# Microglia cause HIV-induced transcriptional and metabolic changes in human neural organoids

## TL;DR

This study shows that microglia in the brain contribute to HIV-related changes in gene activity and metabolism, which could lead to neurological issues in people with HIV.

## Contribution

The study introduces a 3D human neural organoid model to reveal microglia-driven immunometabolic changes caused by HIV-1 infection.

## Key findings

- HIV-1 infection with microglia leads to significant transcriptional changes, including upregulated pro-inflammatory pathways.
- CCR6 is significantly upregulated upon HIV-1 infection, suggesting a role in viral permissiveness.
- Metabolic changes include increased expression of solute carrier genes and altered amino acid metabolism involving arginine, proline, and tyrosine.

## Abstract

Human immunodeficiency virus (HIV) can invade the central nervous system during the initial stages of infection and contribute to HIV-associated neurocognitive disorder, affecting up to 50% of people living with HIV (PLWH). To investigate HIV-1–induced immunometabolic changes in the brain, we used a three-dimensional microglia-embedded human neural organoid model. Transcriptomic analysis and genome-scale metabolic modeling revealed that HIV-1 infection led to more pronounced transcriptional changes in the presence of microglia, including upregulation of pro-inflammatory pathways. We identified CCR6, important for HIV-1 permissiveness, to be significantly upregulated upon infection. Metabolic analysis showed increased expression in metabolite transport-related genes, including solute carrier (SLC) genes and altered amino acid metabolism, particularly involving arginine, proline, and tyrosine. These microglia-driven immunometabolic changes may contribute to neuronal dysregulation and, subsequently, neurological complications, which are often observed in PLWH. Early detection of these alterations could support timely therapeutic intervention to improve HIV-related neurologic insult.

In neuronal organoids, HIV infection drives alternative metabolic pathways to meet increased energy demands, altering metabolite transport and amino acid metabolism while activating microglial glycolysis, inflammatory responses, and astrocyte activation.