Research

History

In 1977, epidemiologic studies revealed the presence of unusual clusters of adult T-cell 
leukemia in some areas of Japan, suggesting that a transmissible agent may be involved 
in the disease. The first description of Human T-cell Lymphotropic Virus type I (HTLV-I) 
came after the discovery of the human T-cell growth factor (Interleukin-2; IL2), allowing 
long term in vitro culture of T-cells and the establishment of T-cell lines from a patient 
with a cutaneous T-cell lymphoma. Soon afterward this virus was identified as the 
etiological agent of ATLL and the terminology HTLV-I was adopted. HTLV-I is transmitted 
through sexual contact, contaminated blood and from mother-to-child by breast feeding. It 
is estimated that 20 to 30 million people worldwide are infected with HTLV-I, which is 
mainly found in endemic areas such as Japan, Africa, South America, the Caribbean basin, 
Southern parts of North America, and Eastern Europe. More than 80,000 
leukemia/lymphoma deaths occur in the United States each year. The human T-cell 
leukemia virus type 1 (HTLV-I) is associated with a fatal and aggressive T-cell type 
leukemia known as Adult T-cell Leukemia/Lymphoma (ATLL). The research conducted in my 
laboratory is divided into three entities.

The HTLV-1 transactivator protein Tax

HTLV-I encodes a transactivator, Tax, which is critical for virus-induced cellular 
immortalization and pathogenesis. Tax stimulates transcription through CREB, NF-kB and 
SRF resulting in deregulated expression of cellular genes leading to leukemia. We are 
interested in the early events of Tax-mediated human T-cell immortalization (IL-2-
dependent). As part of the immortalization process, we are interested in deregulation of 
apoptotic pathways, genetic instability and reactivation of the human telomerase. We 
found that HTLV-I Tax is a strong activator of hTERT expression and activity. We also 
published several studies on telomere length regulation, reversal of HTLV-I transformed 
phenotype, and induction of senescence. We also study new possibilities to prevent the 
growth of HTLV-I leukemic cells. Several studies using novel combinations of drugs have 
yielded encouraging results in vitro.

The HTLV-1 regulator protein p30II

We have found that the HTLV-I p30 II is a post transcriptional negative regulator 
of virus expression (Nature medecine, 2004). The mechanism employed is striking as p30 
specifically retains viral mRNA encoding for positive regulators of virus expression. The 
molecular details are being investigated. We hypothesize that p30 II is required for in vivo 
replication by reducing the levels of Tax and Rex expression, thereby preventing immune 
recognition and clearance of infected cells. Thus, p30 II may serve to promote viral 
persistence and clonal expansion of infected cells through cellular replication and may 
represent a target for the eradication of latent viral reservoir. Our model was subsequently 
confirmed in HTLV-II.

The transformation process by HTLV-1
      
In vitro, infected T-cells usually expand through an initial phase in which cells 
remain strictly dependent on exogenous IL-2, referred to as immortalized. After several 
months in culture a selected clonal or oligo-clonal cell population becomes independent of 
IL-2, referred to as transformed. Biochemically, the distinction between HTLV-1-
immortalized and -transformed T-cells has been associated with constitutive activation of 
the Jak/STAT signaling pathways. These events may reproduce those that occur in vivo 
during the transition of patients from the asymptomatic/chronic to the acute type ATLL, 
with a median survival of 6-9 months. Constitutive activation of the Jak/STAT pathway and 
down regulation of the protein tyrosine phosphatase SHP-1 is a hallmark of the 
transformation process by HTLV-I. In addition, a positive correlation between proliferation 
of infected cells and Jak/STAT activation has been found in ATLL patients. Intriguingly, the 
Jak/STAT pathway is not activated in HTLV-II transformed cells in vitro or ex-vivo patient 
samples and HTLV-II does not induce human T-cell leukemia/ lymphoma. In early stages of 
ATLL viral proteins, Tax and Rex, are involved in up-regulated expression of IL-2 and the IL-
2R (112) and possibly autocrine proliferation of infected cells. Although it is uncertain 
whether or not in late stages of ATLL these proteins are still expressed at sufficient levels 
to maintain activation of the IL-2/ IL-2R pathway, ATLL tumor cells always express high 
levels of IL-2Rα chain and usually display constitutive Jak/STAT pathway activation. In 
support of these observations previous studies have demonstrated that the IL-2/ IL-2R 
signaling pathway is critical for continuous proliferation of ATLL cells and tumor formation 
in a mouse model.