Review
Human T-lymphotropic virus 1: recent knowledge about an ancient infection

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Summary

Human T-lymphotropic virus 1 (HTLV-1) has infected human beings for thousands of years, but knowledge about the infection and its pathogenesis is only recently emerging. The virus can be transmitted from mother to child, through sexual contact, and through contaminated blood products. There are areas in Japan, sub-Saharan Africa, the Caribbean, and South America where more than 1% of the general population is infected. Although the majority of HTLV-1 carriers remain asymptomatic, the virus is associated with severe diseases that can be subdivided into three categories: neoplastic diseases (adult T-cell leukaemia/lymphoma), inflammatory syndromes (HTLV-1-associated myelopathy/tropical spastic paraparesis and uveitis among others), and opportunistic infections (including Strongyloides stercoralis hyperinfection and others). The understanding of the interaction between virus and host response has improved markedly, but there are still no clear surrogate markers for prognosis and there are few treatment options.

Introduction

In 1979, the human T-lymphotropic virus 1 (HTLV-1) was isolated from a patient with a T-cell malignancy.1 This discovery was the first formal proof that human retroviruses exist and suggested their aetiological role in human cancer, a hypothesis that had been proposed decades before.2 It is estimated that 10 to 20 million people worldwide are infected with HTLV-1,3 and although the majority of infected people remain asymptomatic, the virus is associated with exceptionally severe diseases, such as adult T-cell leukaemia/lymphoma (ATL) and an inflammatory disease of the central nervous system called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).4, 5 The growing insight into the pathogenesis of these diseases sheds light upon the functioning of human T cells, the major target of HTLV-1. Nonetheless, it is not yet fully understood why some infected individuals develop associated diseases whereas others do not.6

Section snippets

HTLV-1 and T cells

HTLV-1 is a type C virus belonging to the family of Retroviridae and classified into the genus of Deltaretrovirus. It is a round-shaped, enveloped virus of approximately 100 nm diameter (figure 1A).7 The virion is surrounded by a proteolipid envelope bilayer of host cell membrane origin, equipped with viral transmembrane and surface proteins. The inner envelope contains the matrix layer, which helps to organise the viral components at the inner cell membrane. The icosahedral capsid protects the

Diagnosis of HTLV-1 infection

Serological screening for the presence of HTLV antibodies can either be done by an enzyme immunoassay (EIA) or by a particle agglutination test. The first generation EIAs were based on viral lysate and frequently resulted in false-positive reactions.21 Second generation EIAs using recombinant proteins and/or synthetic HTLV-1 peptides perform better, but confirmatory testing is still recommended to eliminate false-positive reactions and to discriminate between the different HTLV types.22

There

Transmission

HTLV-1 can be transmitted from mother to child through breastfeeding. The risk of infection in children of seropositive mothers correlates with the provirus load in breastmilk, the concordance of HLA class I type between mother and child, and the duration of breastfeeding.33, 34 In several reports from endemic populations, the overall rate of vertical transmission ranged between 15% and 25%, and in subgroups of children who received prolonged breastfeeding, these rates were even higher.35, 36,

Origin, spread, and prevalence

To estimate the global prevalence of HTLV-1 on the basis of published reports is difficult because there are few population-based studies. HTLV-1 prevalence estimates are usually based on serological screening of blood donors, pregnant women, and other selected population groups. Studying the prevalence in healthy donors might underestimate the population prevalence.54 Data from pregnant women may better reflect the general population, although reports from endemic areas suggest that HTLV-1

HTLV-1-associated diseases

Most people infected with HTLV-1 remain asymptomatic throughout life. How many people eventually develop any of the associated diseases depends on several factors, including age and the route of infection.99 Additionally, the incidence of HTLV-1-associated diseases is not uniform across geographical areas.100

Among HTLV-1 carriers, the lifetime risk of developing HAM/TSP ranges from between 0·3% and 4%.101 For ATL, this risk is calculated as 1% to 5% and for HTLV-1-associated diseases in

History

In the 1970s, clinicians in Japan felt that the haematological malignancies they observed did not fit the pattern described in the literature of that time.4 They diagnosed, for instance, few cases of chronic lymphocytic leukaemia on one hand and many acute, aggressive T-cell malignancies on the other, particularly among patients from southwestern Japan. The impression of an autochthonous pathology led to the description of a clinical entity: adult T-cell leukaemia/lymphoma.4, 115

Pathogenesis

ATL is a

History

Long before HTLV-1 was discovered, neurologists had reported the frequent occurrence of a myelopathy of unknown origin in tropical areas. The first descriptions of this syndrome go back to the 19th century.139 The association with HTLV-1 was recognised independently in the Caribbean and in Japan in 1985–1986.5, 140 Soon thereafter, it was agreed to refer to this disease as HTLV-1-associated myelopathy/tropical spastic paraparesis.

Pathogenesis

The main pathological feature of HAM/TSP is a chronic

Strongyloidiasis

Strongyloides stercoralis is an intestinal nematode of tropical regions that can replicate within the human host, an unusual characteristic among helminths. In the normal strongyloides cycle, filariform larvae from the soil penetrate the human skin and migrate to the lungs. The larvae ascend the bronchi and are swallowed. Adult females stay and lay eggs in the intestinal mucosa. Rhabditiform larvae hatch, migrate to the intestinal lumen and pass with the faeces into soil. An autoinfection cycle

Conclusion

A quarter of a century after its first description, HTLV-1 is still a poorly recognised infection. Many carriers remain asymptomatic, which contributes to the silent transmission of the virus. Since several associated diseases can also occur in uninfected people, the role of underlying HTLV-1 often passes unnoticed. Even though important knowledge about the pathogenesis is emerging, there are no clear surrogate markers for follow-up and the proviral lifestyle of HTLV-1 complicates the

Search strategy and selection criteria

We used “human T-lymphotropic virus 1” (MeSH major topic) as the search term in PubMed and considered journal articles in English, Spanish, Portuguese, French, and Dutch. Reference lists of these articles were also reviewed and many articles were identified through searches of the files of the authors. We selected clinical and basic science articles related to prevalence, pathogenesis, diagnosis, clinical management, and prevention of HTLV-1 infection and associated diseases. For the selection

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