Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

Abstract

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.

Sexual transmission of human T-cell lymphotropic virus type 1

“…Therefore, infl ammatory conditions might recruit lymphocytes to the genital tract, where they are infected with HTLV-1 particles. Conditions that are associated with an increased number of lymphocytes in cervicovaginal secretions and semen might result in an increased excretion of infected cells and a consequently higher risk of HTLV sexual transmission 81,82 . Zunt et al 61 detected cervical shedding of HTLV-1 deoxyribonucleic acid (DNA) in 68% of 63 HTLV-1-infected Peruvian sex workers.…”

Animal Models of Bovine Leukemia Virus and Human T-Lymphotrophic Virus Type-1: Insights in Transmission and Pathogenesis

“…Animal models of BLV and HTLV-1 transmission and spread have provided fundamental information about viral and host determinants of infection (2,58,(91)(92)(93). Rabbits are a consistent species to model HTLV-1 infection in humans, as was first reported using intravenous inoculations of the transformed T cell lines from human and rabbit sources.…”

“…In the case of HTLV-1, alternative splicing of ORF I and II yields mRNAs that encode for p27, p12, p30, and p13. The nonstructural genes encoded from ORFs I and II are vital for viral infectivity, maintenance of the virus life cycle, and proviral loads in vivo, as well as host cell activation and regulation of viral gene transcription (58). The genes from ORF I and II can be detected in HTLV-1-positive cell lines and in patients, but detection of the actual proteins has been difficult owing to the low amounts that are expressed (reviewed in Reference 61).…”

“…Thus, by targeting NFkB, the virus activates prosurvival and antiapoptotic genes, enhancing cell survival. HTLV-1 Rex is a 27-kDa phosphoprotein encoded by pX ORF III, which contains an RNAbinding domain, nuclear localization and export sequences, and a multimerization domain (8,58,59). Rex acts posttranscriptionally to facilitate nuclear transport of unspliced and singly spliced viral RNAs to the cytoplasm favoring structural gene translation and viral proteins required for assembly.…”

Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth

“…1,[5][6][7] Worldwide it is estimated that 15-20 million people are infected with HTLV-1, but only 3-5% of the infected subjects develop HAM/TSP. 8,9 Histologically, this disease is considered a central nervous system (CNS) axonopathy caused by alterations in axoplasmic transport, producing a degenerative process in the axon without affecting the cell body. 10 Spinal cord atrophy in HAM/TSP is observed in the thoracolumbar cord followed by cross-sectional studies.…”