For the millions of people living with HIV who have achieved undetectable viral loads, the assumption that brain health is protected may be dangerously incomplete. Cognitive impairment persists at surprisingly high rates despite decades of effective antiretroviral therapy — a paradox that demands closer examination of what is actually happening inside the central nervous system.
A comprehensive review published in Brain, Behavior, and Immunity maps the mechanistic landscape of HIV-associated neurocognitive disorders (HAND), a spectrum that remains prevalent even when systemic viremia is fully suppressed. The CNS functions as a distinct immunological and pharmacological sanctuary where HIV persists within long-lived cellular reservoirs — chiefly microglia and perivascular macrophages — independent of peripheral viral control. These reservoir cells sustain chronic neuroimmune activation through ongoing viral transcription and release of neurotoxic viral proteins, without requiring active neuronal infection. Microglia emerge as central orchestrators of injury: their release of inflammatory mediators, reactive oxygen species, and viral proteins cascades into astrocyte dysfunction, glutamate dysregulation, and progressive synaptic degeneration. Critically, the review also flags emerging preclinical and observational signals suggesting that some antiretroviral agents themselves may contribute to mitochondrial dysfunction and altered glial metabolism — potentially compounding neurocognitive vulnerability in susceptible individuals.
This analysis carries meaningful implications for how clinicians and researchers think about long-term HIV management. The neurological burden of HAND is no longer dominated by full-blown HIV-associated dementia, which cART largely curtailed, but by subtler, milder cognitive deficits that are difficult to detect and attribute. The field is navigating a dual challenge: the virus itself maintains a brain reservoir that current drugs cannot fully silence, while some of those same drugs may carry underappreciated neurotoxic trade-offs. This review is largely observational and synthesizes preclinical data alongside clinical evidence of varying quality — causal links between specific antiretroviral agents and cognitive outcomes remain unconfirmed. Still, it represents a timely consolidation of an underappreciated problem and should reinforce urgency around CNS-penetrant therapeutic strategies and reservoir-targeting approaches as next-generation priorities.