Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

Abstract

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer's disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.

Keywords: HIV; HIV-associated dementia; HIV-associated neurocognitive disorders; HIV-encephalitis; cognitive impairment; host genetics; neuroAIDS; polymorphisms; risk factors.

Figure 1

Categories and types of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), according to the Frascati criteria. When diagnosing patients with HAND, it is important to consider comorbidities, such as substance use and psychiatric illnesses, and to exclude other possible causes. Neurocognitive tests should evaluate at least the following: verbal/language skills, attention-information processing/working memory, memory (both learning and recall), motor skills, sensory perceptual, abstraction/executive function, and speed of information processing. Functional impairments, regarding mental acuity, social interactions, work, and other aspects, are usually self-reported, but witnesses are helpful [16,18]. HIVE, HIV encephalitis.

Figure 2

Pathogenic mechanisms and possible genetic influences that lead to development of HIV-associated neurocognitive disorders. HIV and its proteins (gp120, Tat, Vpr) enter the central nervous system (CNS) mainly through infected monocytes and T cells, but also via transcytosis or paracellularly. Infected and uninfected microglia, perivascular macrophages and astrocytes release neurotoxic substances (including viral proteins, if infected), inflammatory cytokines (particularly TNF-α and IL-β), and various chemokines that further activate the same uninfected cells. Neurotoxic substances include gp120 and Tat, quinolinic acid, glutamate, arachidonic acid, and free radicals such as NO, some inflammatory cytokines (TNF-α), and chemokines and cytokines. The resulting neuronal injury is due to functional damage, such as disruption of bioenergetic homeostasis, oxidative stress, damage to synapses and dendrites, and, to a lesser extent, apoptosis. Chemokines may be protective (some C-chemokines, such as MCP-1/CCL2, MIP-1α/CCL3 and MIP-1β/CCL4) or harmful (some CXC or α chemokines, such as SDF-1). Many bind to the chemokine receptor CCR5 expressed by macrophages and many astrocytes and neurons, and importantly, CCR5 also interacts as a coreceptor with gp120, perhaps directly neurotoxic. Increased glutamate is released by neurons leading to excitotoxicity; ATP and cytokines released by macrophages, and decreased glutamate reuptake by astrocytes (as macrophages release arachidonate). This increases intracellular calcium through N-methyl-d-aspartate (NMDA)-coupled ion channel receptor (NMDAR)-coupled ion channels activated by excessive glutamate and excitotoxic substances. Finally, this results in neuronal injury through free radicals, oxidative damage, and apoptotic pathways. Potential gene variants may influence pathogenic processes by altering expression of cytokines, chemokines, MMPs, HLA types. Neurotransmitter levels (affecting cognitive processes), β-amyloid deposition, susceptibility to oxidative damage and stress, as well as aging, are further affected by genotypes. Gene variants are marked by small ‘chromosomes’ on the side of text, where green indicates protective and red harmful/neurotoxic effects. (TNF-α, tumor necrosis factor-alpha; IL-, interleukin; Tat, transactivator of transcription; gp120, glycoprotein120; NO, nitric oxide; MCP-1, monocyte chemoattractant protein; MIP-1, macrophage inflammatory protein-1; SDF-1, stromal-derived factor; NMDA, N-methyl-d-aspartate; MMP, matrix metalloproteinase; HLA, human leukocyte antigen.)

Figure 3

Common pathways in AD and HAND pathogenesis. In AD and HAND, there are several lines of attack that lead to neurodegeneration. β-amyloid aggregates not only have direct cytotoxic effects on neurons, but also indirectly through the generation and progression of a local neuroinflammation via activated and dystrophic resident glial cells in the vicinity of neurons. The latter, reactive gliosis, brings with its secretion of cytokines and chemokines that are released from microglia predominantly, and reactive astrocytes. The interaction between activated microglia and reactive and astrocytes is an important component of HAND pathogenesis. Secreted factors from microglia include members of the complement system (C1q, C3b, C4d, C5b-9), and pro-inflammatory cytokines TNF-α, and IL-1β, IL-6, IL-10, whereas astrocytes release mainly TNF-α and IL-1β. Enhanced secretion of TGF-β from reactive astrocytes favors activation of microglia. Further, TREM2 is highly expressed by microglia and alleviates pro-inflammatory factor-induced AD pathology by mediating phagocytosis of cell debris [233]. Aβ binds to and reduces TREM2 activity; dysregulation of TREM2 signaling contributes to the pathogenesis of both AD and HAND [234]. One interesting aspect is the release of reactive oxygen species (ROS) which can have multiple effects in this inflammatory process. For example, ROS can induce neuronal protein and lipid oxidation, DNA damage, and impair mitochondrial function by disturbing the oxidative respiratory chain, affecting neuronal transport processes and the ubiquitin-proteasome system. ROS, released from Aβ-stimulated microglia can also induce astrocytes to adopt a neurotoxic phenotype. The net result is the worsening of inflammation and brain damage. The HIV proteins Tat and gp120 activate NMDA receptors triggering excessive glutamate release and excitotoxicity. Tat also activates BACE1 promoting the formation of B-amyloid plaques, and enters neurons via LRP1 to prevent apoE4 uptake, amplifying neurotoxicity. Tat can also be synthesized and released in HIV-infected astrocytes; one source of infection is derived from activated microglia. ApoE4 is known to enhance HIV infection [151]. Neurons and microglia also secrete FGF and BDNF in an attempt to promote neuronal survival. Disease progression, however, results in the failure to repair the injured neurons. (AD, Alzheimer’s Disease; HAND, HIV-associated neurocognitive disorder; TNF-α, tumor necrosis factor-alpha; IL-, interleukin; TGF-β, transforming growth factor beta; TREM2, membrane-bound triggering receptor expressed on myeloid cells 2; ROS, reactive oxygen species; Tat, transactivator of transcription; gp120, glycoprotein120; NMDA, N-methyl-D-aspartate; BACE1, beta-site amyloid-beta precursor protein cleaving enzyme 1; LRP1, low-density lipoprotein receptor-related protein 1; FGF, basic fibroblast growth factor; BDNF, brain-derived neurotrophic factor.)