Research

Viral Oncology

1) Research Line: Pediatric HIV/AIDS
The role of HIV infection in neoplastic pathologies  is attributable to the HIV-induced immunodeficiency. The introduction of Anti Retroviral Therapy (ART) has substantially changed the natural course of HIV infection, increasing patients life expectancy; this has, in turn, increased the incidence of neoplastic pathologies, that are now the main cause of death of HIV-infected patients.Our group has been working on this research area since 1984. During the last 30 years, our research group:1) worked to the development and validation of tests for the diagnosis and monitoring of retroviral infections (among them, we mention the first pilot study based on molecular biology promoted by WHO in 1990);2) contributed to national and international guidelines regarding the diagnosis and monitoring of retroviral infections;3) has become a European reference center for the virological and immunological study of pediatric HIV infections. Our research group benefits from many national and international collaborations (PENTA, ECS).

Current research studies:1)Virus/host interactions in pediatric HIV disease and its progression;2) Neoplastic pathologies in HIV-infected subjects; 3) Pediatric HIV infections in emerging countries; 4) Viral reservoir  and immunophenotypical profile in children and adolescents on ART

5 selected  publications
Klein N et al, Lancet Infect Dis 2015; 15:1108-1114
Chiappini E et al, Cancer Lett 2014; 347:38-45
Zanchetta et al, J Infect Dis 2006;193:1718-1727
De Rossi A et al, J Clin Invest 1996; 97:323-330
Ometto L et al, AIDS 1995; 9:427-434

Funding
PENTA  Foundation
EPIICAL Project

Personnel  involved
Anita De Rossi, Full Professor

group members:
Marisa Zanchetta, IOV Biologist
Francesco Carmona, IOV Fellow
Annalisa Dalzini, Reseach Fellow
Giovanni Ballin, Fellow

2) Research Line: Mechanisms promoting Epstein Barr Virus (EBV)-driven malignancies
Infection of B cells with EBV in vitro causes sustained cell proliferation which may generate immortalized lymphoblastoid cell lines (LCL). This growth-transforming activity is central to the etiology of  B-cell malignancies arising in a context of immunodepression, such as post-transplant lymphoproliferative disorders (PTLD) and Non Hodgkin’s Lymphoma. Besides immunodepression, immune activation by microbial pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) may play an important  role in the expansion of B cells and increase in  EBV level. Notably,  EBV-driven malignancies are associated with the selective expression of latent oncogenic viral proteins, including LMP1, and cell telomerase, which is essential for tumor formation/progression.Previous our studies  have demonstrated that: 1) there is a strong relationship between  proinflammatory cytokines and level of EBV load in cells and  plasma; 2) EBV oncoprotein LMP1 activates at transcriptional level TERT, the catalytic component of telomerase, which, in turn plays an important role in inhibiting the virus lytic cycle. The inhibition of TERT triggers the activation of the viral lytic cycle with death of the infected cells.

Current research studies: 1)Relationship between PAMPs, DAMPs, immune stimulation, EBV reactivation and expansion of EBV infected cells in patients with liver or kidney transplant; 2)The role of circulating TERT mRNA as a diagnostic/prognostic marker of EBV-related malignancies; 3)The inhibition of TERT  as a therapeutic strategy against EBV-driven malignancies.

5 selected publications
Petrara MR et al, Cancer Lett 2015; 369:37-44
Petrara MR et al, J Infect Dis 2014; 310:392-399
Giunco S et al, Clin Cancer Res 2013; 19:2036-2047
Burighel N et al, Haematologica 2006, 91:244-247
Terrin L et al, J Virol 2008; 10175-10187

Funding
AIRC
Istituto Oncologico Veneto 5 x 1000

Personnel involved
De Rossi Anita, Full Professor

Group members
Raffaella Petrara, Assegnista
Silvia Giunco,  IOV Fellow
Manuela Zangrossi, PhD student
Marisa Zanchetta,  IOV biologist IOV
Francesco Carmona, IOV Fellow

3) Research Line: Human T-cell leukemia viruses type 1 and type 2 (HTLV-1 and HTLV-2) as models of T-cell leukemogenesis.
It is estimated that at least 20 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1) or type 2 (HTLV-2). HTLV-1 and HTLV-2 exhibit strikingly different clinical impact, as only HTLV-1 is conclusively associated with adult T-cell leukemia/lymphoma (ATLL) and HTLV-associated myeolopathy/tropical spastic paraparesis (HAM/TSP), while HTLV-2 does not cause hematologic disorders and is only sporadically associated with myelopathy. Over the past 20 years my studies have focused on understanding the molecular mechanisms underlying the persistence in the host and oncogenic properties of HTLVs.  Studies on the alternative splicing pattern of viral mRNAs led to the discovery of novel proteins coded by both HTLV-1 and HTLV-2 and revealed differences in their expression kinetics. My lab has contributed to the understanding of the function of some of these novel viral gene products, including the p13 protein of HTLV-1, which is targeted to the mitochondrial inner membrane where it triggers K+ influx, leading to production of reactive oxygen species (ROS).  Interestingly, in the context of in primary T-cells, these effects resulted in their ROS-dependent activation, while in leukemic T-cells p13 was pro-apoptotic. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels and that it might represent the first example of a “viral tumor suppressor”.  In the context of the HTLV-1 propagation strategy, p13 could increase the pool of “normal” infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host.

Current studies: Building on these findings, current experimental projects are aimed at exploiting HTLV-1 as a model to gain insight into the general mechanisms of T-cell transformation and to develop tumor-specific therapies that exploit the higher ROS set-point of tumor cells to target both ATLL and pediatric T-ALL (T-acute lymphoblastic leukemia). As 25% of T-ALLpatients respond poorly to current therapies and have a dismal prognosis, new effective therapies against these neoplasms are needed. In particular we are testing drug treatments that mimic the anticancer properties of p13 by impinging on the pathways controlling ROS homeostasis.

5 selected publications
Cavallari I et al, J Virol 2015, 90:1486-1498
Ruggero  K et al, J Virol 2014,88:3612-3622
D’Agostino DM et al, Adv Cancer Res 2012; 113:45-83
Rende F et al, Blood 2011; 117:4855-4859
Silic-Benussi M et al,  Blood 2010; 116: 54-62

Funding
AIRC
Istituto Oncologico Veneto 5 x 1000

Personnel involved
Vincenzo Ciminale, Associate Professor

Group members
Ilaria Cavallari, IOV Fellow
Micol Silic-Benussi, IOV Fellow
Francesco Ciccarese, Research Fellow
Gloria Scattolin, PhD student