Acute HIV-1 infection (AHI) is the phase of HIV-1 infection immediately after acquisition, and is characterised by a burst of viraemia, during which 40%-90% of patients develop symptoms of the acute retroviral syndrome (ARS) and many seek medical care . The early events of AHI, when the transmitted founder (T/F) virus encounters the immune system, are thought to be critical to determining the subsequent disease course in the absence of anti-retroviral therapy (ART). After the initial peak of viraemia, virus levels in the blood reach a steady state, referred to as the “set-point” level of plasma viral load (pVL), which strongly predicts clinical outcome without ART . The emergence of HIV-specific cytotoxic T lymphocyte (CTL) responses coincides with the abrupt fall in pVL that occurs during AHI [3, 4] and contributes to determining pVL set-point   . Viral characteristics also contribute to clinical outcome: the viral replicative capacity (vRC, determined using the gag gene of T/F sequences in chimaeric virus studies) correlates with the set-point pVL .
This project will make use of samples collected over time from subjects who presented with AHI and were enrolled within 6 weeks following acquisition enrolled, under protocol C of the International AIDS Vaccine Initiative . In this cohort, it was noted that the presenting ARS symptoms at enrolment differed according to the infecting viral subtype, being much more prevalent in people with acute clade A HIV-1 infection than in those infected with clades C or D . This study will focus on characterising function and phenotype of HIV-specific CTL in these donors, with the aim of determining the characteristics associated with long-term viral control, as well as potential correlations with the presentation of ARS.
Studies will include defining the specificity of CTL responses with ELISpot assays, using flow cytometry to determine the phenotype and function of HIV-specific CTLs, and sorting these cells for transcriptomic and T-cell receptor analysis. It is envisaged that the bulk of the laboratory studies will be carried out in the Kemri-Wellcome Trust Research Programme unit in Kilifi, on the Kenyan coast. This work will complement ongoing and planned studies in these subjects, which currently include measurements of viral diversity and evolution in the HIV-1 env gene, alongside a detailed characterisation of the profiles of soluble factors in plasma (including cytokines, chemokines and immune activation markers) .
This project offers the student an excellent opportunity for training in a range of skills, including cellular immunology (ELISpot assays, flow cytometry and functional assays of CTL activity including the ability to inhibit viral replication in vitro and select HIV “escape” mutants) and bioinformatics analysis. Additional training in scientific writing and dissemination of research findings will be available to the student, as he/she will be encouraged to prepare and present his/her work during regular weekly meetings/scientific presentations and national/international conferences.
Project reference number: 966
|Professor Eduard Sanders||Tropical Medicine||Oxford University, Kilifi||KEN||ESanders@kemri-wellcome.org|
|Professor Sarah L Rowland-Jones||Target Discovery Institute||Oxford University, NDM Research Building||GBRemail@example.com|
|Dr Joakim Esbjornsson||NDM||Oxford University||GBRfirstname.lastname@example.org|
|Dr Eunice Nduati||Tropical Medicine||Oxford University, Kilifi||KEN||Enduati@kilifi.kemri-wellcome.org|
|Dr Amin Hassan||Clinical sciences||Wellcome Trust Kilify||KEN|
There are no publications listed for this DPhil project.