Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

Abstract

Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1β, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

“…However, it is important to note that NK cell function in neonatal mice is developmentally immature and cannot be compared to results from studies in adult mice (106). In contrast, activated microglia have been suggested to contribute immunopathological responses to chronic viral infections of the CNS, such as HIV, as well as to provide early antiviral responses during acute viral encephalitis associated with both flaviviruses and herpes simplex virus (107)(108)(109). However, similar to limitations in our study, the previous studies were often carried out in the presence of peripheral inflammatory responses, and thus, the precise role of microglia in the mechanisms of CNS disease cannot be rigorously assigned.…”

Obesity, Cytokines and Cognition across the Lifespan among People Living with HIV

“…These cytokines can exert their action by crossing the blood-brain barrier directly via active transport mechanisms. Chronic inflammation can also lead to microglial infiltration and activation of factor NFκB [30][31][32][33]. The final result, according to preclinical models, is synaptic remodeling, neuronal apoptosis, and impaired neurogenesis.…”

Antiretroviral Therapy through Barriers: A Prominent Role for Nanotechnology in HIV-1 Eradication from Sanctuaries

“…This fact is clinically relevant, since HIV-1-related brain infection leads to a broad spectrum of complex neurocognitive and organic disorders, altogether called "neuroAIDS" [10]. It includes cognitive decline with impairment of attention, learning and mood disorders up to dementia, and other manifestations such as multifocal leukoencephalopathy, primary CNS lymphoma and tuberculous or cryptococcal meningitis [16]. The advent of ART has drastically reduced the most severe forms of neuroAIDS, but the prevalence of milder neurologic signs (e.g., asymptomatic neurocognitive impairment and mild neurocognitive impairment) remains high, affecting up to half of all HIV-1-infected individuals [17] and conferring a 2-to 6-fold increased risk for the development of symptomatic HIV-1-associated neurocognitive disorder [18].…”