PhD positions

OPEN POSITION:

 

PhD position

Host laboratory: Prof Daniel Kaufmann

Webpage: https://www.chuv.ch/fr/min/min-home/recherche/group-leaders/prof-daniel-kaufmann

 

Contact :

Daniel E. Kaufmann, MD

Chief, Division of Infectious Diseases

Email: daniel.kaufmann@chuv.ch

The laboratory headed by Prof Kaufmann is recruiting a PhD student for a project investigating the molecular basis of HIV-specific T cell dysfunction.

Our research interests:

I am a physician-scientist engaged in fundamental and translational research. Our laboratory primarily focuses on the immunovirology of HIV and SARS-CoV-2 with the aim of fostering the development of vaccination and cure strategies. Our research topics include: i) the understanding of effective CD4 T cell help in antiviral immunity; ii) the causes of virus-specific T cell impairment; iii) single-cell studies of HIV reservoirs; iv) COVID-19 pathogenesis; and v) SARS-CoV-2 vaccine immunity in vulnerable populations. We have a keen interest in the development of new laboratory techniques and analytical approaches to better integrate clinical data with in-depth biomolecular profiling in infectious diseases.

The context:

Antiviral therapy (ART) that blocks HIV replication has enabled a remarkable improvement in the quality of life for people with HIV (PWH). However, populations of white blood cells that specifically recognize HIV, called CD4 and CD8 T lymphocytes, remain unable to effectively combat the virus, which rapidly replicates again if the treatment is discontinued. This compels PWH to continue ART throughout their lives. Moreover, chronic inflammation is often observed, associated with an increased risk of various diseases. New treatments that allow a functional cure and long-term immune control of the residual virus are therefore necessary. We aim to understand the "instruction sets" that determine the functions of these CD4 and CD8 T cells, to identify the mechanisms that prevent the immune system from fighting efficiently against HIV, and to find ways to restore the ability of these T cells to control the virus. To study in great detail virus-specific T cells in human samples, our lab has developed novel methods to accurately identify and live-sort rare antigen-specific CD4 and CD8 T lymphocytes, which can be followed by downstream -omics analyses, such as transcriptomic and epigenomic profiling, or functional assays. Our previous studies have shown extensive differences in the gene expression of HIV-specific CD4 T cells between rare individuals who spontaneously control the virus (elite controllers, EC) and individuals with progressive infection (CP). These differences are only partially corrected by ART. We investigate the molecular basis of these differences using diverse -omics and targeted approaches. at the level of their expression the translated proteins (flow cytometry and proteomics), and metabolic processes. Studies of HIV-specific CD4 T cells at the level of gene programming (epigenetic analyses) and gene expression (transcriptomic analyses) are underway in our lab. We propose here to expand our investigations to new areas: i) HIV-specific CD8 T cells, which are key for viral control; ii) the proteomic and metabolomic underpinning of HIV-specific T cell dysfunction.

The HIV-specific T cell dysfunction projects:

Project #1: Define transcriptional features of HIV-specific CD8 T cells in CPs that are not reversed by ART compared to ECs and identify the epigenetic basis of these differences.

Project #2: Define the proteomic and metabolic alterations of HIV-specific T cells associated with persistent immune dysfunction.

Relevance. Through these studies, we will shed led light onto: i) The molecular processes that are associated with effective HIV-specific T CD8 T cell immunity and the gene modules that are responsive or unresponsive to therapeutic control of viremia; ii) The post-transcriptional, metabolic and functional pathways of CD4 and/or CD8 T cells associated with effective versus impaired immune responses. We will conduct mechanistic studies of "gain of function" and "loss of function" to determine the role of some of the identified genes. The knowledge gained could contribute to new interventions to complement ART in the pursuit of an HIV cure.

Your missions:

You are a PhD candidate interested in applying state-of-the-art technologies to delve deeper into the links between chronic infections, immune dysfunction and metabolomics with the goal of informing novel cure strategies for a major human pathogen. We will define with you a specific thesis subject based on one of the specific aims above, tailored to your background, your interests and building on the progress already made in the lab by the time you join the team. You will design and perform experiments examining blood samples from different cohorts of well-characterized PWH and control participants. You will perform different types of cutting-edge immunological and molecular assays, including tissue culture, high-parameter flow cytometry, proteomic and metabolite profiling and gene expression analysis. You will learn a palette of advanced analytical tools as well work in close collaboration with other team members, bioinformaticians and data scientists. Your missions will also include detailed documentation of the experimental work and presentation of your work at meetings, conferences or symposia.

Your profile:

We are looking for a highly motivated PhD candidate with strong ability to work in a productive and dynamic environment. An excellent team spirit is essential. The sense of organization and rigor are prerequisite to the mastery of the sophisticated techniques used in the laboratory. Good oral and written communication skills in English are essential.

Your qualifications:

  • A master's degree in virology, immunology or related Life Science field, or a degree in Medicine of Pharmacy (or equivalent)
  • You have an excellent ability to learn under supervision
  • You are willing and able to become increasingly proficient and independent in your tasks as your training and experience progress
  • You are rigorous, self-motivated and well organized
  • You have a keen interest in translational research
  • You have good English language skills. Good knowledge of French would be an asset,

Key related recent publications from the Kaufmann lab:

  1. Morou A, Brunet-Ratnasingham E, Dubé M, (…), Finzi A, Douek DC, Kaufmann DE. Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease. Nature Immunology. 2019 Aug;20(8):1059-1070. doi: 10.1038/s41590-019-0418-x. PMID: 31308541.
  2. Niessl J, Baxter AE, Mendoza P, (…) Caskey M, Nussenzweig MC, Kaufmann DE. Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity. Nature Medicine. 2020 Feb;26(2):222-227. doi: 10.1038/s41591-019-0747-1. PMID: 32015556.
  3. Brunet-Ratnasingham E, Morou A, Dubé M, Niessl J, Baxter AE, Tastet O, Brassard N, Ortega-Delgado G, Charlebois R, Freeman GJ, Tremblay C, Routy JP, Kaufmann DE. EBioMedicine. 2022 Oct;84:104254. doi: 10.1016/j.ebiom.2022.104254. Epub 2022 Sep 20.PMID: 36150362.

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