Project 458909

Once viruses have infected our cells, they use our cellular machinery to replicate and eventually infect new cells. But there is a catch. Transcription by our polymerase (RNAPII) is usually paused shortly after it has initiated. This pause allows gene expression to be regulated and for the newly formed transcripts to be capped, an important modification to ensure the stability of the messenger RNA (mRNA). Therefore, viruses that are transcribed by RNAPII must find a way to either get around this pause or to use it to their advantage. My project focuses on two viruses that have found ways to use this pause to their advantage: the influenza A virus (IAV) and HIV. IAV produces its own polymerase, responsible for viral transcription and replication. But while IAV does not directly use RNAPII, it still interacts with it as the viral polymerase cannot cap its mRNAs. Therefore, the viral polymerase interacts with RNAPII during its pause to steal the cap structure from its nascent mRNA in a process called cap-snatching. HIV, on the other hand, is directly transcribed by RNAPII. In actively infected cells, HIV uses one of its viral proteins (Tat) to release the pause and stimulate transcription of viral genes. However, HIV can enter latency, a state characterized by minimal viral transcription in the infected cells, leading to suboptimal levels of Tat and a longer transcriptional pause. Due to their minimal viral transcription, these latently infected cells are not detected by antiretrovirals and create viral reservoirs. My project focuses the use of a protein (HDAg-S) from the hepatitis delta virus as a mean to stimulate transcription by RNAPII. I hypothesize that using HDAg-S on IAV infected cells would lead to a reduction in cap-snatching and therefore viral transcription and replication. Also, using HDAg-S on HIV-infected individuals would stimulate transcription of latent viruses, leading to their reactivation and them finally being detected by antiretrovirals.