HIV and the Nervous System

Abstract

Human immunodeficiency virus (HIV) infection in the pre‐antiretroviral drug era was known to cause a variety of neurological syndromes, including HIV‐associated dementia, myelopathy, peripheral neuropathy, opportunistic infections of the nervous system and primary central nervous system (CNS) lymphoma. The era of efficient combined antiretroviral treatment has led to a shift in the nature of these syndromes, yet HIV infection is still a major cause of neurological disease, typically causing a more chronic effect, as is the case in mild cognitive impairment attributed to the virus. The mechanisms underlying this chronic effect are related to the CNS being a viral reservoir, as HIV does not directly infect neurons but does reside in different cells of the nervous system such as macrophages, microglia and astrocytes, implicating neuronal injury using neurotoxic viral factors and initiating processes of neuroinflammation and neurodegeneration. In addition, the antiretroviral treatment itself is responsible for some aspects of neurological morbidity, mainly peripheral neuropathy and possible CNS manifestations of immune reconstitution inflammatory syndrome after treatment is initiated.

Key Concepts

  • HIV‐1 invades the nervous system during early infection, frequently infecting perivascular macrophages, microglia and astrocytes.
  • The central nervous system is a potential reservoir for HIV‐1, challenging eradication and leading to chronic neurological complications despite antiretroviral treatment.
  • Neurotoxic viral factors, neuroinflammation and neurodegeneration are the main mechanisms underlying neuropathogenesis of HIV‐1.
  • The main neurotoxic viral proteins are gp120, transactivator of transcription (Tat), Vpr and Nef.
  • CNS‐infiltrating monocytes are the primary blood‐derived contributors to neuroinflammation in HIV infection, leading to gliosis and astrocytosis and the release of inflammatory cytokines such as TNF‐α, IL‐1β and interferons.
  • Neurodegeneration has been shown to be mediated by DNA damage and mitochondrial abnormalities but also by other processes including protein aggregates, cellular senescence and epigenetic alterations.
  • The major neurological syndrome seen in cases of treated HIV infection is mild neurocognitive impairment.
  • In untreated patients, opportunistic infections, HIV‐myelopathy and primary CNS lymphoma and are the main causes of neurological disease.
  • Antiretroviral treatment can also lead to a neurological sequela, whether due to direct neurological side effects of drugs or due to the indirect consequences of immune reconstitution inflammatory syndrome (IRIS).

Keywords: HIV; AIDS; brain; PML; toxoplasmosis; dementia; cryptococcal meningitis; neuropathy; myelopathy

Figure 1. Mechanisms of CNS injury in HIV infection. HIV, human immunodeficiency virus; CNS, central nervous system; IL, interleukin; TNF‐α, tumour necrosis factor alpha; IFN, interferons; IP‐10, interferon γ‐induced protein 10; NMDA‐R, N‐methyl‐d‐aspartic‐acid receptor; DAT, dopamine transporter; Aβ, amyloid‐beta.
Figure 2. Main neurological complications in HIV‐infected patients. HIV, human immunodeficiency virus; CNS, central nervous system; cART, antiretroviral treatment.
Figure 3. Brain MRI of a patient with HIV‐associated dementia. This image from a T2‐FLAIR sequence shows diffuse white matter changes and generalised atrophy, in a 59‐year‐old man whom was poorly adherent to his antiretroviral treatment and presented with progressive cognitive decline. His cognition and the abnormal white matter signal improved with stable antiretroviral treatment; MRI, magnetic resonance imaging; HIV, human immunodeficiency virus.
Figure 4. Brain MRI scans of a patient with cerebral toxoplasmosis. A 46‐year‐old man with a new diagnosis of HIV, CD4 count of 37 cells per microliter and viral load of 175 000 copies per milliliter, was also diagnosed with cerebral toxoplasmosis due to right hemiparesis, with imaging showing typical ring‐enhancing lesions in the basal ganglia and left frontal lobe on T1 sequence after injection of gadolinium (a). He was treated with antiretroviral treatment and antiparasitic drugs, and some improvement was noted after 2 weeks of treatment (b), while a nearly complete resolution of the lesions is demonstrated after 1 year (c), in parallel with a complete resolution of symptoms. MRI, magnetic resonance imaging; HIV, human immunodeficiency virus.
Figure 5. Brain MRI of a patient with progressive multifocal leukoencephalopathy (PML). A 48‐year‐old woman presented with aphasia and this image from the T2‐Flair sequence of her brain MRI showed multifocal involvement of the white matter with no evidence of oedema or enhancement (sequence not shown). She was diagnosed with HIV, with a CD4 count of 7 cells per microliter and viral load of more than 100 000 copies per milliliter. The diagnosis of PML was confirmed with a positive PCR test for JC virus in the cerebrospinal fluid. Antiretroviral treatment was initiated. MRI, magnetic resonance imaging; HIV, human immunodeficiency virus; PCR, polymerase chain reaction.
Figure 6. Brain MRI of a patient with PML‐IRIS. A 60‐year‐old man was started on antiretroviral treatment for a new diagnosis of HIV, and 2 months later presented with a gait disorder and cognitive changes. At this time, CD4 count was 150 cells per microliter and the plasma viral load was undetectable. These images from his brain MRI show a subcortical lesion in the right parietal lobe white matter in the T2‐Flair sequence (a), with evidence of multiple punctate foci of enhancement in the T1‐sequence after injection of gadolinium (b). PCR test for JC virus in the cerebrospinal fluid was positive, and he was diagnosed with PML‐IRIS and improved under steroid treatment. MRI, magnetic resonance imaging; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy; IRIS, immune reconstitution inflammatory syndrome.
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Further Reading

Bhatia NS and Chow FC (2016) Neurologic complications in treated HIV‐1 infection. Current Neurology and Neuroscience Reports 16: 62.

Ellis RJ, Calero P and Stockin MD (2009) HIV infection and the central nervous system: a primer. Neuropsychology Review 19: 144–151.

Geretti AM (2017) Human immunodeficiency virus (HIV). In: eLS. John Wiley & Sons, Ltd (Ed.). DOI: 10.1002/9780470015902.a0000417.pub2.

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Valcour V, Sithinamsuwan P, Letendre S and Ances B (2011) Pathogenesis of HIV in the central nervous system. Current HIV/AIDS Reports 8: 54–61.

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Mina, Yair, Smith, Bryan R, and Nath, Avindra(Feb 2020) HIV and the Nervous System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000006.pub2]