Human T-lymphotropic virus 1

From MicrobeWiki, the student-edited microbiology resource

A Microbial Biorealm page on the genus Human T-lymphotropic virus 1

Classification

Higher order taxa

Viruses; Retro-transcribing viruses; Retroviridae; Orthoretrovirinae; Deltaretrovirus; Primate T-lymphotropic Virus-1; Human T-lymphotropic Virus-1

Species

Human T-lymphotropic virus 1 (HTLV-1) is divided into 4 subtypes: A) Cosmopolitan B) Central African Group C) Melanesian Group D) New Central African Group

Description and significance

HTLV-1 is a retrovirus that has infected 10-20 million people worldwide, and is considered the first retrovirus to be causal for Adult T-cell leukemia (ATL). The HTLV-1 virus contains an enveloped virion that is spherical to pleiomorphic and is about 80-100nm in diameter. Transmission occurs through perinatal transmission by blood or breast milk, sexual transmission, or exposure to contaminated blood products. The infectivity of HTLV-1 is tightly cell-associated, and is mediated through a viral synapse, which suggests that the cell-free virus is largely non-infectious. Tax, a viral oncoprotein, is needed to initiate cellular transformation because HTLV-1 does not use viral capture of a cellular proto-oncogene for oncogenesis. Tax transforms cells through various mechanisms, including the creation of chromosomal instability, the amplification of centrosomes, the abrogation of DNA repair, the activation of cyclin-dependent kinases, and the silencing of p53 and spindle assembly checkpoints.

Genome structure

HTLV-1 contains a linear, dimeric, ssRNA(+) genome of 8,507nt , with a 5’-cap and a 3’poly-A tail. There are two long terminal repeats (LTRs) of about 600nt long at the 5’ and 3’ ends that contain the U3, R, and U5 regions. There is also a primer binding site (PBS) at the 5’end and a polypurine tract (PPT) at the 3’end. In addition to the essential viral genes gag, prt, pol, and env, HTLV-1 encodes regulatory and accessory genes for the pX region open reading frames (ORFs), which are located between the env gene and the 3’ portion of the viral genome. This region contains at least four partially ORFs which encode accessory proteins (p12, p13/p30), the Rex post-transcriptional regulator (ORF III) and the Tax protein (ORF IV). Tax activates transcription initiation from the viral promoter in the U3 region of the long terminal repeat, and Rex regulates viral gene expression post-transcriptionally by facilitating the cytoplasmic expression of the incompletely spliced viral mRNAs.

Virion structure

HTLV-1 is an enveloped virus that contains two identical copies of a plus single-stranded RNA genome and an outer envelope containing protruding viral glycoproteins. This virus is known as a retrovirus because the RNA genome directs the formation of a DNA molecule, which ultimately acts as the template for synthesis of viral mRNA. Because most retroviruses do not kill their host cells, infected cells can replicate, producing daughter cells with integrated proviral DNA. These daughter cells continue to transcribe the proviral DNA and bud progeny virions.

Some retroviruses contain cancer-causing genes called oncogenes. Cells infected by such retroviruses are oncogenically transformed into tumor cells, and are usually specific for certain cell types. HTLV-1 is known to cause leukemia and lymphoma, and primarily infects certain cells of the immune system known as CD4+ T-cells. It is considered a difficult virus to work with, however, because although HLTV-1 has the capacity to infect a number of cell types including T cells, B cells, and endothelial cells, the only cells susceptible to HTLV transformation are primary T-lymphocytes. These specified cells have cell-surface receptors that interact with viral proteins, which accounts for the host-cell specificity of the virus.

Epidemiology

HTLV-1 is anciently related to primate T-cell leukemia viruses (PTLVs) that share molecular and virological features. It is speculated that HTLV-1 was transmitted repeatedly in separate independent events from simians to humans beginning approximately 50,000 years ago. This course resulted in the formation of several viral subtypes around the world; for example, HTLV-3 and HTLV-4 have been identified recently from bush meat hunters in central Africa.

Ten to twenty million people worldwide are infected with HTLV-1, and it is considered an endemic in places such as southwestern Japan, Africa, the Caribbean Islands, and South America. HTLV-1 infection is rare in North Americans and Europeans but is frequent in inhabitants of Melanesia, Papua New Guinea and the Soloman Islands, as well as among Australian aborigines.

Pathology

Because of the long incubation period between viral exposure and disease onset, the exact mechanism of HTLV-1 pathogenesis remains unclear. Research has shown that the host cell's control of HTLV-1 replication is the primary determinant of virus expression and subsequent disease. It is also known that the transmission of HTLV-1 occurs through perinatal transmission by blood or breast milk, sexual transmission, or exposure to contaminated blood products, and that the infected cells must be passed from the infected individual or material because HTLV-1 transmits via cell to cell contact.

The process begins when an infected cell contacts an uninfected cell, forming a microtubule-organizing center (MTOC) that is polarized at the cell-cell junction. A virological synapse is then formed at the interface, which is triggered by the Tax protein located in ORF IV. The HTLV-1 GAG-complex and viral genomic RNAs then accumulate at the synapse and are released into the uninfected cell. The engagement of intercellular adhesion molecule 1 (ICAM1) increases the polarization of the MTOC at the point of contact, indicating that the interaction of ICAM1 and lymphocyte function-associated antigen 1 (LFA1) is important for HTLV-1 infection.

Tax plays an important role in the pathogenesis of HTLV-1 by stimulating viral gene expression and by deregulating expression of cellular genes. Tax has also been shown to activate transcription of a number of cellular genes involved in cell proliferation, and the expression of these growth-related genes has been implicated in contributing to the establishment of HTLV-1 associated pathogenesis. While Tax does not bind directly to DNA, it appears to stimulate RNA synthesis through protein-protein interactions with host cell transcription factors. The most well-studied of these interactions is with the ATF/CREB family of transcription factors, which bind to cyclic AMP-responsive elements in the HTLV-1 long terminal repeats.

HTLV-1 is the causative agent of at least two human diseases, namely adult T-cell leukemia (ATL), and a degenerative neurological disorder known as tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). A proportion of 1-3% of HTLV-1 infected individuals develop these diseases after prolonged viral persistance, usually after two decades of infection for ATL. Tax also plays an important role in the transformation of the virus, for its displays oncogenic potential in several experimental systems including the morphological transformation of rodent fibroblasts, induction of tumors in transgenic animals, and Herpes samiri vector immortalization of human T cells.

Current Research

Enter summarries of the most rescent research here--at least three required

References

[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.

Edited by student of Emily Lilly at University of Massachusetts Dartmouth.