Abstract
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA−CCR7−) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.
Highlights
Human T-lymphotropic virus type 1 (HTLV-1) infects 5–10 million individuals worldwide, with clusters of high endemicity in Japan, the Caribbean, the Middle East, subSaharan Africa, and South America [1]
HTLV-1 is the etiological agent of two lifethreatening diseases: a malignancy of CD4+ T-cells termed adult T-cell leukemia/lymphoma (ATLL) [2,3], and an inflammatory disorder with progressive neurological disability and motor impairment known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [4,5]
The HTLV-1 Proviral Load (PVL) was measured in DNA samples from blood, spleen, and mesenteric lymph nodes (MLN) and the values were normalized to the frequency of human T-cells (CD45+CD3+ cells)
Summary
Human T-lymphotropic virus type 1 (HTLV-1) infects 5–10 million individuals worldwide, with clusters of high endemicity in Japan, the Caribbean, the Middle East, subSaharan Africa, and South America [1]. CD4+ and CD8+ T-cells are the main targets of HTLV-1 infection in vivo. These cells display a CD45RO+ effector/memory phenotype [6] with increased levels of activation markers such as HLA-DR, CD25, and CD69 [7,8,9]. The infection triggers a T helper type 1 (Th1) immune response with robust expression of interferon-γ (IFN-γ) and IFN-γ inducible genes [10,11], and a high frequency of HTLV-1-specific CD8+ T-cells [12,13]. Two viral regulatory proteins are involved in this process: the transactivator (Tax) and the HTLV-1 basic leucine zipper (HBZ) proteins, which induce cell cycle and inhibit apoptosis of infected cells [14,15,16,17,18]. While HBZ is consistently expressed in ATLL cells [20], Tax expression is lost in approximately 60% of the cases [21]
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