HTLV-1 p12I and p30II proteins in viral persistence and pathogenesis

Abstract

The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. Some reports in the literature have indicated a relationship between TP53 status and prognosis especially in non-small-cell lung cancer, breast cancer and NHL.In order to characterize these molecular abnormalities and their clinical significance in prognosis, we also have analyzed the possible correlation between mutations in TP53 gene, clinical findings, response to chemotherapy and survival in 49 children of our series. The mutations of TP53 gene were analyzed by single-strand conformation polymorphism analysis (SSCP) of exons 5 through 9 and direct sequencing. Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 gene mutations. The comparison of EFS curves using the Log-Rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy. Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype. HTLV-1 p12 I and p30 II Proteins in Viral Persistence and Pathogenesis Genoveffa Franchini, Risaku Fukumoto, Mirek Dundr, Valerio William ValeriHTLV-1 is the only retrovirus known to be the etiologic agent of a human cancer, adult T cell leukemia/ lymphoma (ATLL). HTLV-1 as well as some DNA viruses cause lifelong infections. In the case of DNA viruses, the inability of the host's immune response to clear virus-infected cells has been associated with viral latency and/ or the ability of viral-encoded proteins to interfere with the host's immune response to the virus, particularly to evade CTLs, which play a major role in cellular immunity against cell-associated viruses.We hypothesized that this may be the case also for HTLV-1 and focused on both the p12 I and p30 II proteins encoded by alternatively spliced mRNAs from ORFs I and II, respectively, within the 3' end of the viral genome. The HTLV-1 p12 I protein localizes to the ER and Golgi, exhibits weak oncogenic activity, shares aa similarities with the bovine papillomavirus type 1 E5 oncoprotein, and binds to the IL-2R $ and ( c chains. The spliced mRNA encoding p12 I has been detected in in vitro and ex vivo HTLV-1-infected T cells and macrophages. Sera from rabbits experimentally infected with HTLV-1, as well as sera from humans infected with HTLV-1, have been shown to recognize the ORF I product , and a CTL response to ORF I products can be detected in HTLV-1-infected individuals. Ectopic expression in Hela-Tat cells or overexpression of p12 I in PBMCs is associated with enhancement of STAT5 activation and decreased IL-2...