Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis

Abstract

The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. KEY MESSAGES Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND.

Keywords: Anti-retroviral therapy (ART); Chemokines (or chemotactic cytokines); HIV-1-associated neurocognitive disorders (HAND); Human immunodeficiency virus type 1 (HIV-1); Microglia; Reactive oxygen species (ROS).

Graphical abstract

Figure 1.

Schematic representation of mechanisms of HIV neurotoxicity. The Gp41, Gp120, Tat, Vpr, Vpu and Nef viral proteins, that circulate in the blood produce enhanced ROS production, results in alteration of BBB. Different process occurs during the neurotoxicity like enhanced oxidation of DNA nucleic bases, genomic instability, aggregation of ceramide, stimulation of A-type transient outward K + currents by Kv channels, and production of proinflammatory cytokines.

Figure 2.

Schematic representation of the effects of HIV and its viral proteins on the cells of the CNS of HAND patients. HIV enters into the brain, especially perivascular space (the main site for viral replication), within infected macrophages or as free virions or viral particles. HIV infects and activates macrophages, astrocytes and microglia in the perivascular space, the main site for viral replication. Macrophages, and astrocytes and activated microglia contribute to the release of proinflammatory cytokines and chemokines, which provoke additional influx of immune cells and mediate neuronal damage. Conversely, some inflammatory mediators can also promote neuronal survival. HIV induces activated astrocytes which secrete proinflammatory cytokines, chemokines and glutamate. Together with viral proteins and HIV-induced chemokines, these substances overstimulate NMDA receptors, causing excitotoxicity. All the events caused by HIV proteins, excitotoxicity, and inflammation lead to axonal injury and neuronal apoptosis.

Figure 3.

“Shock and kill” strategy involves activating viral replication to eliminate reservoirs and to target latently-infected cells. LRAs have an important role in the reactivate transcription for the “shock”. LRAs promote chromatin decompaction and ARN pol II recruitment to induce virus transcription. ART is maintained during this phase to clear reservoir without virus propagation in other cells. The “kill” can be enhanced by stimulation of the cell-mediated immune response or by using neutralising and/or engineered antibodies. The “block and lock” strategy relates on the induction of a state of deep-latency to prevent HIV-1 transcription. LPA inhibit various step of virus replication, transcription by Tat inhibition and RNA export. One promising LPA is a miRNA which inhibit virus expression.