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Characterisation of immune responses and virus reservoir in treated children with HIV

Supervisors: Prof. Eleni Nastouli, Prof. Nigel Klein, Dr. Kathleen Gärtner, Dr. Dagmar Alber

Background:
This exciting project will give you the opportunity to gain insights into a research laboratory that focuses on HIV and bacterial work in clinical trials. You will join a laboratory with over 25 years of experience in immunology and virology of HIV-1 [example of publications see 1,2].  HIV-1 infection is a chronic disease which requires life-long antiretroviral treatment (ART). Many clinical trials have shown that early initiation of treatment is beneficial for disease outcome. The hallmark of the virus is stable integration into the host genome and it attacks specific immune cells. If left untreated, the immune system will fail, leaving the individual susceptible to opportunistic infections.  In Sub-Saharan Africa HIV-1 exposure and infection in children is still a significant problem, resulting in high infant morbidity and mortality. More than 90% of HIV-infected children live in Sub-Saharan Africa with ART coverage of less than 45% [3]. To suppress the virus it is not only important to keep virus replication under control, but also to maintain a functional immune system. Therefore more effective treatment is urgently needed.  This PhD project will be part of ODYSSEY [4,5], a large clinical trial, which aims to compare the standard drug regimen to the use of a relatively new HIV-1 drug (Dolutegravir, DTG) in children.

Aims/Objectives:
The overall aim of the trial is to assess whether DTG in children is effective and non-inferior compared to standard-of-care (SOC) treatment to improve the lives of children with HIV-1.
Immunology substudy (Alber/Klein): It has been shown that children receiving DTG have higher recovery of CD4+ lymphocytes (the main target cells of HIV-1) compared to SOC. The characterisation of the CD4+ T-cells will determine how well the immune system recovers under DTG treatment.
Virology substudy (Gärtner/Nastouli): The objective will be to determining different virological characteristics, such as virus integration sites in the host genome or the potential of virus re-activation in children on ART [6]. Preliminary work has already started by a PhD student and the aim of the substudy is to build on these results and finalise the integration site testing and analysis, as well as consider further in-depth analysis of the viral reservoir.

Methods:
You will gain experience on how to work in containment level 2 and 3 laboratories and learn a variety of cellular and molecular laboratory techniques as well as learn how to handle large data sets and bioinformatic analysis. Specific methods will include work with HIV+ PBMC samples for isolation of T-lymphocytes, nucleic acid extractions, quantitative and digital PCR, induction assays, FACS-analysis,
ELISA, cloning, Next Generation sequencing and bioinformatic analysis of large data sets (e.g. sequencing data). You will be supervised in the laboratory by Senior post doctorate scientists in the immunology and virology part. Bioinformatics support is in-house.  As the trial is part of an international consortium, it will give you the opportunity to collaborate and network with individuals with different backgrounds (scientists, statisticians, clinicians, social scientists, etc.) around the world at regular meetings and conferences and to be part of an exciting multidisciplinary team.

Timeline:
The trial is fully recruited, the samples have already been collected and most assays have been set up in our laboratory. Therefore, after an initial training period data can be acquired very quickly.

References:
1. Sandgaard, K.S. et al. Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection. Front Immunol 12, 643189 (2021).
2. Foster, C. et al. The CARMA Study: Early Infant Antiretroviral Therapy-Timing Impacts on Total HIV-1 DNA Quantitation 12 Years Later. J Pediatric Infect Dis Soc 10, 295-301 (2021).
3. Burrage, A. et al. Trends in Antiretroviral Therapy Eligibility and Coverage Among Children Aged <15 Years with HIV Infection - 20 PEPFAR-Supported Sub-Saharan African Countries, 2012-2016. MMWR Morb Mortal Wkly Rep 67, 552-555 (2018).
4. https://odysseytrial.org
5. Turkova, A. et al. Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children. N Engl J Med 385, 2531-2543 (2021).
6. Maldarelli, F. et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345, 179-183 (2014).