The interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms

Giulia De Falco1, Cristiana Bellan1, Stefano Lazzi1, PierPaolo2 Claudio, Piero Tosi1, Antonio Giordano2, Caterina Cinti3, Lorenzo Leoncini1; 1University of Siena, Siena (Italy); 2 College of Science & Technology, Temple University, Philadelphia, PA (USA); 3 CNR, Bologna (Italy).

HIV-1 has long been recognized as the etiological agent of acquired immunodeficiency syndrome (AIDS). Altough many neoplasms arise in HIV-1 infected patients more frequently than in other forms of immunosuppression, the role of HIV-1 as an oncogenic virus has not yet been clarified. The HIV-1 gene product Tat, secreted by HIV-1 infected cells and taken up by normal cells, is a likely candidate to contribute to tumor pathogenesis in HIV-1 infected patients because of its growth promoting activity, angiogenic function and antiapoptotic effect. The oncogenic role of Tat is further supported by the development of non Hodgkin's lymphomas in Tat-transgenic mice. Furthermore, a virus-linked mechanism of lymphomagenesis, in AIDS-related lymphomas has recently been proposed, involving the RB2/p130 pathway. The absence of mutation in the RB2/p130 gene and the unusually high percentage of cells expressing pRb2/p130 in tumors with a high proliferative activity such as AIDS-related lymphomas, may in fact suggest a physical interaction of pRb2/p130 with viral oncoproteins. However, little is known about the mechanism by which HIV-1 gene products interact with RB family and other cell cycle regulatory proteins. The aim of our study was to investigate whether Tat could bind to pRb2/p130, thus impairing its tumor suppressor activity. Our results show that the two proteins interact both in vitro and in vivo, through the pocket region of pRb2/p130. Due to the overexpression of pRb2/p130 observed in AIDS-related lymphomas, we investigated whether Tat could influence either the phosphorylation status of pRb2/p130 or its expression at mRNA level. Our results show that Tat does not alter the phosphorylation status of pRb2/p130, but increases its expression at mRNA level. In additon,Tat seems to inactivate the tumor suppressor activity of pRb2/p130, as demonstrated by a colony assay. The interaction between Tat and pRb2/p130 may lead to a deregulation of cell growth control by Rb-related proteins, that may contribute to lymphomagenesis in AIDS patients. The understanding of basic information may be of significance for prognosis and implementing future therapeutic regimens, including the design of novel therapeutic approaches. As a matter of fact, spontaneous regression of HIV-1 associate lymphoproliferative disorders has been reported following highly active antiretroviral therapy.