Human T-lymphotropic Virus 1

Introduction

The human T-lymphotropic virus 1 (HTLV-1) was the first retrovirus identified, even before the human immunodeficiency virus (initially called HTLV-3). It is a delta retrovirus currently linked to various clinical manifestations, from autoimmune disease (such as tropical spastic paraparesis) to immunodysregu­lation (as in the case of infective dermatitis), to infections (crusted scabies) and neoplastic disorders (adult T-cell leukemia lymphoma). Most patients, however, remain asymptomatic throughout their life, ignoring their infectious status, and, therefore, unwittingly transmitting the disease to relatives, partners, and, through blood products, even to people they have never met.

History and Epidemiology

Tropical spastic paraparesis (TSP), also known as HTLV-1-­associated myelopathy (HAM) was described in Jamaica as far back as 1897. Adult T-cell leukemia–lymphoma (ATL) was described as an endemic hematological malignancy in Japan in 1977. However, the correct identification of the virus took place only in 1980, when Gallo and coworkers isolated it from a patient with a hematological malignancy. Infective dermatitis (ID) was clinically described in Jamaican children by Sweet in 1966, but the connection with the HTLV-1 infection was not made until made many years later, in 1990, by La Grenade.

The origin of the virus is, for most researchers, located in Africa, with a shared common origin with simian T-lymphotropic virus (STLV), under the umbrella of the primate T-lymphotropic viruses (PTLV). The spreading of the virus through Central Africa took place around 27 300 years ago. The subtypes of HTLV-1 (a to g), developed around the same time as the simian counterparts, between 21 000 and 5300 years ago.

Around 10–20 million people are infected with HTLV-1 worldwide. Despite the African origin of the virus, only a few countries in that continent, such as Guinea Bissau, Togo, and Cameroon, have reported infection incidence rates of around 1%; this is most likely a result of lack of information rather than the true absence of the infection. Recent reports of series of ID patients from Senegal and South Africa have revealed a wider distribution of the virus through the African continent. In Asia, the highest prevalence is found in specific areas of Southern Japan. Niches of infection have been located in other areas of the Asian continent including Taiwan, the nearby Chinese province of Fujian, and as far as Iran. HTLV-1 is endemic in Papua New Guinea and particularly prevalent in the aboriginal population of Melanesia and Australia (where the HTLV-1 subtype c predominates), Eastern Europe (Romania), the Caribbean (Jamaica and Martinique), and South America (French Guyana, Surinam, Guyana, Brazil, Colombia, Perú, Argentina, and Chile). Prevalence studies in the endemic areas have correctly identified risk factors associated with HTLV-1 infection including older age, female gender, transfusion history, history of prolonged breast-feeding, other sexually transmitted diseases, drug abuse, and low socioeconomic status.

Pathogenesis

Even though both are retroviruses, there are marked differences between HTLV-1 infection and that of HIV. As opposed to HIV, in which most of the infected population will develop some sort of complication as a result of the infection, the majority of HTLV-1-infected populations are asymptomatic carriers (AC) and remain so throughout their lives. No more than 5% of them will eventually develop some complication. The risk of developing HAM / TSP varies from 0.3% to 4%; for ATL, the calculated risk is 1–5%.

Clinical manifestations of the infection are listed in Table 15-1 .

HTLV-1 is a retrovirus with a special tendency to infect human T cells. The mechanisms of transmission are horizontal, through either sexual contact or blood product, or vertical, as in the case of breast-feeding. Blood products may result in transmission rates as high as 40%. Breast-feeding, in comparison, may result in overall rates of 15–25%; prolonged breast-feeding may result in even higher rates. Placental or perinatal transmission of the virus seems to be extremely rare. After the initial infection, the virus is rapidly integrated in the DNA of the infected lymphocyte, inducing a clonal reproduction of such cell, with the provirus included in the genetic material. No viral particles are liberated into the blood stream, so there is no detectable viral load in the serum.

The mechanisms by which the virus produces disease vary, depending on the kind of disease manifestation. In the case of ATL, the genetic material of the virus includes several genes encoding different proteins involved in the pathogenesis of the malignant process. The most significant of those are the Tax protein and HTLV-1 basic leucine zipper (HBZ). The process is initially based on increased production of the Tax protein. Tax promotes the transcription of its own proviral genome, but it also promotes transcription of cellular genes, including cytokine (e.g., interleukin-2), cytokine receptor (interleukin-2Rα), and antiapoptotic genes, resulting in uncontrolled reproduction and survival of CD4, CD25(+) T cells, even those with marked chromosomal abnormalities. However, in later stages, Tax loses its role in leukemogenesis; at which point it is HBZ, with its proliferative capabilities, that takes command of the process. HBZ mRNA has been detected in 100% of ATL cells. Eventually, cells with mutations accumulate, giving origin to a clone of malignant lymphocytes that manifest clinically as either leukemia or lymphoma.

The pathogenesis of ID shares some characteristics with HAM / TSP, including a high proviral load, a predominance of CD8(+) cells in the infiltrate, and high levels of interferon gamma (IFN-γ) and tumor necrosis factor (TNF). However, rather than producing cytotoxicity and tissue damage as in HAM / TSP, the dysregulation at skin level mimics diseases such as atopic dermatitis. Filaggrin in the skin of ID patients has been reported to be low, just as has been commonly reported in atopic dermatitis (AD). Colonization by Staphylococcus aureus and β-hemolytic Streptococcus is also commonly seen in ID and atopic dermatitis, and undoubtedly the presence of those bacteria plays a role in the perpetuation of both processes. IgE levels are characteristically high in atopic dermatitis; in ID, the levels of IgE are higher that in asymptomatic HTLV-1-positive patients, but not as high as in atopic counterparts; coincidentally, pruritus is never as severe in ID as it is in AD.

One question remains to be clarified: why is it that not all, but only a minority, of patients infected with the HTLV-1 develop the clinical manifestations? The answer probably lies in genetic, nutritional, and environmental factors. For example, in Japanese patients, the presence of HLA-An02 and Cn08 is associ­ated with decreased risk of developing HAM / TSP, and lower proviral load.

The almost complete absence of ID in Japanese populations infected with HTLV-1, otherwise susceptible to ATL and HAM / TSP, also underlies the existence of genetic or environmental factors as being important in determining who will become symptomatic from the infection.