retrovirus era. Two years later, a second T-cell lymphotropic virus, referred to as HTLV-2, was documented in a patient who had been diagnosed with hairy cell leukemia,[2, 3] although subsequent studies showed no association between the two processes. In 2005, two novel viruses, HTLV-3 and HTLV-4, were discovered. HTLV-3 was initially isolated from a 62-year-old male pygmy in southern Cameroon.[4] HTLV-4 has been described in African bush meat hunters. Neither HTLV-3 nor HTLV-4 has been linked to human disease, and considerably less is known about these viruses.

All HTLV strains belong 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. Isolation of similar retroviruses in nonhuman primates, simian T-cell lymphotropic viruses (STLV), STLV-1, STLV-2, and STLV-3, have also been discovered, suggesting that HTLV arose as an interspecies transmission between monkeys and humans.[5]

HTLV causes lifelong infection, with the overwhelming majority of cases remaining asymptomatic. However, HTLV-1 has been linked to ATL and HTLV-associated myelopathy, or tropical spastic paraparesis (HAM/TSP). For reasons that are not completely understood, a minority of individuals infected with HTLV-1 develop these symptomatic disease states. HTLV-1 infection and, to a lesser degree, HTLV-2 infection have been associated with various other disease manifestations with varying strengths of evidence; this remains a field requiring further study. Specific disease manifestations, epidemiology, staging, and treatment concerning ATL and HAM/TSP are beyond the scope of this article (see Cutaneous T-Cell Lymphoma and Tropical Myeloneuropathies). No vaccine or antiviral therapy exists for HTLV infection, and viral management focuses on patient education to prevent further spread of infection.

Disease Associations

A causal association between HTLV-1 and ATL and HAM/TSP has been found. Of note, ATL and HAM/TSP are generally mutually exclusive, and only a few individuals with both disorders have been described.[6, 7] Recent evidence has suggested that HTLV-2 is also associated with HAM/TSP, but the evidence is not as robust as the evidence for HTLV-1, so further research is needed. For reasons that are not completely understood, a minority of individuals infected with HTLV-1 develop disease. A higher provirus load increases not only the overall risk of HAM/TSP but also the likelihood that the disease will progress more quickly.[8, 9] ATL develops in 2%-4% and HAM/TSP in 1%-2% of individuals with HTLV-1 infection, respectively.[10]

HTLV-1 has also been associated with various ocular, oral, dermatologic, pulmonary, neurologic, rheumatologic, and infectious manifestations.[11, 8, 12, 13, 14, 15, 16] The evidence supporting these associations is composed of case reports/series and small cohort studies, so the prevalence rate and risk factors for disease are poorly described. Furthermore, the underlying pathophysiologic mechanisms between HTLV-1 infection and disease development are not completely described and require further research.

HTLV-1–associated uveitis/ocular manifestations

This is defined as the presence of HTLV viral sequences and HTLV-infected lymphocytes in the vitreous fluid.[12, 13]

Additional ocular manifestations in individuals with HTLV-1 infection include retinal vasculitis, choroidopathy, and keratopathy.

In 2013, a case report described unilateral intraocular invasion of ATL cells without systemic symptoms following cataract surgery. Antibodies to HTLV-1 were fount, and the vitreous specimen revealed flower cell infiltration with HTLV-1 DNA detected via polymerase chain reaction (PCR).[13]

HTLV-1–associated infective dermatitis

HTLV-1–associated infective dermatitis (IDH) is a chronic severe dermatitis that mainly affects children who have been infected with HTLV via vertical transmission.[17, 18]

IDH is associated with onset of HAM/TSP; 30% of Brazilian children with IDH develop HAM/TSP in adolescence.[8]

Individuals with IDH have a higher proviral load than asymptomatic carriers of HTLV-1. Primo et al reported that the proviral load was not associated with age, duration of infection, duration of breastfeeding, or severity of skin infection.[8]

Additional cutaneous diseases, which are found more frequently in HTLV-1 carriers than in noncarriers, include aphthous stomatitis, eczema, and nongenital warts.[14]

Other diseases associated with HTLV-1 include Sjögren syndrome, polymyositis, and chronic inflammatory arthropathy.[10, 16]

HTLV-1–associated oral manifestations

In addition to Sjögren syndrome, other oral manifestations are becoming apparent. A study of Brazilians with HTLV-1 infection showed that the most common manifestations included xerostomia (26.8%), candidiasis (20.8%), fissured tongue (17.9%), and loss of tongue papillae (17.9%). Patients with HAM/TSP were thrice as likely to have xerostomia than patients without HAM/TSP.[19] Similar results were described by Lins et al.[20]

Garlet et al suggested an association between periodontitis and HTLV-1 in which HTLV plays a direct role in deregulation of cytokines, resulting in an exaggerated immune response against bacteria that cause periodontitis.[21]

HTLV-2

HTLV-2 has been associated with neurologic, pulmonary, and dermatologic disease in small patient populations without a clear delineation of pathophysiology.[22, 23, 24]

HTLV-3 and HTLV-4

Neither HTLV-3 nor HTLV-4 has been associated with specific diseases to date, and further research is ongoing.

Pathophysiology

HTLVs are intracellular proviruses that result in lifelong infection. HTLV-1 invasion of uninfected host cells may occur through (1) formation of a "virological synapse," allowing the viral genome to be passed from one cell to another, (2) creation of a “viral biofilm,” in which viral particles remain tethered at the T-cell surface, and (3) development of “cellular conduits,” in which cytoplasmic projections from an infected cell are aimed at neighboring cells.[25] Once infection has occurred, little replication takes place, and proviral load is propagated by clonal expansion of lymphocytes with integrated proviral DNA.[11]

HTLV primarily affects T lymphocytes. 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.[25]

Owing to HTLV’s reliance on clonal expansion and its low replicating nature, the virus develops little genetic sequence variation.[11] Variations exist in the env gene for each HTLV; they define the HTLV subtypes. The distribution of HTLV-1 and HTLV-2 subtypes is distinct and may be explained by differing evolutionary trends.[26] Six different HTLV-1 subtypes exist, as follows:

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

HTLV-2 is classified into 4 subtypes. Each has a characteristic geographic association, with subtypes C/D having highly specific subpopulations, as follows:

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

Only one subtype of both HTLV-3 and HTLV-4 has been reported, and both were discovered in sub-Saharan Africa.[4, 5] In 2010, no evidence of HTLV-3 and HTLV-4 infection was found in a sample of 1,200 New York State subjects (human and simian subject types) at risk for retroviral infection.[27]

Epidemiology

Occurrence in the United States

In the United States, the overall prevalence of HTLV infection is 22 per 100,000 population, with HTLV-2 more common than HTLV-1. Data collection performed from 2000-2009 among US blood donors has shown a general decline since the 1990s.[28] However, the authors of this study pointed out that this was likely an underestimation of true disease burden.

HTLV-1 infection is more commonly found in immigrants, children of immigrants, sex workers, and persons of Asian descent.[26, 28]

HTLV-2 infection is associated with female sex, older age, nonwhite race/ethnicity, and lower educational level.[28] Additional populations at increased risk of HTLV-2 infection include Native American Indians, with some tribes reporting seroprevalence rates as high as 13%, and intravenous drug abusers, in whom the seroprevalence is estimated to be about 20%, with a disproportionate prevalence among African Americans who inject drugs.[24, 29, 30, 31, 32]

Global occurrence

HTLV disease affects 10-20 million people worldwide.[26] However, these crude estimates are confounded by epidemiologic surveys focusing on geographic areas with high baseline prevalence and high-risk social groups and do not account for parts of the world where routine surveillance is not performed.[33, 34, 35] This research is further limited by challenges with diagnostic testing. The area of highest prevalence is southwestern Japan, but infection is also common in sub-Saharan Africa, the Middle East, and Austro-Melanesia.[36]

Age- and sex-based predilections

The prevalence of HTLV-1 and HTLV-2 infection increases with advancing age, and they are more common in females.[28, 37, 38, 39, 40, 41]

Proposed hypotheses for these findings include a birth cohort effect, with individuals born during the 1960-1970s at higher risk owing to higher injection drug use during that time. An increasing number of sexual encounters over a lifetime is another possible explanation, heightening the risk for sexual acquisition. In older females, a thinning vaginal epithelium and microtrauma during sexual intercourse may be a unique risk factor for infection.[42, 43] Older age has also been hypothesized to be linked to higher proviral loads. Wives of seropositive males older than 60 years have been shown to have a 12-fold higher risk of infection compared with their younger counterparts, presumably from their more infectious partner.[42]

It was once believed that male-to-female sexual transmission was of greater clinical importance; however, Roucoux et al showed that female-to-male sexual transmission may be more important than once thought.[44]

Prognosis

Infection with HTLV-1 or HTLV-2 is lifelong, although most (95%) infected individuals remain asymptomatic throughout life, without progression to any end-point diseases. Mortality and morbidity due to HTLV infection are primarily associated with diseases caused by HTLV-1, namely ATL or HAM/TSP. Individuals with HTLV-1 infection have a 2%-4% and 1%-2% risk of developing ATL and HAM/TSP, respectively.[10]

Biswas et al 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.[22]

Patient Education

Patients determined to have infection with any subtype of HTLV should share this information with their physicians and undergo regular clinic follow-up.

Education should focus on preventing transmission to others through unprotected sexual activity. Sexual partners of patients with a HTLV infection should consider being tested. Infected persons in a mutually monogamous sexual relationship with an HTLV-positive partner require no further recommendations. If the partner is HTLV-negative, the use of latex condoms is advised. Specific testing guidelines for partners of individuals with HTLV-2 infection have not been established.

Patients should be instructed to avoid sharing needles.

Women with HTLV-1 or HTLV-2 infection should not breastfeed their infants. If this is unfeasible (ie, women in underdeveloped countries), breastfeeding should be limited to the first 6 months.

Patients should be counseled against donating blood, body organs, or tissues.

Patients with HTLV-1 infection should be informed about the 1%-5% lifetime chance of developing ATL or HAM/TSP.[45]

 

Presentation

History

Acute HTLV infection is rarely seen or diagnosed, as most infections are asymptomatic. Infection might be diagnosed after an attempted blood donation, a familial history of the infection, or workup of a disease caused by the virus (eg, a recent diagnosis of ATL or HAM/TSP). Suspected cases may prompt investigation for a history of a recent blood-product transfusion or a nursing mother from an endemic area.

When 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) are more likely to yield false-positive results in areas of low prevalence.[46] Therefore, a high-risk individual is anyone with 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

Patients with HAM/TSP may present with weakness and stiffness in the lower limbs (first presenting symptom in 60% of cases[47] ), 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, and/or abdominal pain.[48] A comprehensive review of the signs/symptoms of HAM/TSP and ATL is beyond the scope of this article.

Physical

Physical examination should be comprehensive, evaluating all major organ systems. Special attention should be paid to the neurologic examination, evaluation for lymphadenopathy, and signs of hematologic abnormalities. There are no strict criteria established for physical findings of HAM/TSP; however, the following constellation of physical findings are typical and invariably worsen:[22]

  • 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 with HTLV-1 or HTLV-2 infection:[22]

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

Causes

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 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.[49]

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%.[50, 51, 52]

For HTLV-2, the quantitative risk remains uncertain for both breastfeeding and intrauterine transmission.

Sexual intercourse

Increased exposure and increased proviral load increase the risk of sexual transmission of both HTLV-1 and HTLV-2.[37, 53]

Transfusion/transplantation

The risk of seroconversion due to contaminated blood transfusion has been reported to be 40%-60% and increases in immunosuppressed recipients.[54]

Screening of blood products is standard policy in the United States and many other countries. The United States has been screening donated blood since 1988.[46]

Reports have documented kidney, liver, and lung transplant transmission of HTLV-1.[55, 56]

Intravenous drug use

Transmission via intravenous drug use is mostly linked to HTLV-2. The prevalence of HTLV-2 infection in North American injection drug users ranges from 8%-17%.[24]

Self-flagellation

A report described ten heterosexual males without additional risk factors for HTLV infection who were found to be asymptomatically infected, presumably from using shared knives in religious self-flagellation.[57]

Complications

Complications of HTLV infection result mostly from end-stage diseases rather than the infection itself, as the vast majority of individuals with this infection are asymptomatic.

HTLV-1 is a risk factor for the development of severe strongyloidiasis; close follow-up after treatment for strongyloidiasis is recommended.[58, 59]

Coinfection of either HTLV-1 or HTLV-2 with HIV remains controversial. Conclusive and reproducible data of such coinfections are not yet available, as most of the data are limited by the testing methodology. Theoretically, HTLV-1 and HIV affect the same cell type, and the additive result might be detrimental to the immune system, leading to faster progression to AIDS. Future research might lead to recommendations concerning coinfections (eg, starting HAART or prophylaxis for opportunistic infections); however, no specific guidelines exist at this time.

A 2009 retrospective cohort study of Peruvian men with HIV/HTLV-1 coinfection did not show that coinfection increased the risk of death.[60] This area remains controversial, as some studies show an unfavorable outcome for HIV/HTLV-1 coinfection, while others do not. No evidence has shown that HIV/HTLV-2 coinfection leads to a faster progression to AIDS; in fact, coinfection might have some protective effects based on in vitro studies.[61, 62]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Multiple serologic methodologies are commercially available for the diagnosis of HTLV-1 and HTLV-2 infections. Included in the diagnostic armamentarium are enzyme-linked immunosorbent assays (ELISA), chemiluminescence assays, and particle agglutination assays.

Any positive result in the aforementioned diagnostic studies should be followed by confirmatory western blot, immunofluorescence assay (IFA), or polymerase chain reaction (PCR).

Only individuals with risk factors for HTLV infection should undergo testing.

HTLV ELISA yields very high false-positive rates in areas of low prevalence.[63] In patients in whom testing is deemed to be appropriate, recent test comparisons have found that those widely available perform with similar diagnostic accuracy.[64]

Positive ELISA results in combination with indeterminate western blot findings can be interpreted as follows:

  • Cross-reactivity with Plasmodium falciparum infection
  • HTLV-3 or HTLV-4 infection
  • Delayed seroconversion with low antibody titers
  • False-positive ELISA result

In this setting, western blot testing may be repeated, and, if possible, a different confirmatory laboratory test (ie, HTLV PCR testing) should be performed. In a US-based study including more than 400 patients with indeterminate western blot results, only 1.4% had positive PCR results for HTLV infection.[46]

PCR testing has additional uses. PCR or EIA with virus-specific synthetic peptides is necessary to distinguish between HTLV-1 and HTLV-2. PCR is also required in infants whose results may be false-positive because of circulating maternal anti-HTLV antibodies. PCR also quantifies the proviral load, which is frequently used as a marker for progression, especially in HAM/TSP. It is expressed as “the number of HTLV-1 DNA copies per fixed number of peripheral blood mononuclear cells.”[47]

Patients diagnosed with HTLV-1 or HTLV-2 infection should also undergo the following tests:

  • Complete blood count with differential and peripheral blood smear
  • Complete chemistry with calcium level
  • Liver function tests
  • Lactate dehydrogenase testing
  • HIV screening
  • Viral hepatitis serology (A, B, C)
  • Rapid plasma reagin (RPR)
  • Purified protein derivative (PPD)
  • Strongyloides stercoralis serology and stool examination for ova and parasites (if the appropriate risk factors exist)

Imaging Studies

No specific imaging studies are recommended for asymptomatic HTLV infections. However, imaging studies may be considered in aiding in diagnoses/evaluation of HAM/TSP or ATL.

HAM/TSP

Brain MRI reveals nonspecific periventricular and subcortical white matter lesions in 50%-80% of patients with HAM/TSP; however, these lesions also occur in patients with asymptomatic HTLV-1 infections, and comparisons with controls have not been adequate.[47]

ATL

Chest radiography is important, particularly in patients with ATL, to assess for pulmonary complications, opportunistic infections, and lytic bone lesions.

CT scanning of the neck, thorax, abdomen, and pelvis is crucial in assessing for nodal involvement.[48] It can also aid in further assessment for opportunistic infections (ie, abscess formation, pneumonia, intestinal infections).

Procedures

No specific procedures are recommended for asymptomatic HTLV infections.

Lumbar puncture to evaluate CSF for anti–HTLV-1 antibodies (and/or HTLV-1 proviral load) might be beneficial in establishing a diagnosis of HAM/TSP. The laboratory results often show a mild lymphocyte pleocytosis and increased protein levels. A proviral load ratio of CSF to peripheral blood that exceeds 1 supports a diagnosis of HAM/TSP.[47]

Lymph node biopsy may aid in the diagnosis of ATL.

Histologic Findings

No characteristic histologic findings are associated with asymptomatic HTLV infections.

HAM/TSP histopathology of the spinal cord shows perivascular and parenchymal infiltration of T cells, which worsens with the development of atrophy during disease progression.[47]

Peripheral blood smear is required for definitive diagnosis and categorization of ATL. ATL peripheral blood lymphocytes are found to have convoluted nuclei (cloverleaf or flower lymphocytes); provirus can be detected within these malignant cells.

 

Treatment

Medical Care

No treatments exist for acute or chronic HTLV infection.

Antiretroviral agents have demonstrated the ability to inhibit HTLV replication, but there has been limited research in asymptomatic carriers of HTLV-1, in whom the proviral load is already typically low.[65] In patients with HAM/TSP, who typically have high HTLV-1 viremia, 6-12 months of zidovudine plus lamivudine failed to show clinical benefit.[47]

Thorough neurologic and ophthalmologic examinations, in addition to a complete physical examination, should be performed in patients with HTLV infection.

Additional blood work should also be performed (see Lab Studies).

Good oral care and routine dental follow-up are recommended.

All patients with HTLV-1 or HTLV-2 infection should be counseled extensively on the lifelong implications of infection (see Patient Education).[45]

Consultations

Consultation with an infectious disease specialist is advisable to diagnose HTLV infection.

A hematologist/oncologist should be consulted for patients with ATL.

A neurologist should be consulted for patients with HAM/TSP.

An ophthalmologist should be consulted for patients with ocular symptoms and for routine examinations.

Activity

Use of barrier protection during intercourse is important to prevent the sexual spread of HTLV. In addition, intravenous drug users should avoid sharing needles.

Prevention

Strategies for HTLV infection prevention should include education regarding transmission on a global and individual basis. Both HTLV-1 and HTLV-2 can be transmitted through breastfeeding, sexual contact, and direct blood-to-blood contact.

Women diagnosed with HTLV infection should not breastfeed. In Japan, HTLV screening is a standard procedure in pregnant women, and seropositive women are discouraged from breastfeeding. One caveat is that infant malnutrition results from breastfeeding avoidance in endemic developing nations.

The routine use of latex condoms should be recommended, as well as limiting the number of sexual partners.

Parenteral transmission of HTLV is prevented through abstaining from needle sharing and through blood-donor screening.

 

Medication

Medication Summary

No specific treatments have been proven effective specifically for HTLV-1 or HTLV-2 infection.