Oncogenic mechanisms of AIDS-related neoplasia in humans and SIV infected monkeys

Abstract: Patients with AIDS or immunosuppressive post-transplant therapy are at high risk to develop Kaposi's sarcoma (KS) and malignant lymphoma that represent clinically lethal complications. Lymphomagenesis in simian immunodeficiency virus (SIV) infected cynomolgus monkeys has been shown to be highly similar to lymphomagenesis in immunosuppressed patients. The similarities include association with a Epstein-Barr-like virus, named Herpesvirus Macaca fascicularis-1 (HVMF-1). No animal model equivalent to KS has been found. Since molecular factors involved in cell proliferation and apoptosis of tumors are potential therapeutic targets, the objective of this thesis was to study such factors in AIDS-related neoplasias. In this work, we showed that some SIV infected monkeys developed malignant, diffuse large B-cell lymphomas (DLBCL), with monoclonal or oligoclonal immunoglobulin gene rearrangements. The decline of CD4 positive cells was faster in the animals with oligoclonal sARL. Extracellular matrix proteins and their integrin receptors, which decreased markedly during the germinal center formation in tumor-free human and monkey lymph nodes, were expressed similarly in sARL and human Epstein-Barr virus (EBV)-related lymphomas. sARL showed moderate to high proliferative activity, and a low number of apoptotic cells. These findings suggest a causal relationship between HVMF-1 infection and the control of the cell kinetic parameters in sARL. Abundant tumor infiltrating cytotoxic lymphocytes (CTL) and macrophages that appear not to be functional were demonstrable in the tumors. Different from the human situation, no evidence of mutations in the 5' non-coding region of Bcl-6 gene was detected in sARL, meaning that Bcl-6 abnormalities are not essential for DLBCL development in monkey. Finally, we established a sARL cell line infected with HVMF-1 that, like human EBV infected, cells was tumorigenic in SCID mice. AIDS-related and Endemic Kaposi's sarcoma (AKS, EKS) displayed identical patterns of adhesion molecules suggesting a similar histopathogenesis. Both AKS and EKS were diploid cell lesions with low proliferative activity. Progression to the nodular stage correlated to an increase of Bcl-2 and c-myc expression and a clear decrease in the apoptotic index. KS evolution may therefore be due to the expression of strong cellular and HHV-8-driven antiapoptotic mechanisms leading to the development of a nodular, tumor-like lesion. This study gives further insight into the similarities between human immunodeficiencyrelated lymphomas and the animal model. It defines also in KS possible targets for relevant experimental and therapeutic studies in vivo such as modulation of host antitumor responses and apoptosis-related factors and underlines in general the importance of herpesviruses as tumorigenic elements.