The Interaction of Cell-Human T-cell Leukemia Virus Type 1 (HTLV-1) in the Development of Adult T-cell Leukemia/Lymphoma: The Molecular Aspects of Leukemogenesis

Adult T-cell leukemia (ATLL) is a type of invasive T-cell malignancy that develops after a long-term chronic infection with the lymphotropic T-cell virus type 1 (HTLV-1). The disease typically produces skin lesions of variable kinds, some of which can be similar to Sezary lesions; hypercalcemia with lytic lesions of bones; lymphadenopathy; diagnostic morphology of leukemic cells with lobulated nuclei; and an extremely aggressive clinical course. ATLL also almost always involves the mature CD4+ T-cells. Also, HTLV-1 causes other diseases and mild immune deficiency even in the absence of malignancy besides ATLL. These include the fatal neurologic disease tropical spastic paraparesis (now known as HTLV-associated myelopathy), uveitis and iritis, peripheral neuropathies, and arthritis. All of these diseases could be autoimmune, but their exact mechanisms are not yet known. HTLV-1 was the first human retrovirus to be discovered and it was isolated in 1980 from a cell line of a cutaneous T-lymphocyte lymphoma. HTLV-1 has an ancient origin in the form of simian T-cell leukemia virus 1, different strains of which can be found in African and Asian primates. The virus is not found in American primates. The HTLV-1 virus has a single strand of RNA for its genome and primarily targets the T-cells of the immune system. Phylogenetic analyses have led to the naming of four major types of HTLV-1, each with its own geographic focal areas: Cosmopolitan subtype A (endemic in Japan and found in the Caribbean, Central, and South America, North and West Africa, as well as the Middle East); Central African subtype B; Australia-Melanesian subtype C; and Central African/Pygmies subtype D. Subtype C is the most divergent of the four subtypes, likely reflecting the opportunity for evolution in geographically isolated areas of the Pacific. Antibody tests developed to detect the immunological response to infection with HTLV-1 have been used to investigate the population distribution of infection, modes of transmission, and associations with other diseases. As with other human retroviruses, including most notably HIV, the presence of antibodies in a person is understood to be synonymous with infection, and is lifelong. HTLV-1 infection is a neglected disease despite affecting around 15 million people worldwide and it is the causative agent for two diseases such as adult T-cell leukemia and HTLV-1 associated myelopathy / tropical spastic paraparesis. Simultaneous infection by HTLV-I and the etiology of their pathogenic and disease outcomes have become a global health matter over the past 10 years. Three main methods of virus transmission have been confirmed: 1- mother-to-child transmission: Mother-to-child transmission can be produced through the placenta, perinatally that are uncommon, or by breastfeeding. Nonetheless, evidence suggests that most cases of mother-to-child transmission are produced by ingestion of breast milk. Cell-free virions are not usually detected in breast milk, thus transmission by infected cells is much more plausible. In fact, different types of cells that are found in breast milk such as lymphocytes, macrophages, and epithelial cells of mammary glands can be susceptible to HTLV-1 infection. 2- sexual transmission, mainly from man to woman: Few studies are done about the most frequently affected gender. The initial studies suggested that female to male transmission of HTLV-1 was much more frequent than male to female transmission, but later studies have shown that this difference is not as significant as previously thought, and male to the female transmission could play a more important role. Sexual transmission requires entry through a mucosal barrier, the virus could be transmitted through damaged or infected mucosa or transcytosis across epithelial cells. Consequently, male to female transmission is more efficient in cases of men with a history of penile sores or ulcers. However, the semen also contains several cells that could be infected by HTLV-1, such as CD4+ T-cells, macrophages, and dendritic cells that can have a role in sexual transmission. Regarding female to male transmission, in women infected by HTLV-1, infected cells have been frequently detected in cervical inflammatory secretions and cervix carcinoma. Some of the data obtained studying other retroviruses have been extrapolated to HTLV-1. However, not all this information can be faithfully extrapolated to HTLV, and therefore, further investigations are needed to achieve more accurate data. 3- blood cell components: Blood transmission can occur by transfusion of whole blood or cellular blood products and in the context of needle sharing among intravenous drug users. In the case of blood transmission, passing across a mucosal barrier is not needed, and infected cells can transmit the virus directly by cell-to-cell transmission or by cell-free transmission to dendritic cells. As we saw previously with other routes of transmission, cell to cell transmission is also the most effective way to transmit the virus by blood. A study that compared viral transmission following transfusion of plasma from individuals with different human retroviruses showed that seroconversion occurred in 89% of the individuals who received plasma from HIV-1 infected individuals, but in none of those who received plasma from HTLV-1 or HTLV-2 infected individuals. Several studies suggest that individuals who acquire HTLV-1 by blood are more prone to develop inflammatory disorders, while individuals who acquire the virus during breastfeeding are more likely to develop T cell malignancies. In addition to some factors that can modify this likelihood, such as the age of infection, amount of virus, and immune response, this implies that the mechanism of infection could affect different cell populations and it could be a determinant to develop an inflammatory disease or cancer. A person can be infected with HTLV-I by direct contact with certain body fluids from an infected person. Its prevalence greatly varies in different regions of the world and even in different communities within one restricted region. The virus tends to remain in families due to its routes of transmission. Therefore, the vertical mitotic transmission plays an important role in the persistence of HTLV-I infection. Complex retroviruses such as the HTLVs have an extra gene or several extra genes, but these genes are not oncogenes and cannot be found in normal cellular DNA. The extra gene or genes may cause growth promotion and/or increase of genetic instability. In HTLV-1, the Tax causes growth promotion and increases genetic instability. Mathematical modeling of within-host viral infection has witnessed significant development. Tax-expressing HTLV-infected cells proliferate faster than susceptible CD4+ T cells and silent HTLV-infected cells. This leads to an increase in proviral load. In HTLV-I infection, CTLs also play an effective role in controlling the infection. CTLs can recognize and kill the Tax-expressing HTLV-infected cells moreover, they can reduce the proviral load. Since there is no available antiviral, treatments that can completely eliminate HTLV-I from the body, then this virus, can lead to fatal diseases. HTLV-I is a retrovirus that infects the susceptible CD4+ T cell and destroys its functions. The aim of this study was to evaluate the progress made over the last 30 years in the recognition of HTLV-1 infection, cloning, gene expression, and its resulting cell transformation, as well as methods to prevent human T-cell lymphotropic virus infection and cellular lymphoma/leukemia T cells.

Systematically, we searched PubMed, Google Scholar, Scopus, and Science Direct databases using the following keywords: Leukemia, Lymphoma, ATLL, HTLV-1, and transmission.

HTLV- infections are considered a neglected disease nowadays, and despite recent advances in chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and supportive care, the prognosis of patients with ATLL is one of the weakest among hematologic malignancies. Prenatal screening for HTLV-1 should be performed in endemic areas with accurate information and advice. The development of a safe and effective vaccine can be an important tool in protecting vectors against ATLL. As a result, research to avoid infection and associated diseases focused on the development of effective treatments or vaccines against the virus is needed. In this article, we provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATLL and HTLV diseases.