Enhanced Human T-Cell Lymphotropic Virus Type I Expression Following Induction of the Cellular Stress Response

Abstract

Human T-cell lymphotropic virus type I (HTLV-I) infection is typically associated with long incubation periods between virus exposure and disease manifestation. Although viral protein expression is considered to play an important role in the pathogenesis of HTLV-I-associated diseases, limited information is known regarding host cell mechanisms that control viral gene expression. This study was designed to evaluate modulation of HTLV-I gene expression following induction of the cellular stress response in HTLV-I-infected lymphocytes. The cellular stress response was elicited by treatment with either Na arsenite or thermal stress and was monitored by demonstrating increased expression of the 72-kDa heat shock protein. Induction of the cellular stress response in HTLV-I-infected lymphocytes resulted in significantly increased HTLV-I-mediated syncytia formation due to enhanced HTLV-I envelope (gp46) expression. Intracellular viral proteins and released p24 capsid protein were increased in stressed infected lymphocytes as compared to nonstressed infected lymphocytes. Furthermore, HTLV-I-LTR reporter gene constructs had increased activity (three- to sixfold) in a transiently transfected, uninfected lymphocyte cell line following induction of the cellular stress response. Quantitation of HTLV-I RNA expression by slot blot analysis of infected lymphocytes suggested variable increases in RNA accumulation. Northern blot analysis demonstrated no qualitative changes in expression of RNA species. These data suggest a relationship between modulation of viral replication and a basic cellular response to stress and have important implications for understanding host cell control mechanisms of HTLV-I expression.

Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1– and type 2–infected cells by a caspase-3–dependent mechanism involving Bcl-2 cleavage

“…This could indicate that, after stress, there is a shift toward viral production. Indeed, such an effect has been reported in HTLV-1 cells treated with sodium arsenite 59 and in HHV-8-infected primary effusion lymphoma cells treated with arsenic trioxide (G. Torelli, written communication, 2000). These results would also explain why the addition of As 2 O 3 is effective on freshly isolated ATLL cells, which show little, if any, Tax expression but do show NF-B activity.…”

The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

“…Their results demonstrate a clear increase in all proteins associated with the HTLV-1 full-length mRNA, including the polyproteins GagPol (p65) and Gag (p55), as well as the processed protein products p19 and p24 (77). The same report indicates that similar observations are made 24 h after the induction of cellular stress responses (77). This and a subsequent study from the same group (78) conclude that the increase in viral protein expression under cellular stress conditions is regulated mostly at the level of mRNA translation.…”

“…Andrews et al (77) showed by Western analysis of proteins extracted from HTLV-1-infected cells that viral proteins are expressed at 48 h after the induction of cellular stress response mechanisms using Na arsenite. Their results demonstrate a clear increase in all proteins associated with the HTLV-1 full-length mRNA, including the polyproteins GagPol (p65) and Gag (p55), as well as the processed protein products p19 and p24 (77). The same report indicates that similar observations are made 24 h after the induction of cellular stress responses (77).…”

Transcriptional Modulation of Viral Reporter Gene Constructs Following Induction of the Cellular Stress Response

“…Twenty-four hours following electroporation, the expression of hsp 72 was determined by flow cytometric analysis as previously described (5) and the data presented as the percent expression as compared to non-transfected controls. Transfection of HUT 78 cells by electroporation resulted in increased expression (41%) of hsp 72 (as compared to non-transfected, non-stressed controls) (Fig.…”