Viruses must compete with their host cell for macromolecular machineries at many levels after infection and then use the cell’s resources for virus replication, transcription, processing and transport of mRNAs, and protein synthesis, among others. Transcription is one example of the cell being co-opted by HIV-1, the causative agent of AIDS, where the viral encoded transcriptional regulator Tat is essential for viral replication and persistence infection.
Tat recruits the transcription cellular machinery to the viral promoter, including the transcription elongation factor P-TEFb, to relieve a block in the elongation step of transcription. Besides regulating its own transcriptional program, Tat and other accessory proteins modulate the host-cell gene expression profile, using unknown mechanisms, thus impacting on the progression and pathogenesis of the disease.
Our long-term goals are to understand:
- The molecular basis of HIV and lentiviral transcription
- Why HIV evolved an RNA structure to direct transcription of its genome
- How HIV accessory and regulatory factors de-regulate the host-cell expression profile
- How HIV affects the host-cell chromatin and how it impacts on the pathogenesis of AIDS
- What selective pressures shaped the evolution of co-evolving genes in host-viral transcription complexes
- How these events dictate entry into viral latency or persistent infection.