Human T cell Lympe photropic Virus Type 1(HTLV-1) which also called the Adult T-cell lymphoma virus type-1 is a positive, single stranded RNA. In 1979, Drs. Bernard Poiesz and Francis Ruscetti discovered the first human retrovirus, HTLV. The virus was isolated from the patient with a T-cell malignancy. HTLV has infected human for many decades but the knowledge for this virus has been recently revealed. The virus caused severe disease which are "neoplastic disease (adult T-cell leukaemia/lymphoma), inflammatory syndromes(HTLV-1- associated myelopathy/tropical spastic paraparesis and uveitis amoung(others), and opportunistic infections (including Strongyloides Stercoralis hyperinfection and others)" (Verdonck 266).
A second human retrovirus (HTLV-2) was discovered after HTLV-1. HTLV-2 was found mostly in North, Central and South America as well as central and west Africa. HTLV-2 has approximately 70% similar genome structure with HTLV-1. HTLV-3 and HTLV-4 were discovered after HTLV-2 but HTLV-1 was interested of scientists.
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Roughly 20 million people worldwide are infected with HTLV-1 and 90% of the infected individuals are carriers throughout their lives (Shors 255). In recent years, most developed countries performed HTLV-1 screening of blood donors and many developing countries. Only a small number of HTLV-1 infected individuals develop leukemia and generally occurs decades after initial infection. The development of T-cell malignancy remains poorly understood.
The classifications, structures, life cycle, diseases, treatments of HTLV-1 are discussed in this paper. The public health impact and epidemiology are included as well as the prevention.
Structure and classification of HTLV-1:
Viruses classified based by six different nucleic acids which their genetic information is stored. The six nucleonic acids are double-stranded DNA (+/-), single stranded DNA (+), double stranded RNA (+/-), single stranded RNA (+), single stranded RNA (-), and RNA retroviruses (+). The (+) and the (-) signify complementary strand of nucleic acid. HTLV-1 is from the Retroviridae family, Orthoretrovirinae subfamily, and Deltaretrovirus genus.
In general, the viron consist of enveloped particles about 100-120 nm in diameter. The RNA molecule is 7-10 kilobases in length. The envelope, RNA and proteins are the main components of virion. The proteins made up protease, gag proteins, env proteins and pol proteins. "Gag proteins are major components of the viral capsid, which are about 2000-4000 copies per virion. Protease is expressed differently in different viruses. It functions in proteolytic cleavages during virion maturation to make mature gag and pol proteins. Pol proteins are responsible for synthesis of viral DNA and integration into host DNA after infection. Finally, env proteins play role in association and entry of virion into the host cell"(Coffin 26). Retroviruses are different from DNA viruses because they have RNA in their genome instead of DNA. The RNA must be copied into DNA prior to integration into the host chromosome (Shors 255). Keep in mind, only + mRNA viral could translate to virus protein.
In HTLV-1 life cycle, the single stranded RNA is converted to double stranded DNA and then inserted into the DNA of human host cell. This form of insertion is known as provirus. In other word, usually DNA transcribed into RNA and RNA translated into protein. For retroviruses is different. First the RNA is reverse trascribed into DNA, which integrated into DNA of human host cell, and then goes under the standard transcription, translation process.
ssRNA ---------------ïƒ dsDNAïƒ integration ïƒ mRNA ïƒ protein
Upon entry of the retrovirous, virion associated reverse trascriptase copies genome into a double stranded complementary DNA. In the process, two long terminal repeats (LTRs) are formed (U3-R-U5). Double stranded cDNA integrates randomly to form provirus. Then primary transcript spliced to produce two mRNA: gag-pol and env. The frameshift after gag ORF leads to translation of pol. Then gag cleaved into necleoprotein, capsid and matrix proteins. Later, pol cleaved into protease, ingrase, RDRP and Rnase H.
The HTLV-1 virus "makes optimum use of its genome by using multiple RNA ribosomal frame shifts and transcript splicing patterns, including differential start sites for protein translation" (Verdonck 268).
HTLV-1 infects primarily CD4+ T-lymphocyte. A subset of T-helper cells which called Th1 is activated with this virus. The explosion of Th1 cells and overproduction of Th1 related cytokines is the result of this virus activation. As a result, the cytokines cause a control of the Th2 lymphocytes and decline production of Th2 cytokine. As a result, the infected host cell has decrease ability in an efficient immune response to attack organisms that require mainly Th2 dependent response.
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The term tropism means which cell typesHTLV-1 infected. As it mentioned before, HTLV-1 primarily found in CD4+ T cells. CD8+ T cells, B cells, and dendritic cells are other cell types that contain HTLV-1.
HTLV-1 is transmitted from mother to child either via the placenta during the birth or through breastfeeding. It is transmitted from male to female during sexual intercourse, but there is no evidence of female to male transmission. Blood transfusions are an additional and efficient route of transmission.
The majority of the individuals infected with HTLV-1 are asymptomatic carriers. The virus caused severe disease which are "neoplastic disease (adult T-cell leukaemia/lymphoma), inflammatory syndromes (HTLV-1- associated myelopathy/tropical spastic paraparesis and uveitis amoung others), and opportunistic infections (including Strongyloides Stercoralis hyperinfection and others)" (Verdonck 266). In order for a human being to develop any of the diseases related to this virus depends on few factors. Age, the route of infection, and geographical areas are some of the factors. In addition, urinary tract disorders, arthritis, major depression and fibromyalgia are found in HTLV-1 infected people. Either they related to psychological distress because of the infection or share a pathological mechanism with HTLV-1 associated diseases (Goncalves et al. 577).
Most people have no symptoms and do not get leukemia or myelopathy. Some of the signs and symptoms of HTLV myelopathy are motor and sensory changes in the extremities, spastic gait in combination with weakness of the lower limbs, clonus , bladder dysfunction and bladder cancer (Goncalves et al. 581)
Adult T-cell Leukemia/lymphoma (ATL) is an aggressive type of malignancy of T cells. It has a short survival and found in less than 5% in HTLV-1 infected people. ATL is more common in adults between 20 to 30 years after the beginning of HTLV-1 infection. Also, it's more common in males. People that infected in the childhood have a higher risk of rising ATL (Goncalves et al. 581). For example, in Jamaica and Brazil the occurrence of ATL is predominates in the fourth decades and in Japan in the fifth decades. Based by these data, scientists believed local factors play a role in disease pathogenesis.
Treatment for viral infected disease depends on the type of the disease and the virus. Chemotherapy is the major treatment but it varies from careful observation to aggressive chemotherapy. ATL is the common disease from HTLV but the prognosis for ATL remains poor. Aggressive chemotherapy is required for ATL such as R-CHOP. "Patinent with aggressive ATL have a poor prognosis because of the multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency" (Goncalves et al. 580).
HTLV myelopathy have a limited treatments and it's only focus on symptomatic therapy which may have temporary improvement. Many studies have been done but it did not have clinical benefits. Lately a study of valproic acid combined with zidovudine showed a good result in decreasing the number of cells infected with HTLV.
The prognosis for ATL and other related disease are poor. There is no vaccine available yet but scientistis are trying to control the diease by preventing it. After the transfusion-trransmitted HTLV-1 in japan in 1986, many countries started screening the blood donors(Goncalves et al. 580). HTL-1 positive individual are advised no to donate a blood, organ, or milk. Prenatal screening is mandatory in some geographical region. Safe sex and using the condom is highly recommended and aavoiding multiple partner and receiving sex for money is prohibited. Education and counseling of intravenous drug users (IDU) is effective to reduce the harm of HTLV-1 infection. Counseling includes information about the virus, disease, transmission, the possible source of transmission and training people how to prevent these fatal diseases.
Public health impact:
Epidemiologic aspect of HTLV-1 infection studied through the years. HTLV-1 is endemic in parts of Japan, South America, Africa, and the Caribbean, southern Italy and Taiwan. The reasons why is endemic in Japan and not the neighbor countries such as Korea and china is not known. In United States, the HTLV-1 infected populations are found among the IV-drug users. Also, it's more significant in African American than any race especially in the southeast part of the country.
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The city of Mashhad is the capital of Khorasan, the northeastern province of Iran, which has been recognized as an area where HTLV-1 infection is endemic. According to Mohammad Reza Abbaszadegan's research, 28,926 donors with a mean age of 32 years were screened in a 6 months period. Of these donor, 228 tested positive by ELISA. The prevalence of HTLV-1 infection in their study was 0.77% among blood bank donors, which reconfirms the city of Mashhad as an area where the virus is endemic compared to other region in the world. The incidence was correlated with increasing age, and it was higher in female than in males (Abbaszadegan 2593).
After 25 years of its first discovery, HTLV-1 is still a poorly known infection. The disease could occur in uninfected people, so the role of HTLV-1 stayed unnoticed. The treatment is restricted to symptomatic relief. Unclear proviral lifestyle of HTLV-1 causes of not having antiviral drugs. My cousin died because of ATL at the age of 18. I hope, the discovery the treatment for this disease happen very soon so it put a smile on people's face.
Abbaszadegan, Mohammad Reza., Mehran Gholamin, Abbas Tabatabaee, Reza Farid, Massoud
Houshmand, and Morteza Abbaszadegan. "Prevalence of Human T-Lymphotropic Virus Type 1 among Blood Donors from Mashhad, Iran." Journal of Clinical Microbiology. 41 (2003): 2593-2595
Verdonck, Kristien., Elsa Gonzalez, Sonia Van Dooren, Anne-Mieke Vandamme, Guido
Vanham, Eduardo Gotuzzo. "Human T-Lymphotropic virus 1: recent knowledge about an ancient infection." Lancet infected Disease. 7 (2007): 266-281.
Goncalves, Denise Utsch., Fernando Augusto Proietti, Joao Gabriel Ramos Ribas, Marcelo
Grossi Araujo, Sonia Regina Pinheiro, Antonio Carlos Guedes, and Anna Barbara F. Carneiro-Proietti. "Epidemiology, Treatment, and Prevention of Human T-cell Leukemia Virus Type 1-associatted Disease." Clinical Microbiology Reviews. 23 (2010): 577-589.
Shors, Teri. Understanding VirusesÂ . Massachusetts: Jones and Bartelett, 2009.