Project A2: Andrea Thoma-Kreß

Virology

Head of Institute:
Prof. Dr. med. Klaus Überla

Enhancing immunogenicity of Human T-cell leukaemia virus Type 1 (HTLV-1) by interfering with viral transcription

Human T-cell leukaemia virus type 1 (HTLV-1) is a highly oncogenic retrovirus causing Adult T-cell leukemia/lymphoma (ATLL) or inflammatory diseases in up to 10 % of infected people. Worldwide, at least 5-10 million people are infected with this yet neglected human oncogenic retrovirus. However, it is assumed that the number of unknown cases is much higher since statistics on HTLV-1 prevalence are lacking for several highly populated regions. Asymptomatic carriers are mainly unaware of their infection and may pass the infection to other people since HTLV-1 infection is not part of sexual health screening in most countries. Upon cell-to-cell transmission and infection of CD4+ T cells, HTLV-1 integrates into the host cell genome. Virus replication is stimulated by the viral transactivator protein Tax, which recruits host cell factors like positive transcription elongation factor b (p-TEFb) to the viral promoter, and by mitotic expansion of infected cells. Since viral gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, new therapeutic strategies aim to transiently activate viral gene expression and antigen presentation of Tax to disturb the equilibrium in favour of an enhanced CTL response towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. The composition of the protein complex guiding viral gene expression is only partially understood, and systematic analyses and comparisons of compounds affecting viral transcription are lacking. Previously, we identified strong and specific upregulation of the transcription elongation factor ELL2 in HTLV-1-infected cells. ELL2 strongly enhances Tax-mediated transactivation of the HTLV-1 promoter, and ELL2 and Tax are part of a common protein complex. However, the detailed composition of this complex and its impact on viral reactivation are unclear. In this project we aim to discover strategies to enhance HTLV 1 gene expression and immunogenicity of HTLV-1. Overall, this project will help to gain novel insights into host factors and chemical compounds required for manipulating viral gene expression, and thus, immunogenicity of HTLV-1.

Figure 1. Manipulation of HTLV-1 transcription may affect viral immunogenicity. Starting from recent findings that Tax not only forms complexes with p-TEFb and BRD4, but also with the transcription elongation factor ELL2, we seek to elucidate the composition of the protein complex guiding viral transcription, and the relative contribution of identified host proteins on viral gene expression. Beyond, we aim to compare the impact of selected histone deacetylase (HDAC) inhibitors and transcription activators on HTLV-1 expression. Upon evaluating cytotoxic T-cell responses after manipulation of viral transcription, this project should help to improve strategies to enhance the immunogenicity of HTLV-1.
 
Contact
Dr. rer. nat. Andrea Thoma-Kreß
phone: +49 9131 85-26429
e-mail: andrea.thoma-kress@uk-erlangen.de
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