HIV-1 mediated reprogramming of T cell gene expression networks

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Virus infection triggers two fundamental types of cellular response: those that inhibit infection (termed immune responses) and those that promote virus production, persistence and/or dissemination (here called reprogramming). The balance between these opposing forms of response dictates the overall outcome of infection and, ultimately, contributes to the pathogenic consequences for the infected host. To date, little is understood regarding the capacity of the pathogenic retrovirus, HIV-1, to reprogramme infected T lymphocytes, or the consequences of such changes for altering cell function. This project will build upon a substantial body of data where we have demonstrated that HIV-1 reorganises the transcriptional landscape of T lymphocytes within the first few hours of infection. We will employ a multi-disciplinary approach including virology, molecular genetics, biochemistry, high-throughput nucleic acid sequencing, single-cell analytics and bioinformatics to tackle the following key questions. One, what are the virus determinants that drive these RNA expression changes and through which signalling pathways do they operate? Two, what genome-wide alterations in chromatin and epigenetic marks underpin changes in RNA levels, and which steps of RNA biogenesis are regulated? Three, do all cells respond to infection equivalently or is there cell-to-cell variation; and if the latter, what cell-specific signatures underpin the differences? Four, how does reprogramming impact the fate of HIV-1 infection, perhaps by altering virus production or persistence (a form of which is called latency)? Together, insight in these areas will yield new information on the dynamic interplay between HIV-1 and its human host.