Fate of microglia during HIV‐1 infection: From activation to senescence?

Abstract

Microglia support productive human immunodeficiency virus type 1 (HIV-1) infection and disturbed microglial function could contribute to the development of HIV-associated neurocognitive disorders (HAND). Better understanding of how HIV-1 infection and viral protein exposure modulate microglial function during the course of infection could lead to the identification of novel therapeutic targets for both the eradication of HIV-1 reservoir and treatment of neurocognitive deficits. This review first describes microglial origins and function in the normal central nervous system (CNS), and the changes that occur during aging. We then critically discuss how HIV-1 infection and exposure to viral proteins such as Tat and gp120 affect various aspects of microglial homeostasis including activation, cellular metabolism and cell cycle regulation, through pathways implicated in cellular stress responses including p38 mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB). We thus propose that the functions of human microglia evolve during both healthy and pathological aging. Aging-associated dysfunction of microglia comprises phenotypes resembling cellular senescence, which could contribute to cognitive impairments observed in various neurodegenerative diseases. In addition, microglia seem to develop characteristics that could be related to cellular senescence post-HIV-1 infection and after exposure to HIV-1 viral proteins. However, despite its potential role as a component of HAND and likely other neurocognitive disorders, microglia senescence has not been well characterized and should be the focus of future studies, which could have high translational relevance.

Astrocyte senescence: Evidence and significance

“…In fact, cellular senescence has been identified in microglia (Flanary, Sammons, Nguyen, Walker, & Streit, ), oligodendrocytes (Al‐Mashhadi et al, ), neural stem cells (He et al, ), and even neurons (Jurk et al, ). We have recently demonstrated that microglia can senesce in response to HIV infection and have proposed that microglia may transition from activation to senescence (Chen, Partridge, Sell, Torres, & Martin‐Garcia, ; Chen et al, ). Thus, the link between other CNS cell senescence and age‐associated neurodegenerative disease should be further explored.…”

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…As an example, "humanized" bone marrow chimeric mice are susceptible to brain infection by HIV, when the transplanted cells develop into cells with microglia properties within the CNS (Mathews et al, 2019). In addition, as shown by single cell gene expression analysis, chronic microglia infection in the AIDS brain may result in their functional impairment and senescence, which may impair their homeostatic function in chronic brain inflammation (Chen, Partridge, Sell, Torres, & Martin-Garcia, 2017;Ginsberg et al, 2018).…”

HIV Tat causes synapse loss in a mouse model of HIV‐associated neurocognitive disorder that is independent of the classical complement cascade component C1q

“…Although cART suppresses viral replication, some viral proteins such as Tat, are still made by infected macrophages, microglia, and astrocytes. Viral proteins released from infected glia can harm adjacent neurons directly or indirectly by activating the immune system and triggering the production of cytokines, complement proteins, and reactive oxygen species (Bansal et al, ; Buscemi, Ramonet, & Geiger, ; Chen, Partridge, Sell, Torres, & Martin‐Garcia, ; Jadhav, Krause, & Singh, ; Marker et al, ; Nitkiewicz et al, ; Williams et al, ; Youn, Ju, Choi, & Park, ). Simply exposing the brain to Tat causes neuropathologic changes that are relevant to HAND.…”