Cell transformation byHerpesvirus saimiri

Abstract

Herpesvirus saimiri (Saimiriine herpesvirus-2), a g2-herpesvirus (rhadinovirus) of non-human primates, causes T-lymphoproliferative diseases in susceptible organisms and transforms human and non-human T lymphocytes to continuous growth in vitro in the absence of stimulation. T cells transformed by H. saimiri retain many characteristics of intact T lymphocytes, such as the sensitivity to interleukin-2 and the ability to recognize the corresponding antigens. As a result, H. saimiri is widely used in immunobiology for immortalization of various difficult-to-obtain and/or -to-maintain T cells in order to obtain useful experimental models. In particular, H. saimiri-transformed human T cells are highly susceptible to infection with HIV-1 and -2. This makes them a convenient tool for propagation of poorly replicating strains of HIV, including primary clinical isolates. Therefore, the mechanisms mediating transformation of T cells by H. saimiri are of considerable interest. A single transformation-associated protein, StpA or StpB, mediates cell transformation by H. saimiri strains of group A or B, respectively. Strains of group C, which exhibit the highest oncogenic potential, have two proteins involved in transformation-StpC and Tip. Both proteins have been shown to dramatically affect signal transduction pathways leading to the activation of crucial transcription factors. This review is focused on the biological effects and molecular mechanisms of action of proteins involved in H. saimiri-dependent transformation.

Viral Modulation of T-Cell Receptor Signaling

“…Herpesvirus saimiri (HVS) is a T-lymphotropic virus that leads to leukemias and lymphomas in certain species of nonhuman primates (39,151). HVS encodes at least three gene products that modulate TcR function.…”

TheHerpesvirus saimiriSmall Nuclear RNAs Recruit AU-Rich Element-Binding Proteins but Do Not Alter Host AU-Rich Element-Containing mRNA Levels in Virally Transformed T Cells

“…Prior to stimulation, immunoblots revealed no detectable expression of TTP (Fig. 7A, lane 1), despite the fact that our HVS-transformed T cells appear to have an activated phenotype in many other respects (74). After stimulation of both wild-type and mutant HVS-transformed T cells of both cell sets, TTP expression was seen, with maximal induction occurring with 25 ng of PMA/ml and 625 ng of ionomycin/ml for 3 to 6 h (Fig.…”

“…Cultured T cells transformed by HVS show modified expression of cytokines and other ARE-containing genes, including IL-2, IL-3, gamma interferon, TNF-␣, TNF-␤, and a homolog of 39,74). Thus, it has been proposed that the ARE-containing HSURs compete with less abundant host mRNAs for host cell ARE-binding proteins in latently infected, transformed T cells (26,58).…”

Herpesvirus Saimiri Terminal Membrane Proteins Modulate HIV-1 Replication By Altering Nef and Tat Functions

“…Lck kinase activity is increased by Tip [21,30,31], while several studies have indicated that Nef inhibits Lck kinase activity [11,18,19]. StpC, also a type II membrane protein interacts with the Ras GTPase, TRAF-2 and -6 and leads to increase NF-B activation (reviewed in Brinkmann and Schulz [8]; Tsygankov [45]). Since Tip and StpC interact with or influence host factors integral to HIV-1 replication we designed experiments to determine the role interactions between TMPs and host proteins have in the paradoxical effects of Tip and StpC on HIV-1 replication and reactivation.…”