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. [8, 11, 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. [25] 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. [26, 27] Once infection has occurred, little replication takes place, and proviral load is propagated by clonal expansion of lymphocytes with integrated proviral DNA. [11, 25, 26]
HTLV primarily affects T lymphocytes. HTLV-1 predominantly affects CD4 lymphocytes, whereas 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. [27]
Owing to HTLV’s reliance on clonal expansion and its low replicating nature, the virus develops little genetic sequence variation. [11, 25, 26] 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. [28] Six different HTLV-1 subtypes exist, as follows:
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Subtype A (cosmopolitan subtype) - Japan
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Subtypes B, D, and F - Central Africa
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Subtype C - Melanesia
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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:
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Subtypes A and B - Western Hemisphere and Europe; sporadic distribution in Asia and Africa
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Subtype C - Kayapo indigenous people of the Amazon and urban Brazilian populations
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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. [29]
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. [30] 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. [28, 30]
HTLV-2 infection is associated with female sex, older age, nonwhite race/ethnicity, and lower educational level. [30] Additional populations at increased risk for 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, 31, 32, 33, 34]
Global occurrence
HTLV disease affects 10-20 million people worldwide. [28] 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. [35, 36, 37] 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. [38]
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. [30, 39, 40, 41, 42, 43]
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. [44, 45] 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 for infection compared with their younger counterparts, presumably from their more infectious partner. [44]
It once was 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. [46]
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 neurologic 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. [47]
