Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management

Despite the success of antiretroviral therapy (ART) in suppressing viral replication and extending life, a significant proportion of people living with HIV continue to experience neurocognitive impairment (NCI). This condition, characterized by difficulties with attention, focus, and memory, persists even when viral loads are undetectable in the blood and cerebrospinal fluid. The shift from frank dementia to milder, chronic forms of NCI has prompted a re-evaluation of the underlying causes, moving away from the idea of a single viral mechanism toward a multi-system model of brain injury.

Research suggests that HIV-associated NCI is driven by both direct and indirect effects. Even when replication is suppressed, HIV proviruses persist in the brain, particularly within myeloid cells like microglia and macrophages. These cells can continue to produce viral proteins (such as Tat, Nef, and gp120) and inflammatory mediators that trigger neuronal oxidative stress, mitochondrial dysfunction, and synaptic pruning. Furthermore, the blood–brain barrier (BBB) can be compromised by chronic inflammation and ART-induced side effects, allowing systemic inflammatory factors to enter the central nervous system and exacerbate neuronal damage.

As the population of people living with HIV ages, the contribution of non-HIV factors has become increasingly prominent. Comorbidities such as diabetes mellitus, hypertension, and metabolic syndrome are highly prevalent and appear to be major drivers of cognitive decline. These conditions, often exacerbated by chronic systemic inflammation, may now be the primary source of brain injury in many patients. Additionally, the gut microbiome and co-infections like cytomegalovirus (CMV) are emerging as significant contributors to the inflammatory milieu that impacts cognitive health.