1) Research Line: HIV and premature and accelerated biological and immunological senescence
Our group, active since 1984, has advanced retroviral diagnostics, contributed to clinical guidelines, and serves as a European reference center for pediatric HIV studies, supported by extensive national and international collaborations. In the last 10 years has contributed to demonstrating that, in perinatally HIV-infected youth, persistent viral reservoirs drive chronic inflammation and immune activation, promoting biological and immunological senescence (shorter telomeres, exhausted/senescent immune cells), potentially leading to health decline and premature age-related conditions, including cancer.

Current research studies:
1) Virus/host interactions in pediatric HIV disease and its progression;
2) Neoplastic pathologies in people living with HIV;
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 with perinatally acquired HIV on ART as well as adults living with HIV, who acquired the infection in adulthood, on ART.

5 selected publications

• Petrara MR, Ruffoni E, Carmona F, Cavallari I, Zampieri S, Morello M, Del Bianco P, Rampon O, Cotugno N, Palma P, Rossi P, Giaquinto C, Giunco S, De Rossi A. HIV reservoir and premature aging: risk factors for aging-associated illnesses in adolescents and young adults with perinatally acquired HIV. PLoS Pathog. 2024;20(9):e1012547. doi: 10.1371/journal.ppat.1012547.
• Dalzini A, Ballin G, Dominguez-Rodriguez S, Rojo P, Petrara MR, Foster C, Cotugno N, Ruggiero A, Nastouli E, Klein N, Rinaldi S, Pahwa S, Rossi P, Giaquinto C, Palma P, De Rossi A; EPIICAL Consortium. Size of HIV-1 reservoir is associated with telomere shortening and immunosenescence in early-treated European children with perinatally acquired HIV-1. J Int AIDS Soc. 2021;24(11):e25847. doi: 10.1002/jia2.25847.
• Dalzini A, Petrara MR, Ballin G, Zanchetta M, Giaquinto C, De Rossi A. Biological Aging and Immune Senescence in Children with Perinatally Acquired HIV. J Immunol Res. 2020;2020:8041616. doi: 10.1155/2020/8041616.
• Gianesin K, Noguera-Julian A, Zanchetta M, Del Bianco P, Petrara MR, Freguja R, Rampon O, Fortuny C, Camós M, Mozzo E, Giaquinto C, De Rossi A. Premature aging and immune senescence in HIV-infected children. AIDS. 2016;30(9):1363-73. doi: 10.1097/QAD.0000000000001093.
• Chiappini E, Berti E, Gianesin K, Petrara MR, Galli L, Giaquinto C, de Martino M, De Rossi A. Pediatric human immunodeficiency virus infection and cancer in the highly active antiretroviral treatment (HAART) era. Cancer Lett. 2014;347(1):38-45. doi: 10.1016/j.canlet.2014.02.002.

Funding
PENTA Foundation
EPIICAL Project
SID-DiSCOG, UNIPD

Personnel involved
Silvia Giunco, Researcher (RTDb)

group members:
Maria Raffaella Petrara, IOV Health Researcher
Francesco Carmona, IOV Research Collaborator
Jacopo Lidonnici, PhD student
Elena Ruffoni, IOV Fellow

2) 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.

Current research studies:
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.

Ongoing 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, Shalaby S, Ruffoni E, Taborelli M, Carmona F, Giunco S, Del Bianco P, Piselli P, Serraino D, Cillo U, Dolcetti R, Burra P, De Rossi A. Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients. Front Oncol. 2022;12:899170. doi: 10.3389/fonc.2022.899170.
• Petrara MR, Serraino D, Di Bella C, Neri F, Del Bianco P, Brutti M, Carmona F, Ballin G, Zanini S, Rigotti P, Furian L, De Rossi A. Immune activation, immune senescence and levels of Epstein Barr Virus in kidney transplant patients: Impact of mTOR inhibitors. Cancer Lett. 2020;469:323-331. doi: 10.1016/j.canlet.2019.10.045.
• Petrara MR, Penazzato M, Massavon W, Nabachwa S, Nannyonga M, Mazza A, Gianesin K, Del Bianco P, Lundin R, Sumpter C, Zanchetta M, Giaquinto C, De Rossi A. Epstein-Barr virus load in children infected with human immunodeficiency virus type 1 in Uganda. J Infect Dis. 2014;210(3):392-9. doi: 10.1093/infdis/jiu099.
• Giunco S, Celeghin A, Gianesin K, Dolcetti R, Indraccolo S, De Rossi A. Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus. Cell Death Dis. 2015;6(5):e1774. doi: 10.1038/cddis.2015.145.
• Giunco S, Dolcetti R, Keppel S, Celeghin A, Indraccolo S, Dal Col J, Mastorci K, De Rossi A. hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies. Clin Cancer Res. 2013;19(8):2036-47. doi: 10.1158/1078-0432.CCR-12-2537.

Funding
AIRC
Istituto Oncologico Veneto 5 x 1000
SID-DiSCOG, UNIPD

Personnel involved
Silvia Giunco, Researcher (RTDb)

Group members
Maria Raffaella Petrara, IOV Health Researcher
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

Funding
AIRC
UNIPD intramural funding

Personnel involved
Vincenzo Ciminale, Full 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