Viral Oncology

1) Research Line: Pediatric HIV/AIDS
The role of HIV infection in neoplastic pathologies is attributable to HIV-induced immunodeficiency. Despite the introduction of antiretroviral therapy (ART), which partially restores immune functions, HIV-infected individuals remain at a higher incidence of malignancies than the age-matched general population, due to premature aging and accelerated immune senescence processes induced by chronic viral immune activation. Our group has been working on this research area since 1984. During this period, our research group:1) worked on 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 markers of inflammation, immune activation and premature immune and biological aging in children and adolescents on ART.

5 selected publications
Dalzini A et al. J Int AIDS Soc. 2021; 24:e25847
Gianesin K et al. AIDS 2016; 30:1363‐1373
Klein N et al, Lancet Infect Dis 2015; 15:1108-1114
Chiappini E et al, Cancer Lett 2014; 347:38-45
Ometto L et al, AIDS 1995; 9:427-434

PENTA Foundation

Personnel involved
Anita De Rossi, Full Professor

group members:
Maria Raffaella Petrara, Research fellow
Ilaria Cavallari, IOV Biologist
Francesco Carmona, IOV Research Collaborator
Elena Ruffoni, IOV 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. EBV-induced immortalization is associated with telomerase expression, essential for tumor formation/progression. These growth-transforming activities are central to the etiology of B-cell malignancies arising in the context of immunodepression, such as post-transplant lymphoproliferative disorders (PTLD). Besides immunodepression, persistent immune activation and chronic inflammation, induced by release of microbial pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) into circulation, play an important role in the expansion of B cells and increase EBV levels. Our previous studies have demonstrated that: 1) there is a strong relationship between proinflammatory cytokines and the level of EBV load in cells and plasma; 2) different immunosuppressive strategies in transplanted patients may impact inflammation/immune activation and senescence status, pivotal factors of EBV-associated PTLD onset; 3) EBV latent oncoprotein LMP1 activates at transcriptional level TERT, the catalytic component of telomerase which, in turn, is central in the maintenance of the latent tumorigenic viral program and its inhibition induces the EBV lytic cycle and cell death.

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 MRet al, Front Oncol 2022; 12:899170.
Petrara MR et al, Cancer Lett 2020; 469:323-331.
Petrara MR et al, J Infect Dis 2014; 310:392-399
Giunco S et al, Clin Cancer Res 2013; 19:2036-2047
Terrin L et al, J Virol 2008; 10175-10187

Istituto Oncologico Veneto 5 x 1000

Personnel involved
De Rossi Anita, Full Professor

Group members
Maria Raffaella Petrara, Research Fellow
Silvia Giunco, Researcher (RTDa)
Francesco Carmona, IOV Research Collaborator
Elena Ruffoni, IOV Fellow

3) Human T-cell leukemia viruses type 1 (HTLV-1) as a model of T-cell leukemogenesis.

It is estimated that at least 10 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1), a retrovirus that is recognized as the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-associated myeolopathy/tropical spastic paraparesis (HAM/TSP). Over the past 20 years, my studies have focused on understanding the replication strategy and oncogenic properties of HTLV-1.  My lab has contributed to the understanding of the discovery and functional characterization of novel viral gene products, including p13, 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 result in their activation, while in leukemic T-cells p13 is pro-apoptotic. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels. This model implies that 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-ALL patients 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
­D'Agostino DM, et al., Frontiers in Immunology, 2022; 13: 974088.
­Cavallari I et al, J Virol 2015, 90:1486-1498.
­Ruggero  K et al, J Virol 2014,88:3612-3622.
­Rende F et al, Blood 2011; 117:4855-4859.
­Silic-Benussi M et al, Blood 2010; 116: 54-62

UNIPD intramural funding

Personnel involved
Vincenzo Ciminale, Associate Professor

Group members
Ilaria Cavallari, Postdoctoral Fellow
Micol Silic-Benussi, Postdoctoral Fellow
Loredana Urso Postdoctoral Fellow
Vittoria Raimondi Postdoctoral Fellow
Francesco Ciccarese, Postdoctoral Fellow
Evgenyia Sharova, Postdoctoral Fellow
Irene Bertazzolo, Ph.D. Student
Arezoo Darbandi, Ph.D. Student