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

Despite the success of antiretroviral therapy (ART) in suppressing systemic HIV-1 replication, 15% to 60% of people living with HIV-1 continue to experience HIV-1-associated neurocognitive disorder (HAND). This persistence suggests that the central nervous system (CNS) acts as a distinct reservoir where current treatments are less effective. The authors argue that the traditional focus on viral load alone is insufficient to explain HAND, as the disorder may stem from a complex interplay between viral persistence, chronic neuroinflammation, and the toxic side effects of ART itself.

The paper posits that microglia—the primary immune cells of the brain—serve as a critical reservoir for latent HIV-1. Unlike peripheral reservoirs, HIV-1 latency in microglia is highly sensitive to the cellular activation state. The authors describe a mechanism where pro-inflammatory cytokines and signals from damaged neurons can reverse this latency, leading to intermittent bursts of viral transcription. This reactivation not only produces viral proteins like Tat and Nef, which are directly neurotoxic, but also triggers the microglia to release further inflammatory cytokines, creating a vicious cycle of neuroinflammation and neuronal damage.

Because ART does not target proviral transcription, it fails to prevent the reactivation of latent HIV-1. The authors suggest that future therapeutic strategies should focus on dual-action agents that can both suppress HIV-1 transcription and dampen microglial activation. Specifically, they highlight the potential of nuclear receptor agonists, such as Nurr1 and glucocorticoid receptor ligands, which have shown promise in preclinical models for silencing HIV-1 and promoting a quiescent, neuroprotective microglial phenotype. By stabilizing microglia in this resting state, it may be possible to break the cycle of reactivation and mitigate the progression of HAND.