Turning defense into damage: HIV-driven amyloidogenesis and neurotoxicity.

With the continued spread of human immunodeficiency virus 1 (HIV-1) and its ability to enter and persist within the central nervous system (CNS), concerns have arisen regarding its impact on cognitive health. Indeed, during the early stages of the HIV pandemic, when effective treatments were unavailable, severe neurocognitive impairment was common. Although the widespread use of antiretroviral therapy (ART) has markedly reduced the severity, milder forms of HIV-associated neurocognitive disorders (HAND) remain prevalent. Similar to Alzheimer's disease (AD), elevated amyloid-β (Aβ) accumulation has been observed both intracellularly and extracellularly in the brains of HIV-infected individuals, based on autopsy studies. Aβ is generated through the amyloidogenic processing of amyloid precursor protein (APP), which is abundantly expressed in the brain. While the APP's role in AD pathogenesis has been well established, its broader physiological functions, particularly in the context of viral infections such as HIV-1, remain poorly understood. In the CNS, microglia are crucial for maintaining brain homeostasis and defending against viral infections. HIV-1, however, targets microglia, disrupting their antiviral capacity and contributing to neurotoxicity through multiple mechanisms, such as the release of viral proteins and host-derived neurotoxic factors including proinflammatory cytokines and Aβ. Moreover, HIV-infected microglia can influence neighboring cells such as astrocytes and neurons, further amplifying neurodegenerative processes. This review will focus on recent advances in understanding the antiviral role of APP and its processing during HIV-1 infection, highlighting how APP-mediated defense mechanisms intersect with neurotoxic pathways and the intercellular regulatory networks that link APP to HAND.