Human T-Cell Lymphotropic Viruses (HTLV)
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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] In the United States, the overall prevalence 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. [5]
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.
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-1 [6] ; 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. [7]
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. [8] 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. [9] Furthermore, Tax is inherent to both HTLV-1 and HTLV-2, although HTLV-1 is more pathogenic. [10, 11]
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. [12] The expression of the HBZ gene also correlates with the provirus load of HTLV-1.
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.
See the list below:
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%. [13, 14, 15]
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. [16]
Transfusion: The risk of seroconversion due to contaminated blood transfusion has been reported to be 40%-60% and increases in immunosuppressed recipients. [17]
Transplant: Reports have documented kidney, liver, and lung transplant transmission of HTLV-1. [18]
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%. [19]
Six different HTLV-1 subclasses exist, and each subtype is endemic to a particular region. [4] . HTLV-1 clustering occurs, as evidenced by a high prevalence in southwestern Japan despite a low prevalence in neighboring regions (eg, Korea, China, eastern Russia), although the cause of this is unknown. [20]
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. [21, 22]
ATL develops in 2%-4% of individuals with HTLV-1 infection. [23] Four clinical subtypes of ATL have been described. [24]
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. [23]
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. [25]
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. [26]
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. [27]
HTLV-1–associated uveitis/ocular manifestations [28, 29]
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.
In 2013, a case report described unilateral intraocular invasion of ATL cells without systemic symptoms following cataract surgery. Antibodies to HTLV-1 were positive, and the vitreous specimen revealed flower cell infiltration with HTLV-1 DNA detected via polymerase chain reaction (PCR). [29]
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. [26]
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. [26]
Additional cutaneous diseases, which are found more frequently in HTLV-1 carriers than in noncarriers, include aphthous stomatitis, eczema, and nongenital warts. [30]
Other diseases associated with HTLV-1 include Sjögren syndrome, polymyositis, and chronic inflammatory arthropathy. [31, 23]
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 the most common manifestations were xerostomia (26.8%), candidiasis (20.8%), fissured tongue (17.9%), and loss of tongue papillae (17.9%). Patients with HAM/TSP were 3 times more likely to have xerostomia than patients without HAM/TSP. [32] 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 the bacteria causing periodontitis. [33]
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. [34, 27]
Case reports have linked HTLV-2 infection with pneumonia, bronchitis, arthritis, asthma, and dermatitis. [19]
These HTLV subtypes were first isolated in 2005. HTLV-3 was initially isolated from a 62-year-old male pygmy in southern Cameroon. [35] 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. In 2010, no evidence of HTLV-3 and HTLV-4 infection was found in a sample of 1200 New York State subjects (human and simian subject types) at risk for retroviral infection. [36]
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. [7]
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.
United States
HTLV-1
HTLV-1 infection is linked to immigrants, children of immigrants, sex workers, and injection drug users. [4]
Based on transfusion data from 2000-2009 among first-time donors, the prevalence of HTLV-1 was 5.1 cases per 100,000 population and was associated with female sex, older age, and black and Asian race/ethnicity. [37]
HTLV-2
Based on transfusion data from 2000-2009 among first-time donors, the prevalence of HTLV-2 was 14.7 cases per 100,000 population and was associated with female sex, older age, nonwhite race/ethnicity, lower educational level, and residence in the western and southwestern United States. [37]
In the United States, HTLV-2 infection affects Native American Indians. Some tribes have seroprevalence rates as high as 13%. [19]
Intravenous drug users, in whom the seroprevalence is estimated to be about 20%, with a disproportionate share occurring in African American injection drug users. [19]
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 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. [38]
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. [27]
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.
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. [39]
HAM/TSP disproportionately affects females (with a female-to-male ratio as high as 2:1). [4]
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.
Infection with HTLV-1 or HTLV-2 is lifelong, and most (95%) infected individuals remain asymptomatic throughout life, without progression to any end-point diseases.
The latency period for ATL is about 20-40 years. Patients with smoldering and chronic type ATL live an average of 2 years, and those with acute and lymphoma-type ATL live an average of 6 months. Chemotherapy or interferon plus antiretroviral drugs can produce complete remission, but the median survival remains under 2 years.
HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) carries a poor prognosis. The latency period ranges from a few months to 30 years postinfection. Within 10 years of onset, despite therapy, most patients are unable to walk unassisted and are wheelchair-bound within 21 years. [40]
Patients determined to have infection with any subtype of HTLV should share this information with their physicians and undergo regular follow-up.
Education should focus on preventing transmission to others through unprotected sexual activity. Sexual partners of patients with HTLV-1 infection who are in a mutually monogamous sexual relationship should consider being tested. If the partner is positive then no further recommendation is warranted. If the partner is negative, then the use of latex condoms is advised. Specific testing guidelines for partners of HTLV-2 infected individuals have not been established.
Patients should be instructed to avoid sharing needles.
Women with HTLV-1 or HTLV-2 infection should not breast feed their infants. If this is unfeasible (ie, women in undeveloped 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%-6% lifetime chance of developing ATL or HAM/TSP. [41]
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Ewa Maria Szczypinska, MD Fellow, Department of Infectious Diseases, Orlando Health
Ewa Maria Szczypinska, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Mark R Wallace, MD, FACP, FIDSA Clinical Professor of Medicine, Florida State University College of Medicine; Clinical Professor of Medicine, University of Central Florida College of Medicine
Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, Florida Infectious Diseases Society
Disclosure: Nothing to disclose.
Booth Wainscoat, DO Assistant Director, Division of Infectious Disease, Hartford Hospital; Assistant Professor of Clinical Medicine, University of Connecticut School of Medicine
Booth Wainscoat, DO is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Received consulting fee from Gilead for consulting.
Christopher Mark Salas, MD Fellow, Department of Infectious Diseases, Lifespan, The Warren Alpert Medical School of Brown University
Disclosure: Nothing to disclose.
Josiah D Rich, MD, MPH Professor of Medicine and Epidemiology, Brown University Medical School
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, Rhode Island Medical Society
Disclosure: Received ownership interest from alkermes stockholder for none; Received ownership interest from isis stockholder for none; Received ownership interest from repligen for none.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Joseph F John, Jr, MD, FACP, FIDSA, FSHEA Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Joseph F John, Jr, MD, FACP, FIDSA, FSHEA is a member of the following medical societies: Charleston County Medical Association, Infectious Diseases Society of America, South Carolina Infectious Diseases Society
Disclosure: Nothing to disclose.
Pranatharthi Haran Chandrasekar, MBBS, MD Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine
Pranatharthi Haran Chandrasekar, MBBS, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, International Immunocompromised Host Society, Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Joseph R Masci, MD, FACP, FCCP Professor of Medicine, Professor of Preventive Medicine, Icahn School of Medicine at Mount Sinai; Director of Medicine, Elmhurst Hospital Center
Joseph R Masci, MD, FACP, FCCP is a member of the following medical societies: American Association for the Advancement of Science, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International AIDS Society, International Society for Infectious Diseases, New York Academy of Medicine, New York Academy of Sciences, Physicians for Social Responsibility, Royal Society of Medicine, Association of Program Directors in Internal Medicine, Physicians for Human Rights, Association of Professors of Medicine, HIV Medicine Association, American Academy of HIV Medicine, Association of Specialty Professors, International Association of Providers of AIDS Care, Federation of American Scientists, American Society of Tropical Medicine and Hygiene
Disclosure: Nothing to disclose.
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