Perturbing the crosstalk between microglia and neurons uncovers mechanisms underpinning neuronal damage and repair in HIV central nervous system infection

A central nervous system HIV-1 latent reservoir occurs due to poor drug penetration and weakened immune surveillance. Implications are: 1) aetiology in HIV-associated brain injury (HABI), 2) viral rebound if treatment ceases, 3) barrier to cure and 4) implications for neurodevelopment in babies born to mothers with HIV. Microglia are immune cell types in the brain. Regulated crosstalk between microglia and developing neurons is essential for normal neuronal development. I hypothesise that disruption of this crosstalk by either HIV replication in microglia and consequent neuroinflammation or through interaction with C-C chemokine receptor type 5 expressed on various brain cells or other CD4-independent pathways, causes aberrant intracellular signalling, which alters cytokine and chemokine levels, leading to inflammation, calcium influx and apoptosis in neurons. Additionally, this crosstalk can be perturbed by epigenetic modifications including histone acetylation and methylation. Building upon research in my PhD, I will utilise biobanked specimens from characterised clinical cohorts and physiologically relevant models; 2D iPSC-derived microglia/neuron co-cultures and 3D brain organoids, as well as develop new skills in multiomic approaches, to uncover host-pathogen interactions underlying HIV neuroinflammation. This will give me a platform to develop an independent research program on therapeutic targets for HABI and viral-mediated neurodevelopmental problems.