AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

A number of viruses are known to infect human lymphocytes, such as Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), cytomegalovirus (CMV), and retroviruses. Among them, 6 distinct retroviruses have been described: human T-cell lymphotrophic virus type 1 (HTLV-1), HTLV-2, HTLV-3, HTLV-4, HIV-1 (formerly known as HTLV-3), and HIV-2. Four of these—HTLV-1, HTLV-2, HIV-1, and HIV-2—are actively spreading in epidemics. Approximately 20 million people worldwide are infected with either HTLV-1 or HTLV-2. The HTL viruses are distinguished from HIV by the fact that they lead to lymphoproliferative disorders, whereas HIV clearly induces lymphocytosis.

Although the acute HTLV infection is innocuous, leukocytes will eventually proliferate in the bloodstream or the CNS in as many as 5% of latently infected persons. At least 500,000 of the individuals who are currently infected with HTLV-1 are expected to develop an essentially untreatable and rapidly fatal leukemia after a few decades of latent infection. A separate group will experience a debilitating myelopathy. Still others will experience uveitis, infectious dermatitis, or other inflammatory disorders. HTLV-1 has been proven to be the etiologic agent for these disorders.

In contrast, disease associations have only been proposed for HTLV-2. The newest HTL viruses—HTLV-3 and HTLV-4—have only recently been described in a small number of Africans with no particular illness. It may only be a matter of time until the next HTLV is discovered, but for now, the primary concern is the impact of HTLV-1. Additionally, co-infection of HIV and either HTLV-1 or HTLV-2 has growing implications, particularlyin the developing world and among injection drug users.

What we know about the HTL viruses is derived from a dynamic chapter in the history of science. The discovery of HTLV was only possible because of ground-breaking achievements in oncogenesis, cell culture and cytokines, the discovery of parallel viral infections in other vertebrates, and, perhaps most profound, a critical amendment to the central dogma of genetics. These efforts were united under a central question in medicine: Do viruses cause cancer?

By 1910, cancer cells were understood to divide in a manner similar to healthy ones, differing only in their tendency to invade healthy tissue. Infectious agents invisible to the light microscope and capable of passing through an ultrafilter impenetrable to bacteria had been discovered and termed viruses.

In 1911, the idea that cancer could be caused by a virus was developed when Peyton Rous transmitted solid tumors of chickens by transplanting tissue. The scientific community remained skeptical and focused on the hormonal and genetic causes of cancer. By the 1950s, viruses were known to be capable of introducing parts of their genetic material into a host cell and of redirecting the cell's activity; thus, the idea was promoted that oncogenes were healthy host genes that were virally altered. Many viral oncogenes have since been identified.

The idea that retroviruses could be responsible for human leukemia was not in favor for most of the 20th century, primarily because retroviruses were easy to recognize in nature and primate leukemias were not caused by viruses. This all changed, however, in the early 1970s, when bovine leukemia virus (BLV) and gibbon ape leukemia virus (GALV) were discovered. Unique to BLV was its very low level of replication, which contrasted with the high level of replication of previously "easily detectable" retroviruses in nature. This discovery led to increased interest in a potential human lymphotrophic virus but would require a more sensitive method of detection. The eventual discovery of the DNA polymerase of retroviruses would resolve this issue.

In the late 1960s, Howard Temin predicted, rather unconventionally, that retroviruses could replicate their RNA genome by first transcribing it into DNA as a so-called provirus. In 1970, Temin proved this to be a fact, which was also reported separately by David Baltimore. The discovery of reverse transcriptase (RT) was revolutionary because it overturned the central dogma of molecular biology that genetic information passes in one direction, from DNA to RNA to protein. This replication feature (ie, reverse transcriptase) distinguishes the viral family Retroviridae, the retroviruses. By detecting RT, one can infer that retrovirus is present.

At this same time, Gallo and colleagues were actively pursuing research on human blood cells in hopes of discovering the cause of adult lymphocytic leukemias. RT was found in some adult leukemia cases as early as 1972, but isolation of a lymphotrophic retrovirus was not possible because of the inability to promote culture of human myeloid leukemia cells in liquid culture. In timely fashion, Gallo and associates isolated a T-cell mitogenic factor, now known as interleukin-2 (IL-2), which solved the problem of myeloid cell culture. This achievement set the stage for isolation of the RT producing virus in humans. The first human leukemic retrovirus detection was made in 1979 by Minna and Gazdar, but it was Poiesz and Gallo, in 1980, who demonstrated the infectivity, antibody response, and evidence of provirus from the first human T-cell lymphotrophic virus (HTLV-1), isolated from an adult with a cutaneous T-cell malignancy.

The disease entity caused by HTLV-1 was best described in a cluster of patients in southwest Japan, in the Kyushu area, during the 1970s. Takatsuki and associates defined this group of leukemias as having characteristic cutaneous findings and hypercalcemia. He called it ATL, or adult T-cell leukemia. In 1981, Hinuma isolated adult T-cell leukemia virus (ATLV) in Japanese patients with adult T-cell leukemia (ATL). Ultimately, HTLV-1 and ATLV were determined to be the same entity. Later, additional clusters of ATL were described in patients from the Caribbean, the Americas, and England—all of whom had ancestry tied to specific African regions.

Subsequent work by Gessain (1985) associated the virus with spastic paraparesis, a neurologic disorder that is also called HTLV-1–associated myelopathy (HAM). Thus, HTLV-1 has 2 associated diseases. In 1982, Kalyanaraman isolated a related virus, human T-cell leukemia virus type 2 (HTLV-2), from a 37-year-old white man. The connection between HTLV-2 virus and disease remains unproven, although the strongest links appear with neurologic disorders.

Pathophysiology

Acute HTLV infection is rarely seen or diagnosed. Early seroconversions have been described in some cases following blood transfusions, but no clinical syndrome has been described. However, the early replication events of HTLV are critical to its permanent integration into human lymphocytes and its potential for causing future disease.

HTLV has a unique genome among retroviruses that highlights its unusual pathogenesis. It has the same gag-pol-env motif, with flanking long terminal repeat sequences (LTR), as all retroviruses. However, it includes a fourth sequence (xP), which participates in open-reading-frame transcription and leads to what are likely pathogenic products: Tax, Rex, p12, p13, and p30. It is through a unique feedback mechanism involving Tax and Rex that early, rapid replication of the virus is achieved, followed by abrupt inhibition of viral replication. This replication surge and termination sequence allow for dissemination in acute infection, followed by a quiescent phase in which HTLV evades host immune defenses. This places HTLV in the unique category of delta retroviruses, whose only other members are a few nonhuman viruses: BLV, STLV (simian T-cell leukemia virus), and PTLV (primate T-cell leukemia virus).

Regarding the T-cell leukemia that occurs in about 3-5% of individuals with HTLV-1, the exact mechanism of viral pathogenesis is still under investigation. In vitro studies suggest that Tax contributes in a number of ways to promotion of cellular genes that either cause cell proliferation or inhibit nucleic acid repair mechanisms. For example, Tax not only is a transcription activator for HTLV but also enhances IL-2 receptor (IL-2R) production in leukemic cells via an NF-kB pathway. This may help explain why ATL cells are associated with high numbers of IL-2R. Also, by mediating an NF-kB pathway, Tax is able to inhibit normal apoptosis of lymphocytes and therefore perpetuate their growth. Furthermore, Tax is an inhibitor of tumor suppressor genes, including p16INK4, p15INK4, and APC.

It has also been observed that cells tend to accumulate damaged DNA and proliferate when Tax is active. This is attributed to the Tax-induced inhibition of DNA topoisomerase-I and DNA beta-polymerase. More important, to create effective therapeutic interventions or prevent ATL from occurring in HTLV-1–positive individuals, a better understanding of the in vivo mechanisms that generate malignancy is needed. For now, the greatest impact on disease management is in the area of prevention of HTLV transmission.

As for the neurologic sequelae of HTLV infection, the pathogenesis remains speculative. It is not clear how HTLV crosses the blood-brain barrier (BBB). One investigation demonstrated clonal lines of T cells in the CSF of 5 HAM/TSP (HTLV-1–associated myelopathy/tropical spastic paraparesis) patients. All these clonal cells shared identical DNA integration sites, suggesting that a single HTLV-infected lymphocyte had successfully crossed the BBB. It has also been demonstrated that HTLV can spread by cell-to-cell contact without replication.

The human immune response to HTLV infection is also unique and appears to vary depending on whether a patient develops malignancy or myelopathy. HTLV predominantly infects and integrates in lymphocytes, but several nonlymphocytic cell lines also support HTLV infection. Recent evidence proves that the glucose transporter GLUT-1 is a supportive receptor for HTLV-1 cell entry. The ubiquitous nature of GLUT-1 may help explain the wider tropism for HTLV-1. However, HTLV-1 is principally T-cell tropic, primarily infecting CD4⁺ cells, whereas HTLV-2 primarily affects CD8⁺ cells.

Once the infection is transmitted, a host antibody response generally develops within 4-8 weeks and remains present for the remainder of life. Interestingly, patients who develop the most robust antibody response appear to be at greater risk for HAM/TSP. Although these antibodies have neutralizing activity in vitro, they do not correlate with protective immunity in actual patients. Cell-mediated responses are also different, depending on the sequelae of HTLV infection.

Cytotoxic T-cell lymphocytes (CTLs) are observed to have a profound impact on HTLV-infected cells. Still, cell-mediated responses are unable to eradicate an HTLV infection, perhaps because of the ability of the viruses to spread without replication through cell-to-cell contact. In HAM/TSP patients, the CTL response is especially robust and seems to contribute to the inflammatory degeneration in the CNS. On the other hand, CTL responses are blunted in patients with ATL, which contributes to the expansion of transformed cells.

Epidemiology

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

Today, the primary mode of HTLV-1 transmission is breastfeeding. The mechanism is explained by HTLV-infected T cells in breast milk passing from mother to child. Any other activity that can pass infected T cells is a potential route of transmission. In the absence of blood-bank screening, blood-product transfusions are a major contributor around the world. Other routes that continue to contribute to HTLV epidemics are sexual contact (primarily males transmitting to females), childbirth, and injection drug use.

The risk of vertical transmission of HTLV-1 from an infected mother is 20%. This appears to be primarily due to duration of breastfeeding but is also influenced by proviral load and quantity of maternal antibodies. Intrauterine infection appears to be rare.

Risk of seroconversion from contaminated transfusion has been reported to be 40-60%, with seroconversion occurring 7-8 weeks after transfusion. The disease most commonly associated with HTLV infection via transfusion is HAM/TSP, whereas such transmission is rare with ATL.

Regardless of endemicity, HTLV infection is directly associated with increasing age and female gender.

Human T-cell lymphotrophic virus type 1

Six different HTLV-1 subclasses exist. Each subtype is endemic to a particular region:

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

In nonendemic countries such as the United States, HTLV-1 has a seroprevalence of 0.01-0.03%. In these populations, the infection is primarily limited to immigrants, children of immigrants, sex workers, and injection drug users.

HTLV-1 is the etiologic agent for 4 diseases (ATL and HAM/TSP are generally mutually exclusive, with only a few cases of patients presenting with both disorders):

• ATL
• HAM/TSP
• HTLV-associated uveitis
• IDH (HTLV-1–associated infective dermatitis)

ATL is a category of 4 unique malignant conditions:

• Acute ATL: Acute ATL comprises 55-75% of all ATL cases. This classic form of ATL is characterized by lymphadenopathy, both in the periphery and within body cavities. Other frequent features are hepatosplenomegaly, hypercalcemia, and lytic bone lesions. The cutaneous lesions are classified as indolent, nodular, indurated, and, occasionally, diffuse with features of exfoliation and erythroderma. Death is frequently associated with pulmonary complications, opportunistic infections, and sepsis.
• Chronic ATL: Chronic ATL is a less common presentation that invariably develops into acute ATL. The blood smear shows that more than 3% of lymphocytes are atypical.
• Smoldering ATL: Smoldering ATL is similar to chronic ATL except that the peripheral smear suggests that less than 3% of lymphocytes are atypical.
• Lymphoma-type ATL: Lymphoma-type ATL occurs in 10-15% of ATL cases and is diagnosed on the basis of absence of blood and bone marrow involvement. The key to the diagnosis is distinguishing it from the spectrum of cutaneous T-cell lymphomas, which includes mycosis fungoides and Sézary syndrome. Patients with lymphoma-type ATL are, by definition, HTLV-1 positive, and provirus can be detected in the malignant cells on biopsy. These patients have large, firm peripheral lymphadenopathy, and at least one third of patients have cutaneous findings.

HAM/TSP is a slowly progressive degenerative disease that primarily affects the corticospinal tracts of the thoracic spinal cord. The ensuing disease results in weakness and spasticity, predominantly in the lower limbs, along with sphincter and sensory dysfunction. Major pathologic findings include inflammatory perivascular and parenchymal infiltration by mononuclear cells. This leads to degeneration and fibrosis in the CNS white matter. This inflammatory observation, in addition to associations with HLA subtypes, leads researchers to speculate that an immunologic mechanism is involved in the development of HAM/TSP.

HTLV-associated uveitis is defined by the presence of HTLV viral sequences and HTLV-infected lymphocytes in vitreous fluid.

IDH, or HTLV-associated infectious dermatitis, is a chronic and severe form of childhood dermatitis. In most described cases of IDH, patients acquired HTLV through vertical transmission in Jamaica. IDH is commonly exudative and spreads throughout the face, neck, and scalp. Other signs of the disorder include crusting or drainage of the nostrils and a diffuse papular rash. A recent association has been made between IDH and onset of HAM/TSP.

Human T-cell lymphotrophic virus type 2

Unlike HTLV-1, which is a true human leukemia virus, HTLV-2 has no proven causative role in human lymphoproliferative diseases. However, the discovery of HTLV-2 as a lymphotrophic virus centered on its association with various human leukemias.

In 1982, Kalyanaraman identified the HTLV-2 virus in cell lines from a patient with atypical hairy cell leukemia (HCL), the first disease thought to be associated with the virus. Rosenblatt (1988) had similar findings in another patient, but subsequent studies failed to confirm the association of HTLV-2 with HCL.

Another hematologic disorder linked with HTLV-2 is large granular lymphocytic leukemia (LGL), which was discovered by Loughran in 1992. A subsequent study by Martin in 1993, however, showed no HTLV-2 virus in the relevant cells of a patient with large granular lymphocytosis, which often leads to a tentative diagnosis of LGL. Pawson disputes the link in a 1997 study by demonstrating a significant number of LGL cases with no HTLV-1 or HTLV-2 infection.

The list of HTLV-2 disease associations is growing. However, to date, no conclusive evidence has proven that HTLV-2 is an etiologic agent in disease. Berger (1991), among others, has linked HTLV-2 to neurologic diseases of varying degrees that resemble HAM/TSP. There are many case reports that have linked HTLV-2 to pneumonia, bronchitis, and tuberculosis. HTLV-2 produces no clear immunocompromised state, which leads some researchers to speculate that the virus promotes an enhanced inflammatory response to these pulmonary infections and thereby creates an autoimmune problem. This may also explain links between HTLV-2 and arthritis, asthma, and dermatitis.

Overall, the health problem associated with HTLV-2 is indeterminate. Likewise, mortality studies have no consensus on persons infected with HTLV-2. HTLV-2 infection has not been found to influence mortality of injection drug users and patients with tuberculosis. Findings in a recent prospective study of blood donors from 5 major US cities were conflicted but suggested an increased all-cause mortality rate in HTLV-2–infected donors.

How or whether co-infection with HIV affects HTLV disease progression is a subject of controversy. A case series in Trinidad and Miami showed more rapid progression of HIV to AIDS in patients with HTLV disease, and other case reports have shown a more rapid progression of HTLV-2–associated lymphoma in patients with HIV. An analysis by Hershow and colleagues (1996) showed support for HIV to AIDS disease progression in HTLV-2/HIV co-infected individuals.

Currently, HTLV-2 is classified into 4 distinct 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

In North America, the distribution of HTLV-2 is predominantly in American Indians and persons who use intravenous drugs. Some American Indian tribes have seroprevalence rates as high as 13%. Injection drug users in certain urban groups in the United States have HTLV-2 rates of about 20%. The seroprevalence rate of HTLV-2 is disproportionately high in African American injection drug users, which may be the result of a genetic predisposition originating from African ancestry or related to socioeconomic factors.

Human T-cell lymphotrophic virus type 3

Initially, a third HTLV was isolated in association with AIDS. This virus proved to have pathogenic and genetic characteristics distinctly different from those of HTLV-1 and HTLV-2. Therefore, this third HTLV underwent a name change to HIV. Recently, a true third HTLV, which bears resemblance to simian T-cell leukemia virus 3 (STLV-3), was isolated from a pygmy in southern Cameroon (Calattini, 2005). Further investigation into the extent of HTLV-3 in other regions is pending.

Human T-cell lymphotrophic virus type 4

A fourth HTLV has also been described in Africa bushmeat hunters, but it has no similar simian counterpart (Wolfe, 2005).

Frequency

United States

Distribution of HTLV-1 and that of HTLV-2 differ markedly, and the true distribution is somewhat complicated by early serologic assays that failed to distinguish between the 2 biologically similar retroviruses. HTLV-2 has low endemicity in immigrant populations such as blacks in the southeastern United States. HTLV-2 is endemic in certain American Indian tribes and in injection drug users and their sexual partners.

International

HTLV-2 is endemic in injection drug users and their sexual partners around the world. HTLV-1 is endemic at high rates in southwestern Japan, where HTLV-1 was originally reported. Japan has both low and high endemic microregions and an estimated 1.2 million HTLV-1 carriers. South America, northern Oceania, tropical Africa, and the Caribbean basin also have high endemic rates. In Asia, HTLV-1 is found in high concentration only in a tribe of hunter-gatherers in the Philippines. Other small clusters have high-endemic rates, such as the Mashadi Jewish people of northern Iran and various immigrant populations from endemic areas.

Mortality/Morbidity

A person with HTLV-1 has a cumulative lifetime risk of 1-4% of developing HAM/TSP or ATL. The latency period for ATL typically is 30-50 years. ATL is a rapidly progressive and fatal malignancy, with a median survival time of 2 years. HAM/TSP onset can be as fast as 3 months when infection is caused by blood transfusion. Three years of latency is typical, and 20-30 years is possible.

Sex

In endemic areas, seropositivity is clustered in families and especially women, suggesting transmission occurs more frequently from men to women and from women to children than from women to men. Some studies suggest that women are over 100 times more likely to contract the disease from a male partner than the reverse. HAM/TSP disproportionately affects females (with a female-to-male ratio as high as 2:1), whereas ATL is slightly more prevalent in males.

Age

Both endemic and nonendemic populations experience an increase in the prevalence of HTLV-1 and HTLV-2 with increasing age. Onset of ATL disease and its symptoms is often delayed until later in life.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Acute HTLV infection is rarely suspected and generally innocuous. Because of the low viral replication of HTLV, there is rarely a clinical prodrome. Suspected cases may lead one to investigate, for example, a recent blood-product transfusion from an unscreened bank or nursing mothers in endemic areas.

In suspecting latent HTLV infection, the most important historical information pertains to risk assessment. Because there is an inherent problem with detecting accurate seroprevalence in low-endemic populations, it is important to stratify a patient's risk. Over 50% of enzyme immunoassays (EIAs) can be falsely positive in areas of low prevalence. Therefore, the high-risk individual is anyone who has any of the following characteristics:

• Has lived or lives in an endemic area (ie, Japan, Jamaica, the Caribbean, Central or West Africa)
• Is an 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 there is not 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

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 after blood transfusion infections. Patients with HAM/TSP may present with weakness and stiffness in the lower limbs, urinary incontinence, and lower back pain.

Physical

Patients with HAM/TSP may present with motor and sensory changes in the lower extremities. Findings from proprioceptive and sensory examination of the lower extremities are also routinely abnormal. They may have distinct sphincter dysfunction upon rectal examination.

ATL has the following 4 distinct types and characteristics:

• Acute ATL
• • Short and aggressive clinical prodrome
  • Hypercalcemia, lytic bone lesions, pulmonary involvement, and lymphocytosis
  • Hepatosplenomegaly, cutaneous lesions (indolent, nodular, indurated, exfoliative, or erythrodermal)
• Smoldering ATL
• • Abnormal lymphocytes of 3% or less
  • Malignant cells with monoclonal proviral integration
  • Skin lesions
  • Occasionally, pulmonary involvement
  • No hypercalcemia, lymphadenopathy, or other visceral involvement
  • Serum lactase dehydrogenase level may be elevated
• Chronic ATL
• • No hypercalcemia, ascites, or pleural effusion
  • No CNS, bone, or GI involvement
  • Possible lymphadenopathy, hepatomegaly, splenomegaly, skin involvement, or pulmonary involvement
  • Serum lactate dehydrogenase level 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 are clinically indistinguishable from cutaneous T-cell lymphomas

Causes

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

• Apparently, a prolonged period of sexual contact is necessary for disease transmission. Unlike with HIV, homosexual contact does not appear to result in greater transmissibility than heterosexual contact.
• Blood transfusion is very effective at transmitting HTLV-1 or HTLV-2 without a prolonged period of contact. Screening is policy in Canada, France, Japan, and the United States. The United States has been screening donated blood since 1988.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

For ATL:

Cutaneous T-cell lymphoma
Mycosis fungoides
Sézary syndrome

For HAM:

Multiple sclerosis
Vacuolar myelopathy of HIV
Toxic neuropathies
Malnutrition
Other infection
Other spinal cord or CSF disorders

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• HTLV-1 and HTLV-2 infection are detected with enzyme-linked immunosorbent assay (ELISA)
• All HTLV ELISA-positive cases must be confirmed with either Western blot, immunofluorescence assay (IFA), or polymerase chain reaction (PCR).
• False-positive rates for HTLV ELISA are very high in areas of low prevalence. For example, ELISA HTLV-positive blood donors in nonendemic areas prove to be negative in confirmatory testing as often as 60-80% of the time.
• PCR or EIA with virus-specific synthetic peptides is necessary to distinguish between HTLV-1 and HTLV-2. PCR is also useful in infants who are suspected of having false-positive results because of circulating maternal anti-HTLV antibodies.
• HAM/TSP has recently been associated with characteristic HTLV proviral loads in the CSF. In one study of 17 HAM/TSP patients, all patients had more than 10% of CSF cells with HTLV provirus. The same group also had a greater than 1% ratio of CSF to PBMC (peripheral blood mononuclear cells) infected cells.
• Screening for HIV should be strongly considered.
• Other routine blood work should include CBC with differential, complete chemistry with calcium level, and liver function tests, including lactate dehydrogenase (LDH).
• Also recommended are viral hepatitis serology, rapid plasma reagin (RPR), purified protein derivative (PPD), Strongyloides stercoralis serology, and stool examination for ova and parasites.

Imaging Studies

• Patients with HAM/TSP usually have normal findings, other than spinal cord atrophy, on myelography and CT scans. Far more useful is MRI, which shows diffuse high-intensity signals in the thoracic cord on T2-weighted images. MRI abnormalities are sensitive but not specific for HAM/TSP.
• Chest radiography is important, particularly in ATL patients, to assess for pulmonary complications, opportunistic infections, and lytic bone lesions.

Procedures

• Patients with HAM have delayed visual and somatosensory evoked potentials.

Histologic Findings

Biopsy 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. Also, Southern hybridization will reveal clonal rearrangements of the T cell receptor Vb and Bg regions.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

No treatment intervention exists for acute HTLV infection, but all HTLV-positive patients should be counseled extensively on the lifelong implications of this infection. Specifically, education should focus on preventing transmission to others through unprotected sexual activity, injection drug use, breastfeeding, or childbearing. Also, in areas where blood-bank screening is not available, HTLV-positive patients should avoid donating blood products. Naturally, HTLV-positive patients should be informed about the 1-4% chance of developing ATL or HAM/TSP generally by their fourth or fifth decade.

• ATL is treatable with chemotherapy; however, no known regimen increases the median survival time of 2 years. Complete remission can occur, but relapse is common. The standard first-line chemotherapy regimen is CHOP (cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin], and prednisone) or a similar variation. Other available chemotherapy regimens include interferon alfa, topoisomerase inhibitors, zidovudine and interferon alfa, arsenic trioxide and interferon alfa, blockade of NF-êB with several experimental agents, and monoclonal antibodies against the IL-2R and other receptors on ATL cells.
• ATL has been reported to be caused by allogeneic stem cell transplants and cytoreductive chemotherapy. The first report of ATL being cured was in Japan in 1996 and was defined by the absence of disease and undetectable HTLV by DNA PCR in the peripheral blood. Further transplant cases have had varying success. Transplants rarely increase median survival beyond 2 years. Additional therapies include adjuvant external-beam radiation, psoralen and longwave ultraviolet light (PUVA) therapy, and bisphosphonates for hypercalcemia. Current investigational therapies include vaccination against the HTLV-1 transcription regulator, Tax. Mouse models have shown promising results for both prophylactic and therapeutic Tax-directed vaccination in the setting of stem cell transplant.
• It is equally important to monitor for opportunistic infections in ATL patients. Strong consideration should be given toward prophylactic use of trimethoprim-sulfamethoxazole for PCP prevention and use of INH as prophylaxis in PPD-positive patients. Case reports encourage careful surveillance for CMV, Strongyloides stercoralis, Norwegian scabies, disseminated molluscum contagiosum, extrapulmonary histoplasmosis, and complications of staphylococcal and streptococcal skin infections.
• HAM/TSP treatment options are even more limited. Antiretroviral drugs have not been proven to be effective for this myelopathy. Corticosteroids, plasmapheresis, cyclophosphamide, and interferon occasionally produce temporary improvement in signs and symptoms associated with HAM/TSP.

Consultations

Consultation with an infectious disease specialist is advisable to diagnose HTLV infection. A consultation with a hematologist/oncologist is indicated if ATL is present, and a consultation with a neurologist is indicated if HAM/TSP is present.

Diet

Breastfeeding is not recommended for mothers positive for HTLV-1 because of significant transmission rates to infants.

Activity

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

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

As yet, no specific treatments have been proven to be effective for HTLV-1 or HTLV-2.

Antiretroviral agents have demonstrated encouraging results in vitro for inhibition of HTLV replication. Similar in vivo activity, however, has not been shown.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Deterrence/Prevention

• No proven HTLV-1 or HTLV-2 prevention strategies are available, although transmission by blood transfusion can be prevented with blood-donor screening for HTLV-1 and HTLV-2. Perhaps the most aggressive prevention efforts have been made in Japan, where HTLV-1–positive mothers are discouraged from breastfeeding. An 80% reduction in the vertical transmission rate has been reported through breastfeeding avoidance. HTLV screening during pregnancy is standard procedure in Japan and Martinique. Infant malnutrition may be a concern regarding the enforcement of breastfeeding avoidance in developing nations endemic for HTLV.
• Other helpful measures include the use of condoms and the avoidance of shared injection equipment by injection drug users.

Complications

• Patients with ATL are immunocompromised, which leads to opportunistic infections, including the following:
• • Pneumocystis jiroveci pneumonia
  • Cryptococcal meningitis
  • Fungal infections
  • Viral infections (eg, cytomegalovirus, herpes zoster, herpes simplex)
  • Strongyloides stercoralis
• Co-infection of either HTLV-1 or HTLV-2 with HIV remains a controversial topic.
• • Conclusive and reproducible data pertaining to disease consequences of such co-infection are not yet available. What is clear is that co-infection does exist and appears to be most prevalent in urban areas, with injection drug use contributing significantly to co-infection rates.
  • Observations in New Orleans suggest that risk for neurologic complications is increased in co-infected patients. HAM/TSP needs to be distinguished from vacuolar myelopathy, which is associated with HIV. Further data suggest that both HTLV-1 and HTLV-2 patients have a higher viral burden in PBMC samples if they are co-infected with HIV.
  • In co-infected patients receiving highly active anti-retroviral therapy (HAART), suppression of HTLV levels has not been convincingly demonstrated. For now, HTLV-HIV co-infection appears to be an epidemic that is increasing even in the United States, where the seroprevalence rate is higher in African American females.

Prognosis

• Infection with HTLV-1 or HTLV-2 is permanent, and patients are usually asymptomatic.
• ATL often does not proceed to advanced stages; if it does, patients with smoldering ATL live an average of 2 years, and those with acute ATL live an average of 6 months. Chemotherapy or interferon plus antiretroviral drugs can cause complete remission in a significant proportion of cases, but median survival remains up to 2 years.
• HAM/TSP may respond to treatment; if it does not, prognosis is poor. Within 10 years, many patients are bedridden or unable to walk unassisted.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Andrade TM, Dourado I, Galvao-Castro B. Associations among HTLV-I, HTLV-II, and HIV in injecting drug users in Salvador, Brazil. J Acquir Immune Defic Syndr Hum Retrovirol. Jun 1 1998;18(2):186-7. [Medline].
• Aye MM, Matsuoka E, Moritoyo T, et al. Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system. Acta Neuropathol (Berl). Sep 2000;100(3):245-52. [Medline].
• Beilke MA, Japa S, Moeller-Hadi C, et al. Tropical spastic paraparesis/human T leukemia virus type 1-associated myelopathy in HIV type 1-coinfected patients. Clin Infect Dis. Sep 15 2005;41(6):e57-63.
• Berger JR, Svenningsson A, Raffanti S, Resnick L. Tropical spastic paraparesis-like illness occurring in a patient dually infected with HIV-1 and HTLV-II. Neurology. Jan 1991;41(1):85-7. [Medline].
• Borg A, Yin JA, Johnson PR, et al. Successful treatment of HTLV-1-associated acute adult T-cell leukaemia lymphoma by allogeneic bone marrow transplantation. Br J Haematol. Sep 1996;94(4):713-5.
• Calattini S, Chevalier SA, Duprez R, et al. Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa. Retrovirology. May 9 2005;2(1):30.
• Castilla J, Pachon I, Gonzalez MP, et al. Seroprevalence of HIV and HTLV in a representative sample of the Spanish population. Epidemiol Infect. Aug 2000;125(1):159-62. [Medline].
• Cavrois M, Gessain A, Gout O, et al. Common human T cell leukemia virus type 1 (HTLV-1) integration sites in cerebrospinal fluid and blood lymphocytes of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis indicate that HTLV-1 crosses the blood-brain barrier via clonal. J Infect Dis. Oct 2000;182(4):1044-50. [Medline].
• Edlich RF, Arnette JA, Williams FM, et al. Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I). J Emerg Med. Jan 2000;18(1):109-19. [Medline].
• Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2. Retrovirology. Mar 2 2005;2(1):17.
• Gessain A, Barin F, Vernant JC, et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. Aug 24 1985;2(8452):407-10. [Medline].
• 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. Jul 1992;66(7):4570-5.
• Hall WW, Takahashi H, Liu C, et al. Multiple isolates and characteristics of human T-cell leukemia virus type II. J Virol. Apr 1992;66(4):2456-63.
• Haoudi A, Daniels RC, Wong E, et al. Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response. J Biol Chem. Sep 26 2003;278(39):37736-44.
• Hershow RC, Galai N, Fukuda K, et al. An international collaborative study of the effects of coinfection with human T-lymphotropic virus type II on human immunodeficiency virus type 1 disease progression in injection drug users. J Infect Dis. Aug 1996;174(2):309-17.
• Hinuma Y, Nagata K, Hanaoka M, et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. Oct 1981;78(10):6476-80.
• Hisada M, Maloney EM, Sawada T, et al. Virus markers associated with vertical transmission of human T lymphotropic virus type 1 in Jamaica. Clin Infect Dis. Jun 15 2002;34(12):1551-7.
• Hjelle B, Zhu SW, Takahashi H, et al. Endemic human T cell leukemia virus type II infection in southwestern US Indians involves two prototype variants of virus. J Infect Dis. Sep 1993;168(3):737-40.
• 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. Mar 1 2002;185(5):691-5.
• Igakura T, Stinchcombe JC, Goon PK, et al. Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science. Mar 14 2003;299(5613):1713-6.
• Jeang KT. Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kappa B. Cytokine Growth Factor Rev. Jun-Sep 2001;12(2-3):207-17.
• Jeffery KJ, Usuku K, Hall SE, et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci U S A. Mar 30 1999;96(7):3848-53.
• Kalyanaraman VS, Sarngadharan MG, Robert-Guroff M, et al. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science. Nov 5 1982;218(4572):571-3. [Medline].
• Kannagi M, Ohashi T, Harashima N, et al. Immunological risks of adult T-cell leukemia at primary HTLV-I infection. Trends Microbiol. Jul 2004;12(7):346-52.
• LaGrenade L, Hanchard B, Fletcher V, et al. Infective dermatitis of Jamaican children: a marker for HTLV-I infection. Lancet. Dec 1 1990;336(8727):1345-7.
• Lee HH, Weiss SH, Brown LS, et al. Patterns of HIV-1 and HTLV-I/II in intravenous drug abusers from the middle atlantic and central regions of the USA. J Infect Dis. Aug 1990;162(2):347-52.
• Lezin A, Olindo S, Oliere S, et al. Human T lymphotropic virus type I (HTLV-I) proviral load in cerebrospinal fluid: a new criterion for the diagnosis of HTLV-I-associated myelopathy/tropical spastic paraparesis?. J Infect Dis. Jun 1 2005;191(11):1830-4. [Medline].
• Li HC, Biggar RJ, Miley WJ, et al. Provirus load in breast milk and risk of mother-to-child transmission of human T lymphotropic virus type I. J Infect Dis. Oct 1 2004;190(7):1275-8.
• Loughran TP Jr, Coyle T, Sherman MP, et al. Detection of human T-cell leukemia/lymphoma virus, type II, in a patient with large granular lymphocyte leukemia. Blood. Sep 1 1992;80(5):1116-9. [Medline].
• Manel N, Kim FJ, Kinet S, et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell. Nov 14 2003;115(4):449-59.
• Martin MP, Biggar RJ, Hamlin-Green G, et al. Large granular lymphocytosis in a patient infected with HTLV-II. AIDS Res Hum Retroviruses. Aug 1993;9(8):715-9. [Medline].
• Matsuoka M. Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology. Apr 26 2005;2(1):27.
• Melo J, Beby-Defaux A, Faria C, et al. HIV and HTLV prevalences among women seen for sexually transmitted diseases or pregnancy follow-up in Maputo, Mozambique. J Acquir Immune Defic Syndr. Feb 1 2000;23(2):203-4. [Medline].
• Mori N, Yamada Y, Ikeda S, et al. Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells. Blood. Sep 1 2002;100(5):1828-34.
• Murphy EL, Mahieux R, de The G, et al. Molecular epidemiology of HTLV-II among United States blood donors and intravenous drug users: an age-cohort effect for HTLV-II RFLP type aO. Virology. Mar 15 1998;242(2):425-34. [Medline].
• Murphy EL, Wang B, Sacher RA, et al. Respiratory and urinary tract infections, arthritis, and asthma associated with HTLV-I and HTLV-II infection. Emerg Infect Dis. Jan 2004;10(1):109-16.
• Murphy EL, Watanabe K, Nass CC, et al. Evidence among blood donors for a 30-year-old epidemic of human T lymphotropic virus type II infection in the United States. J Infect Dis. Dec 1999;180(6):1777-83.
• Nasr R, El-Sabban ME, Karam JA, et al. Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene. Jan 13 2005;24(3):419-30.
• Ohashi T, Hanabuchi S, Kato H, et al. Prevention of adult T-cell leukemia-like lymphoproliferative disease in rats by adoptively transferred T cells from a donor immunized with human T-cell leukemia virus type 1 Tax-coding DNA vaccine. J Virol. Oct 2000;74(20):9610-6.
• Orland JR, Wang B, Wright DJ, et al. Increased mortality associated with HTLV-II infection in blood donors: a prospective cohort study. Retrovirology. Mar 24 2004;1(1):4.
• Osame M, Usuku K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet. May 3 1986;1(8488):1031-2.
• Pawson R, Schulz TF, Matutes E, Catovsky D. The human T-cell lymphotropic viruses types I/II are not involved in T prolymphocytic leukemia and large granular lymphocytic leukemia. Leukemia. Aug 1997;11(8):1305-11. [Medline].
• Poiesz B, Dube D, Dube S, et al. HTLV-II-associated cutaneous T-cell lymphoma in a patient with HIV-1 infection. N Engl J Med. Mar 30 2000;342(13):930-6. [Medline].
• 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 U S A. Dec 1980;77(12):7415-9. [Medline].
• Portis T, Harding JC, Ratner L, et al. The contribution of NF-kappa B activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors. Blood. Aug 15 2001;98(4):1200-8.
• Porto AF, Santos SB, Muniz AL, et al. Helminthic infection down-regulates type 1 immune responses in human T cell lymphotropic virus type 1 (HTLV-1) carriers and is more prevalent in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. J Infect Dis. Feb 15 2005;191(4):612-8.
• Primo JR, Brites C, Oliveira Mde F, et al. Infective dermatitis and human T cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis in childhood and adolescence. Clin Infect Dis. Aug 15 2005;41(4):535-41.
• Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. Sep 5 2005;24(39):6058-68.
• Rosenblatt JD, Giorgi JV, Golde DW, et al. Integrated human T-cell leukemia virus II genome in CD8+ T cells from a patient with "atypical" hairy cell leukemia: evidence for distinct T and B cell lymphoproliferative disorders. Blood. Feb 1988;71(2):363-9. [Medline].
• Roucoux DF, Murphy EL. The epidemiology and disease outcomes of human T-lymphotropic virus type II. AIDS Rev. Jul-Sep 2004;6(3):144-54.
• Rous P. Landmark article (JAMA 1911;56:198). Transmission of a malignant new growth by means of a cell-free filtrate. By Peyton Rous. JAMA. Sep 16 1983;250(11):1445-9. [Medline].
• Safaeian M, Wilson LE, Taylor E, et al. HTLV-II and bacterial infections among injection drug users. J Acquir Immune Defic Syndr. Aug 15 2000;24(5):483-7. [Medline].
• Salemi M, Lewis M, Egan JF, et al. Different population dynamics of human T cell lymphotropic virus type II in intravenous drug users compared with endemically infected tribes. Proc Natl Acad Sci U S A. Nov 9 1999;96(23):13253-8.
• Seiki M, Hattori S, Yoshida M. '. Proc. Natl. Acad. Sci. USA. 1982;79:6899â€"6902.
• Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. Nov 1991;79(3):428-37. [Medline].
• Shuh M, Beilke M. The human T-cell leukemia virus type 1 (HTLV-1): new insights into the clinical aspects and molecular pathogenesis of adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM). Microsc Res Tech. Nov 2005;68(3-4):176-96.
• Tajima K. Worldwide distribution of HTLV. Jpn J Cancer Res. Jan 1998;89(1):inside front cover. [Medline].
• Taylor GP, Matsuoka M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene. Sep 5 2005;24(39):6047-57.
• Telzak EE, Hershow R, Kalish LA, et al. Seroprevalence of HTLV-I and HTLV-II among a cohort of HIV-infected women and women at risk for HIV infection. Women''s Interagency HIV Study. J Acquir Immune Defic Syndr Hum Retrovirol. Dec 15 1998;19(5):513-8. [Medline].
• Temin HM, Mizutani S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature. Jun 27 1970;226(252):1211-3. [Medline].
• Tsukasaki K, Maeda T, Arimura K, et al. Poor outcome of autologous stem cell transplantation for adult T cell leukemia/lymphoma: a case report and review of the literature. Bone Marrow Transplant. Jan 1999;23(1):87-9.
• Uchiyama T, Yodoi J, Sagawa K, et al. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. Sep 1977;50(3):481-92.
• Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. Jan 2001;27(1):15-20.
• Vine AM, Witkover AD, Lloyd AL, et al. Polygenic control of human T lymphotropic virus type I (HTLV-I) provirus load and the risk of HTLV-I-associated myelopathy/tropical spastic paraparesis. J Infect Dis. Oct 1 2002;186(7):932-9.
• Waldmann TA, White JD, Goldman CK, et al. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood. Sep 15 1993;82(6):1701-12.
• Wolfe ND, Heneine W, Carr JK, et al. Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc Natl Acad Sci U S A. May 31 2005;102(22):7994-9.
• Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001;19:475-96.
• Zhang Z, Zhang M, Ravetch JV, et al. Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507. Blood. Jul 1 2003;102(1):284-8.

Article Last Updated: Jul 13, 2006