Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo

Abstract

BackgroundAdult T cell leukemia results from the malignant transformation of a CD4+ lymphoid clone carrying an integrated HTLV-1 provirus that has undergone several oncogenic events over a 30-60 year period of persistent clonal expansion. Both CD4+ and CD8+ lymphocytes are infected in vivo; their expansion relies on CD4+ cell cycling and on the prevention of CD8+ cell death. Cloned infected CD4+ but not CD8+ T cells from patients without malignancy also add up nuclear and mitotic defects typical of genetic instability related to theexpression of the virus-encoded oncogene tax. HTLV-1 expression is cancer-prone in vitro, but in vivo numerous selection forces act to maintain T cell homeostasis and are possibly involved in clonal selection.ResultsHere we demonstrate that the HTLV-1 associated CD4+ preleukemic phenotype and the specific patterns of CD4+ and CD8+ clonal expansion are in vivo selected processes. By comparing the effects of recent (1 month) experimental infections performed in vitro and those observed in cloned T cells from patients infected for >6-26 years, we found that in chronically HTLV-1 infected individuals, HTLV-1 positive clones are selected for tax expression. In vivo, infected CD4+ cells are positively selected for cell cycling whereas infected CD8+ cells and uninfected CD4+ cells are negatively selected for the same processes. In contrast, the known HTLV-1-dependent prevention of CD8+ T cell death pertains to both in vivo and in vitro infected cells.ConclusionsTherefore, virus-cell interactions alone are not sufficient to initiate early leukemogenesis in vivo.

Human T cell leukemia virus type 1 (HTLV-1) and oncogene or oncomiR addiction?

“…Hence, the expression of Tax-alone in transgenic mice was found to be fully proficient for in vivo tumorigenesis [12][13][14]. Indeed, current data are consistent with the notion that Tax expression in infected humans greatly accelerates the in vivo cycling of T cells [15]. Intriguingly, when ATL patients are followed over time, a puzzling finding reveals that Tax expression in vivo is absent from approximately 60% of late leukemias [16].…”

Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy

“…This asymmetry in detection may be because HTLV-1 infection recruits CD4+ T-cells into proliferative cell cycling while it seems to simply delay cell death in CD8+ T-cells (Sibon et al 2006). Thus, the differential outcome of the virus on CD4+ and CD8+ cell proliferation may be more important than receptor-binding and cellular entry differences in dictating the apparent specificity for CD4+ cells (Zane et al 2010). However, there is also evidence that cellular receptors play an important role in determining the cellular tropism of HTLV-1 (Jones et al 2006).…”

“…In this regard, the virus’ strategy to increase the number of infected cells by promoting cellular proliferation is purposeful. Indeed, a long standing observation is that HTLV-1 induces clonal proliferation of infected cells in vivo (Cavrois et al 1998) (Etoh et al 1997) (Zane et al 2010). …”

The Cellular Autophagy Pathway Modulates Human T-Cell Leukemia Virus Type 1 Replication

“…After 3 days, the cells were washed with PBS three times to remove the MT2 or Jurkat cells; the washed adherent HeLa cells were then lysed for Western blotting or fixed by 4% paraformaldehyde in PBS for confocal microscopy analysis. For HTLV-1 infection of primary peripheral blood mononuclear cells (PBMCs), PBMCs were enriched from donor blood using Ficoll density gradient separation, and 1 ϫ 10 6 cells were cocultured with lethally ␥-irradiated (60 Gy) MT2 cells at a ratio of 5:1 in RPMI 1640 with 10% FBS, 2 mM/liter L-glutamine, and antibiotics in the presence of 100 U/ml of recombinant interleukin-2 for 14 days as described previously (55).…”

“…The HTLV-1 Tax protein increases cellular proliferation (55,61), inhibits apoptosis (62), impairs cell cycle checkpoints (62,63), and induces DNA damage (64)(65)(66)(67)(68). We wondered whether Tax also contributes to HTLV-1-induced autophagosome accumulation ( Fig.…”