Elucidating the Molecular Mechanisms that Mediate DKD Progression in Patients Living with HIV

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SUMMARY With the aging of the HIV-infected population, and their prolonged exposure to cART regimens that may promote the development of diabetes, the prevalence of diabetic kidney disease (DKD) is increasing in patients living with HIV (PLWH). In two recent studies, we and others have confirmed the additive/synergistic effects of HIV infection and diabetes on the progression of DKD. Studies have demonstrated that HIV can infect kidney cells, and that the kidney serves as a reservoir for HIV replication. Recent findings suggest that HIV is present in the kidney even in cART-treated HIV patients. To determine how chronic HIV infection in patients with low or undetectable viral load aggravates DKD, we generated a doxycycline-inducible kidney cell-specific HIV transgenic mouse the expresses low levels of HIV genes. With this model, we confirmed that low level of HIV gene expression did not cause kidney injury alone. However, aggravated DKD was observed after induction of diabetes, suggesting an additive/synergistic effect of HIV and diabetes on DKD progression (Feng J. Kidney Int. 2021). For this project, we will further investigate the molecular mechanisms by which chronic HIV infection induces the progression of DKD in both mouse models and human patients with HIV to accelerate the discovery of new drug targets and therapeutics to treat these patients. Toward this goal, we propose the following specific aims: Aim 1: Perform comprehensive bulk and single-cell RNA-sequencing of the kidneys and kidney immune cells from the mice with both diabetes and low HIV gene expression as compared to control mice, and mice with HIV or diabetes alone. Aim 2: Perform formalin fixed paraffin embedded slides-based RNA-capture sequencing, scRNA-seq, immunostaining, and in-situ hybridization of kidneys from patients with DKD alone, and from those with both HIV infection and DKD. Aim 3: Integrate these datasets together with publicly available datasets to identify gene expression signatures mediating the additive/synergistic effects of HIV and diabetes on DKD progression. Utilize the Connectivity Mapping approach to identify potential drugs and small molecules which could reverse these gene signatures similarly to the approach described in our recent study (Zhang L. Diabetes 2020). Develop a web-portal to serve and interact with all project data. Aim 4: Validate predicted drugs from aim 3 in the animal model described in the aim 1. Overall, this project will enable us to identify potential new mechanisms, new drug targets, and potential new therapeutics to halt the progression of DKD in PLWH.