Rewiring the Nucleolus to Support HIV-1 Virus Replication
Human immunodeficiency virus (HIV)-1 is one of a number of viruses that rely heavily on the cell machinery in the host to replicate and establish an infection. The findings of new research describe how HIV-1 virus triggers changes in the cellular environment to boost protein production activities and support its replication strategy.
A viral transactivator (Tat) protein is known to be essential for HIV-1 viral replication to occur and it localises at the nucleolus. However, to date, the role of the nucleolus in HIV-1 replication has been unclear. Often described as a ribosome factory, the nucleolus is a cellular structure dedicated to building the component units for ribosomes, which are essential to the process of making proteins. Dr Virginie Gautier, principal investigator in the Centre for Research in Infectious Diseases wanted to establish if the interaction of Tat with nucleolar machinery contributes to HIV-1 infection.
In collaboration with Dr Giuliano Elia, director of the proteomics core facility in UCD Conway Institute, the research team used a cellular model of Jurkat T-cells that stably express HIV-1 Tat to build the protein profile of the nucleolus and the changes occurring in it. This is the first such analysis of how the proteomic landscape of the nucleolus is altered in response to the expression of HIV-1 Tat in T-cells of the immune system. The UCD research team quantified 520 nucleolar proteins in the model system including 49 proteins that showed significantly increased levels.
Dr Giuliano Elia said:
We used pathway analysis & network reconstruction to map how these proteins participate in interconnected networks that converge to rewire the dynamic activities of the nucleous. This rewiring seems to favour biosynthetic activities and may contribute to creating a cellular environment that supports robust HIV-1 production.
PhD student and first author on this scientific paper, Mohamed Ali Jarboui said:
The changes in nucleolar protein abundance that we identified have not been associated with HIV-1 pathogenesis before. Of these, the proteins linked to metabolic pathways may provide new potential targets and avenues for therapeutic intervention in patients with this disease.
Commenting on the significance of the findings, Dr Virginie Gautier said:
Key signalling pathways converge to the nucleolus, which plays a central role in sensing and responding to energy, stress, and nutriment availability. In this context, our analysis provided new insights into how Tat mediates the segregation and compartmentalisation of signalling molecules into or out of the nucleolus. Ongoing research, funded by HRB, IRC and UCD-seed funding, currently aims at dissecting the role of these signalling and metabolic pathways into the regulation of HIV-1 latency, one of the remaining barriers to a HIV cure.
This research study was funded through the University College Dublin-National Virus Reference laboratory (NVRL).
Reference and more information
Jarboui MA, Bidoia C, Woods E, Roe B, Wynne K, et al. (2012) Nucleolar Protein Trafficking in Response to HIV-1 Tat: Rewiring the Nucleolus. PLoS ONE 7(11): e48702. doi:10.1371/journal.pone.0048702
This is the second paper published as part of the PhD thesis of Mohamed Ali Jarboui. He is currently working as a post-doctoral researcher in the Medical Proteome Centre, Institute for Ophthalmic Research in the University of Tuebingen, Germany.
This piece was first published on the UCD Conway Institute website.