HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities

Abstract

Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.

Fig. 1

Toxicity pathways induced by HIV-associated soluble factors. Inflammatory molecules released from microglia/macrophages and astrocytes evoke NMDAR activation, as well as activation of metabotropic glutamate receptors (mGluR), receptor tyrosine kinases (RTK), voltage-gated potassium channels (Kv), other G-protein-coupled receptors (GPCR), and potentially major histocompatability complex subtype 1 receptors (MHC I). Excess calcium influx, as well as release of intracellular calcium via IP3 receptors, leads to activation of calpains and other calcium-dependent proteases, which are known to cleave postsynaptic density proteins such as PSD-95 leading to synaptic dysfunction and disassembly

Fig. 2

Diagram detailing the numerous processes evoked by HIV infection in the brain that affect neuronal function and survival. Excess glutamate from the extracellular fluid and released from astrocytes causes excitotoxic mechanisms, such as dendritic beading, sustained NMDAR activation, increased calcium influx, and increased intracellular release of calcium. Ultimately, these processes lead to disruption of the postsynaptic density and loss of synapses. Viral proteins such, as gp120 and TAT, activate chemokine receptors, CXCR4 and CCR5, and can increase voltage-gated calcium (Cav) channels and potassium channels (Kv), leading to activation of cellular death pathways that result in mitochondrial depolarization, cytochrome p450 (Cp450) release, and ultimately DNA fragmentation associated with apoptosis. Viral proteins can also evoke increased Na⁺/H⁺ exchange, thereby increasing the pH inside astrocytes which promotes increased glutamate release and decreased glutamate uptake, thereby furthering excitotoxic damage

Fig. 3

Diagram detailing the various checkpoints of adult neurogenesis that can be affected by HIV infection in the brain. Neural progenitor cells and their supporting astrocytes can be damaged by inflammation associated with HIV infection. Multinucleated giant cells and microglia, especially near the rostral migratory stream, could also contribute to toxicity and damage to NPCs and immature neurons. Differentiating NPCs, as well as their integration into existing synaptic circuits, can also be affected