Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

Abstract

As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

Figure 1

Invasion of the blood brain barrier. HIV-1 infected immune cells release toxic viral products and inflammatory cytokines leading to degradation of tight junction proteins, oxidative stress and up-regulation of adhesion molecules. This results in the increased permeability of the blood brain barrier and increased migration of immune cells across the barrier. HIV-1 infiltrates the BBB early after infection [29] using HIV-infected monocytic cells as a “Trojan horse” for entry into brain [30].

Figure 2

Mechanisms of gp120 neurotoxicity. (1) gp120 can bind to the NMDA receptor and lead to excessive opening of NMDAR-gated cation channels, allowing the influx of calcium ions to toxic levels [54]. (2) gp120 can directly bind to either CCR5 or CXCR4, activating an p38-MAPK mediated signaling cascade that leads to neuronal apoptosis [56]. The gp120-CXCR4 binding also up-regulates the expression of the nicotinic receptor α7, which increases cellular permeability to [Ca²⁺] influx and contributes to cell death [61].

Figure 3

Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].

Figure 4

Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].