Physiology and therapeutic modulation of oxidative phosphorylation in HIV-1 infected cells. at University of Bristol on FindAPhD.com

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Dr Iart Luca Shytaj No more applications being accepted Competition Funded PhD Project (UK Students Only)

Bristol United Kingdom Biochemistry Cell Biology Immunology Molecular Biology Virology

About the Project

About the Project

Almost 4 decades after its isolation the human immunodeficiency virus (HIV-1) is still a leading cause of morbidity and mortality infecting an estimated 38.4 million people worldwide (World Health Organization. The ongoing pandemic is fuelled by the fact that, despite the introduction of combinations of effective antiretroviral drugs (ARVs), a scalable cure remains elusive. The persistence of HIV during standard treatments is largely due to the presence of sanctuaries where the virus can remain hidden in a latent form, shielded from ARVs and from the immune system. Understanding the mechanisms behind latent HIV persistence is therefore essential to develop novel treatments to eliminate these viral sanctuaries.

My laboratory investigates the interplay between cellular metabolism and viral infection, with special focus on latent HIV-1 infection. Cellular metabolism encompasses the fundamental biochemical reactions that are required by cells to convert or utilise energy, and we, and others, have shown that latent HIV-1 infection is associated with profound metabolic rearrangements. In particular, latently HIV-1 infected cells are characterised by increased reliance on systems to detoxify derivatives of oxygen consumption. These derivatives, called reactive oxygen species, are mainly generated during cellular respiration (OXPHOS) in mitochondria, but their precise source and regulation in latently infected cells are yet unexplored.

This project will study the regulation of the OXPHOS pathway in primary blood cells infected with HIV-1, and in patient-derived cells. Key steps of the pathway, or its related effectors, will be further explored for their potential to serve as therapeutic targets (e.g. to induce selective death of latently infected cells). The studentship will include training in multi-omics sample preparation and data analysis together with virologic, biochemical and imaging techniques. Overall, the project is expected to shed new light on how latent HIV alters cellular respiration to ensure its own survival, and how this process can be exploited to attempt eradication of HIV sanctuaries. Moreover, these results could contribute to a broader, integrated picture of the hijacking of cellular metabolism by human retroviruses.

The student will join a novel, dynamic, international research group situated in the School of Cellular and Molecular Medicine at the University of Bristol. The work will be conducted in a multidisciplinary environment with great opportunities for building and expanding collaborations, including in topics relevant to the project such as immunology and biochemistry. The city is lively, multicultural, and regularly named among the best places to live in the UK.

Webpage

https://www.bristol.ac.uk/people/person/Iart%20Luca-Shytaj-adae6fa4-b8f2-4f6a-8c3e-533b57699602/

Keywords: Bristol, Virology, HIV, Mitochondria, Cellular metabolism.

Funding Notes

This project is available for UK students. Please contact Dr Shytaj directly for information about the project and how to apply ([Email Address Removed]). We are keen to recruit a diverse range of students and to ensure our research is open to all. We particularly welcome applications from groups traditionally under-represented in life sciences research. The annual stipend is set at the current UKRI recommendation of £17,668. Tuition fees and research costs are fully supported by the studentship. The studentship also includes allowance for paid sick leave and parental leave, in addition to 5 weeks of paid leave each year.

References

References:
Shytaj IL, Procopio FA, Tarek M, Carlon-Andres I, Tang HY, Goldman AR, Munshi M, Kumar Pal V, Forcato M, Sreeram S, Leskov K, Ye F, Lucic B, Cruz N, Ndhlovu LC, Bicciato S, Padilla-Parra S, Diaz RS, Singh A, Lusic M, Karn J, Alvarez-Carbonell D, Savarino A. Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress. EMBO Mol Med. 2021 Aug 9;13(8):e13901.
Shytaj IL, Lucic B, Forcato M, Penzo C, Billingsley J, Laketa V, Bosinger S, Stanic M, Gregoretti F, Antonelli L, Oliva G, Frese CK, Trifunovic A, Galy B, Eibl C, Silvestri G, Bicciato S, Savarino A, Lusic M. Alterations of redox and iron metabolism accompany the development of HIV latency. EMBO J. 2020 May 4;39(9):e102209.
Benhar M, Shytaj IL, Stamler JS, Savarino A. Dual targeting of the thioredoxin and glutathione systems in cancer and HIV. J Clin Invest. 2016 May 2;126(5):1630-9.
Shytaj IL, Nickel G, Arts E, Farrell N, Biffoni M, Pal R, Chung HK, LaBranche C, Montefiori D, Vargas-Inchaustegui D, Robert-Guroff M, Lewis MG, Sacha JB, Palamara AT, Savarino A. Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection. J Virol. 2015 Aug;89(15):7521-35.

Where will I study?

University of Bristol

The University''s outstanding reputation makes our students highly attractive to employers. Bristol is ranked joint seventh in the UK for graduate employability (QS Graduate Employability Rankings 2022).