What we are learning on HTLV-1 pathogenesis from animal models

Abstract

Isolated and identified more than 30 years ago, human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma, an aggressive lymphoproliferative disease of activated CD4+ T cells, and other inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. A variety of animal models have contributed to the fundamental knowledge of HTLV-1 transmission, pathogenesis, and to the design of novel therapies to treat HTLV-1-associated diseases. Small animal models (rabbits, rats, and mice) as well as large animal models (monkeys) have been utilized to significantly advance characterization of the viral proteins and of virus-infected cells in the early steps of infection, as well as in the development of leukemogenic and immunopathogenic processes. Over the past two decades, the creation of new immunocompromised mouse strains that are robustly reconstituted with a functional human immune system (HIS) after being transplanted with human tissues or progenitor cells has revolutionized the in vivo investigation of viral infection and pathogenesis. Recent observations obtained in HTLV-1-infected humanized HIS mice that develop lymphomas provide the opportunity to study the evolution of the proviral clonality in human T cells present in different lymphoid organs. Current progress in the improvement of those humanized models will favor the testing of drugs and the development of targeted therapies against HTLV-1-associated diseases.

Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission

“…One of the major remaining questions on MTCT concerns the sites of primary passage/infection of HTLV-1 in the digestive tract. The mechanisms of HTLV-1 infection after oral inoculation should be addressed in vivo using a humanized mouse as a model of HTLV-1 infection [ 63 , 64 , 65 ], in complement to the rabbit model. In particular, combination of histopathological studies and bioluminescence imaging will allow determining the preferential sites of HTLV-1 entry (palatine tonsils, and/or gut).…”

Studies of retroviral infection in humanized mice

“…These models have provided complementary information to data obtained from other animal models of HTLV, which do not adequately model all aspects of viral pathogenesis, particularly the complex mechanisms underlying the process of leukemogenesis (Dodon et al, 2012). Early humanized mouse studies with HTLV focused on the use of SCID mice as recipients in a hu-PBL-SCID model, where PBL from asymptomatic HTLV-1 positive individuals or patients diagnosed with ATL or HAM/TSP were introduced to the mice (Feuer et al, 1993).…”

“…While rabbit, non-human primate, and rat models of HTLV-1 infection also exist, they similarly have limitations that make complementary studies with humanized mice valuable (reviewed in Dodon et al (2012)). For these reasons humanized mouse models have been extensively utilized to study many aspects of pathogenesis and treatment of retroviruses which infect humans.…”

Of mice, men, and HTLV-1

“…The observations reported by Tezuka et al present an interesting and original contribution of mouse models for biomedical research. 3 During the last 5 decades, intensive efforts to generate mouse models that allow a long-term reconstitution of the human hematolymphoid system (hHLS) in vivo have been achieved by successful genetic modifications of severe combined immunodeficient (scid) mice and by improving the engraftment procedures for human stem cells (hSCs). 4 Likewise, a stable ratio of B cells to T cells in the peripheral blood of these mice indicated the formation of a stable immune system.…”