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.

IntroductionHuman T lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL)/lymphoma and is strongly associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of other immune-mediated disorders. 1-3 Despite a strong immune response against HTLV-1, the virus typically is maintained as a persistent infection throughout the lifetime of infected subjects. Critical immunologic parameters, including efficient cytotoxic T-cell responses against HTLV-1-expressing cells, determine viral loads throughout the course of infection and are linked to disease outcomes. 4,5 There have been several reports focused on the effect of immune suppression on pathogenesis of HTLV-1 disease. 6-9 HTLV-1-infected patients who are concurrently treated with immunosuppressive drugs, typically for organ or bone marrow transplantation procedures, often exhibit an accelerated or altered course for the development of HTLV-1-associated diseases. [10][11][12][13] These patients typically receive drugs such as cyclosporine A (CsA) and tacrolimus (FK-506) to prevent organ graft rejection. There are limited reports of the effects of immune suppression on early HTLV-1 infection because of the lack of clinical materials and inability to simulate the initial exposure of HTLV-1 infection on humans.We have used the rabbit model of HTLV-1 infection, in part, because of the ease and consistency of transmission of the viral infection in this species. Rabbits have been used to confirm routes of transmission for the virus infection, monitor sequential immune responses against HTLV-1 infection, test vaccine approaches, and determine virus-host relationships during the course of infection. [14][15][16][17][18] Our current study reported in this work tested the effects of immune suppression on the early spread of HTLV-1 infection in an established rabbit model. New Zealand white rabbits were divided into groups and treated with 10 mg/kg CsA, 20 mg/kg CsA, or saline vehicle control before infection by intravenous inoculation of HTLV-1-infected rabbit cells. Another group of rabbits was treated with 20 mg/kg CsA 1 week after HTLV-1 infection. Plasma CsA concentrations were monitored to ensure that therapeutic concentrations of the drug were obtained during treatment periods. Immune suppression was monitored in the rabbits by measuring lymphocyte proliferation to a recall antigen and mitogen stimulation, as well as flow cytometry and hematologic analysis. HTLV-1 viral expression in rabbits was monitored by testing ex vivo lymphocyte HTLV-1 p19 production, serologic parameters, and proviral loads from peripheral blood lymphocyte cultures. CsA treatment before HTLV-1 infection enhanced early viral expression compared with untreated HTLV-1-infected rabbits, and did alter long-term viral expression parameters. However, CsA treatment 1 week after infection diminished HTLV-1 expression throughout the 10-week study course. Our data indicate that immunologic control during early virus exposure determine...

Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.

Rabbits have served as a valuable animal model for the pathogenesis of various human diseases, including those related to agents that gain entry through the gastrointestinal tract such as human T cell leukemia virus type 1. However, limited information is available regarding the spatial distribution and phenotypic characterization of major rabbit leukocyte populations in mucosa-associated lymphoid tissues. Herein, we describe the spatial distribution and phenotypic characterization of leukocytes from gut-associated lymphoid tissues (GALT) from 12-week-old New Zealand White rabbits. Our data indicate that rabbits have similar distribution of leukocyte subsets as humans, both in the GALT inductive and effector sites and in mesenteric lymph nodes, spleen, and peripheral blood. GALT inductive sites, including appendix, cecal tonsil, Peyer's patches, and ileocecal plaque, had variable B cell/T cell ratios (ranging from 4.0 to 0.8) with a predominance of CD4 T cells within the T cell population in all four tissues. Intraepithelial and lamina propria compartments contained mostly T cells, with CD4 T cells predominating in the lamina propria compartment and CD8 T cells predominating in the intraepithelial compartment. Mesenteric lymph node, peripheral blood, and splenic samples contained approximately equal percentages of B cells and T cells, with a high proportion of CD4 T cells compared with CD8 T cells. Collectively, our data indicate that New Zealand White rabbits are comparable with humans throughout their GALT and support future studies that use the rabbit model to study human gut-associated disease or infectious agents that gain entry by the oral route.

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