Essential Role of HTLV-1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice

Human T cell leukemia virus type-1 (HTLV-1) is the ethological agent of adult T cell leukemia/lymphoma (ATLL) and a number of lymphocyte-mediated inflammatory conditions, including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 orf-I encodes two proteins, p8 and p12, whose function in humans is to counteract innate and adaptive responses and support viral transmission. However, the in vivo requirements for orf-I expression vary in different animal models. In macaques, the ablation of orf-I expression by the mutation of its ATG initiation codon abolishes the infectivity of the molecular clone HTLV-1p12KO In rabbits, HTLV-1p12KO is infective and persists efficiently. We used humanized mouse models to assess the infectivity of both HTLV-1WT and HTLV-1p12KO We found that NOD/SCID/?C-/- c-kit+ mice engrafted with human tissues one day from birth, designated NSG-1d, are highly susceptible to infection by HTLV-1WT and a syndrome characterized by the rapid polyclonal proliferation and infiltration of CD4+CD25+ T cells to vital organs, weight loss, and death. HTLV-1 clonality studies revealed the presence of multiple clones of low abundance, confirming the polyclonal expansion of HTLV-1-infected cells in vivo Infection by HTLV-1p12KO in a Bone Marrow-Liver-Thymus (BLT) mouse model prone to graft-versus-host disease occurred only following reversion of the orf-I initiation codon mutation within weeks of exposure and was associated with high HTLV-1 DNA in blood and the expansion of CD4+CD25+ T cells. Thus, the incomplete reconstitution of the human immune system in BLT mice may provide a window of opportunity for HTLV-1 replication and the selection of viral variants with higher fitness.IMPORTANCE Humanized mice constitute a useful model for studying the HTLV-1-associated polyclonal proliferation of CD4+ T cells and viral integration sites in the human genome. The rapid death of infected animals, however, appears to preclude the clonal selection typically observed in human ATLL, which normally develops in 2 - 5% of individuals infected with HTLV-1. Nevertheless, the expansion of multiple clones of low abundance in these humanized mice mirrors the early phase of HTLV-1 infection in humans, providing a useful model to investigate approaches to inhibit virus-induced CD4+ T cell proliferation. Copyright © 2019 American Society for Microbiology.

See More