Revectorisation of HIV-1 for human T cell gene therapy

To start:
01/10/2020

Supervisors:
Professor Michael Malim and Dr Conrad Vink

This fully-funded 4-year BBSRC Collaborative Training Partnership PhD studentship will bridge the Department of Infectious Diseases at King’s College London, a leading centre for research on host-pathogen interactions, with the Cell & Gene Therapy Department at GSK that develops state-of-the-art technologies for viral vector production.

Background:
Lentiviral vectors have been used as efficient gene transfer tools for the past two decades for basic research and therapeutic applications. Original vector design was based on the theoretical understanding of the HIV-1 replication of the 1990s. In current third generation lentiviral vectors (Dull et al 1998, PubMed ID 9765382), the HIV-1 genome is organised in three distinct plasmids supplying all the viral elements needed for gene transfer into many cell types when combined with a vector that expresses the VSV-G envelope.

While most lentiviral vector gene transfer applications to date have been based on transduction of cells ex vivo, there is growing interest in the in vivo use of lentiviral vectors. Due to their central role in both innate and adaptive immunity, CD4+ T cells are a key target for genetic modification for therapeutic applications (Zhou et al 2015, PubMed ID 26232436, reviewed in Frank et al 2019, PubMed ID 30417026). HIV-1 has natural tropism towards CD4+ T cells but this has been largely neglected in lentiviral vectorology.

The aims of this project are to build upon methods and materials available from the past two decades of fundamental HIV-1 research to generate a vector production system yielding high infectivity lentiviral vectors capable of targeting CD4+ T cells.

Research Plan:
This project will use cutting-edge technologies in cell culture systems, next generation sequencing, flow cytometry and molecular genetic engineering to address the following:

- Identification of an envelope glycoprotein from wildtype HIV-1 strains capable of efficient transduction of CD4+ T cells

- Testing the effect of HIV-1 accessory genes on CD4+ T cell transduction efficiency

- Quantification of off-target transduction and developing practical improvements to increase the specificity of gene delivery

- Comparison of the improved vector and production system with currently used VSVg-pseudotyped 3rd generation vectors in target cell transduction models.

Research environment and application:
During this project, the research will take place both at King’s College London (Guy’s campus) and GSK (Stevenage). The student will train in a wide range of techniques, supervised by Professor Michael Malim (KCL), Dr. Luis Apolonia (KCL), and Dr. Conrad Vink (GSK). The PhD will formally start on the 1st October 2020.

We seek a highly motivated candidate, with a bioscience BSc Honours degree (First or Upper Second) or MSc (Distinction or Merit). The studentship is available to applicants who meet the UKRI residency requirement, i.e. to have been residing in the UK for at least 3 years continuously prior to the start of the PhD. Candidates must apply through the King’s application portal.

English language requirements:
Band D (please refer to King’s English language requirements)

Contact information for enquiries
Enquiries can be made via e-mail to: [Email Address Removed]

How to apply:

1) Register a new account and login at King’s Apply
2) Search for the programme: Immunology and Microbial Science Research MPhil/PhD (Full-time)
3) Open a new application selecting a start date (1st October 2020)
4) Complete and submit your application, noting the following:

· Include a supporting personal statement
· References
· CV
· Indicate the supervisor name and project title and reference (2020/SIMS/GSK01) when prompted during the application.

Once you have applied, you will need to follow admissions’ instructions and return their requested documents before your application can be passed to the school’s operations officer (education) for processing. Eligible candidates will be selected for a formal interview.

Please note that the applications portal deadlines are for admissions to receive applications only and are separate to the closing date stated on this advert.