HIV-1 infection of human microglia activates inflammatory pathways associated with HIV-associated neurocognitive disorders (HAND)

Abstract

HIV-associated neurocognitive disorders (HAND) cause significant dysfunction among people living with HIV. Microglia are the primary immune cells of the central nervous system and are readily infected by HIV. Microglia are thought to contribute to neuroinflammation and cognitive dysfunction in neurodegenerative diseases such as Alzheimer’s Disease and are likely to play an important role in the pathogenesis of HAND. In order to identify pathways that may contribute to neuropathogenesis in HAND, we infected induced pluripotent stem cell-derived microglia (iMG) with HIV and defined gene expression changes over an 8-day period. Monocyte-derived macrophages (MDMs) were studied in parallel in order to elucidate common pathways stimulated in myeloid cells and to define unique aspects of microglia infection. Infection of iMG led to the induction of a robust early inflammatory response triggered within hours of infection, a pattern that differed significantly from that seen in MDMs. Remarkably, gene expression changes in iMG reproduced many of the characteristic genetic signatures previously defined as HAND signatures from brain tissues obtained from individuals clinically diagnosed with HAND. Interferon-mediated signaling pathways were strongly activated following HIV infection of iMG, leading to enhanced expression of multiple HIV restriction factors, yet viral replication in iMG remained robust. These findings suggest that HIV infection of microglia is the key driver of neuroinflammation in the CNS of HIV-infected individuals. Further studies of infected microglia are likely to aid in understanding the pathogenesis of HAND and in evaluating therapeutic strategies to limit or eliminate HIV-induced neuropathogenesis.

Competing Interest Statement

The authors have declared no competing interest.