Christophe P. Nicot, PhD
Professor, Department of Pathology & Laboratory Medicine
Director, Center for Viral Pathogenesis
PhD, University of Bordeaux, France, 1995
Postdoctoral: National Cancer Institute, Uniformed Services University of the Health Sciences, Case Western Reserve University
In 1977, epidemiologic studies revealed the presence of unusual clusters of adult T-cellleukemia 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.
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.
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.
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.