The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder

Abstract

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% of HIV-1-infected patients receiving ART exhibit neuroinflammation and symptoms of HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that the emergence of HIV-1 from latency in microglia underlies both neuroinflammation in the CNS and the progression of HAND. Recent molecular studies of cellular silencing mechanisms of HIV-1 in microglia show that HIV-1 latency can be reversed both by proinflammatory cytokines and by signals from damaged neurons, potentially creating intermittent cycles of HIV-1 reactivation and silencing in the brain. We posit that anti-inflammatory agents that also block HIV-1 reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for the treatment of HAND.

Keywords: HIV-1 latency; HIV-1-associated neurocognitive disorder; anti-inflammatory strategies; antiretroviral therapy; microglial cell activation.

Figure 1.. Schematic illustration of the interactions between neurons, astrocytes, and microglia in heathy vs. HAND human brains.

In a healthy brain, neurons and astrocytes induce microglia to attain a surveillance and neuroprotective phenotype by signaling though factors such as fractalkine CX3CL1, CD200, TGFβ1/2, and Wnt [77]. During HIV-1 infections, the “high-jacked” infected monocytes and CD4⁺ T cells allow viral entry into the brain. Viral particles can also enter the brain by damaging the blood-brain barrier (BBB), altering endothelial cell permeability, or through transcytosis [18]. HIV-1 can establish latent reservoirs in microglia. Reactivation of latent HIV-1 causes a microglial shift to a reactive state, resulting in the release of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8, CCL2, and CCL5, reactive oxygen species (ROS), and reactive nitrogen species (RNS) [34]. Microglia activation can also cause astrocytes to shift to a reactive state, with secretion of more inflammatory cytokines [72]. Viral proteins such as gp120, Nef, Tat can directly cause neuronal damage and disrupt astrocyte glutamate transporters, resulting in glutamate imbalance in the brain and excitotoxicity of neurons [18,83]. Neural damage-associated molecular pattern (DAMP) molecules and ADP can further cause microglia hyperactivation and HIV-1 reactivation, thus initiating a cycle of progressive neural inflammation. This figure was created using BioRender.com.

Key Figure, Figure 2.. Model for the regulation of HIV-1 transcription by inflammation and neuronal interactions.

HIV-1 can infect homeostatic (“ramified”) microglia. However, HIV-1 transcription might become quickly silenced by the recruitment of Nurr1 and the CoREST repressor complex to the long-term repeat regions, based on preliminary findings [48]. In the presence of “Off signals” produced by healthy neurons, HIV-1 infected cells are further suppressed by glucocorticoids (GC) [46] or other anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β, produced by neurons. Latently infected cells can become fully reactive in the presence of exogenous pro-inflammatory activators, including LPS, GM-CSF, TNF-α and IFN-γ [33]. This leads to the activation of NF-κB, which can bind the LTR and activate HIV-1 transcription, releasing viral proteins such as Tat, Env, and Nef -- known neurotoxins. In addition to stimulating HIV-1 expression, NF-κB can activate a variety of cellular inflammatory markers and release additional neurotoxic cytokines including TNF-α, IL-β, and IL-6. This may lead to neuronal damage, further activating infected microglia due to the release of DAMPs [34]. These mechanisms may parallel the sensing behavior of uninfected microglia during a wide variety of neurodegenerative diseases, but microglial activation may become highly exacerbated when HIV-1 is present [40,61,81].