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HIV and antiretroviral therapy in the brain: neuronal injury and repair

Key Points

  • Human immunodeficiency virus (HIV) enters the CNS during the earliest stages of infection. Among neurotropic viruses, many of which cause disease in less than 5% of infected individuals, HIV is distinctly neurovirulent, resulting in neurocognitive impairment in 50% or more of patients.

  • Combination antiretroviral therapy (cART) has markedly prolonged survival and benefited health for many HIV-infected individuals in the United States. At the same time, cART has altered the character of the predominant neurological manifestation of HIV infection from a devastating, severe dementia to a chronic, milder degree of neurocognitive impairment.

  • Clinicians, scientists and the general public have increasingly recognized in recent years the adverse impact of milder degrees of neurocognitive impairment that do not meet the criteria for dementia. Common examples of this include HIV-related neurocognitive disorders, mild cognitive impairment as a precursor to Alzheimer's disease and sports-related post-concussion brain injury.

  • The possible impact of milder degrees of cognitive impairment in HIV-infected individuals who survive for decades is not yet well known. Ongoing studies are characterizing long-term effects on activities of daily living, medication adherence and vocational achievement.

  • Synaptodendritic injury is a specific type of neuronal injury comprising structural and chemical changes that affect the 'business ends' of neurons — the synapses at which they communicate and interact with one another. Synaptodendritic injury correlates closely to the presence and severity of neurocognitive disorders in HIV.

  • By carefully selecting specific antiretrovirals and supplementing them with neuroprotective agents, physicians might be able to facilitate innate CNS repair in HIV infection, promoting enhanced synaptodendritic plasticity, neural functioning and improved clinical neurological status.

Abstract

Approximately 40 million people worldwide are infected with human immunodeficiency virus (HIV). Despite HIV's known propensity to infect the CNS and cause neurological disease, HIV neurocognitive disorders remain under-recognized. Although combination antiretroviral therapy has improved the health of millions of those living with HIV, the penetration into the CNS of many such therapies is limited, and patients' quality of life continues to be diminished by milder, residual neurocognitive impairment. Synaptodendritic neuronal injury is emerging as an important mediator of such deficits in HIV. By carefully selecting specific antiretrovirals and supplementing them with neuroprotective agents, physicians might be able to facilitate innate CNS repair, promoting enhanced synaptodendritic plasticity, neural function and clinical neurological status.

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Figure 1: Severe synaptodendritic injury in HIV infection.
Figure 2: Rapid reversal of dendritic beading.
Figure 3: Simplified gene map of HIV-1 indicating reported effects of viral gene products on cells of the CNS.
Figure 4: Changes in the prevalence of HIV-associated brain disorders and survival in the eras pre-cART and post-cART.
Figure 5: Schematic time course of HIV neurocognitive impairment and the effects of cART.

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Acknowledgements

The authors wish to thank A. Bhatt and F. Duitch for their assistance with preparing the manuscript. The authors also wish to acknowledge the contributions of our colleagues in the HIV Neurobehavioral Research Center (HNRC) Group whose insights have contributed to the concepts in this review. The San Diego HNRC group is affiliated with the University of California, San Diego, USA, the Naval Hospital, San Diego, and the San Diego Veterans Affairs Healthcare System, and includes: I. Grant, J. H. Atkinson, J. A. McCutchan and T. D. Marcotte; Naval Hospital San Diego: M. R. Wallace; Neuromedical Component: J. A. McCutchan, R. J. Ellis, S. Letendre, R. Schrier; Neurobehavioural Component: R. K. Heaton, M. Cherner, S. P. Woods; Imaging Component: T. Jernigan, J. Hesselink, M. J. Taylor; Neurobiology Component: E. Masliah, I. Everall, D. Langford; Clinical Trials Component: J. A. McCutchan, J. H. Atkinson, R. J. Ellis, S. Letendre; Data Management Unit: A. C. Gamst, C. Cushman, D. R. Masys; Statistics Unit: I. Abramson, D. Lazzaretto and T. Wolfson. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. The HNRC is supported by a Center award from the National Institute of Mental Health.

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DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

Huntington's disease

Parkinson's disease

schizophrenia

FURTHER INFORMATION

HIV Neurobehavioral Research Center

Glossary

Combination antiretroviral therapy

(cART). A strategy by which multiple anti-human immuno-deficiency virus drugs are used in specific combinations to suppress viral replication and thereby reverse and prevent progressive immune deficiency and restore health.

Neurotropism

The capacity of a pathogen, such as a virus, to invade the CNS and infect its cells.

Neurovirulence

The capacity of a pathogen to cause disease of the nervous system.

Efflux transporter

A cellular protein that pumps substrate (such as a drug) out of the cell.

HIV encephalitis

Brain inflammation (infiltration of leukocytes and activation of CNS glia) accompanied by the expression of viral nucleic acids and proteins.

Synaptodendritic injury

Anatomical and functional damage to pre- and postsynaptic structures that occurs without neuron death, and is potentially reversible.

Borna disease

A newly classified non-segmented negative-strand RNA virus causing a sporadic, transmissible, progressive neurological disease in many species. Infection causes movement and behavioural disturbances reminiscent of some neuropsychiatric syndromes. Evidence in recent years indicates that Borna disease virus infects humans; it might be associated with various neuropsychiatric disorders, including schizophrenia.

Hippocampal dentate gyrus

Grey matter composed of three layers situated above the gyrus hippocampi. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, the axons of which pass through the polymorphic layer and end on the dendrites of pyramidal cells in the hippocampus.

Dendritic beading

Bulging or knotted appearance of dendrites, indicative of excitotoxic stress or ischaemic injury.

Axoplasmic flow

Directed transport of organelles and molecules along a nerve cell axon. Transport can be from the cell body or towards the cell body.

Envelope protein

Glycoprotein expressed on the surface of the human immunodeficiency virus particle.

Activation state

Intercellular signalling through chemical mediators such as cytokines can result in changes in the activation state such that target cells (for example, immune cells and glia) change their metabolic activity, gene transcription, protein expression, morphology and other characteristics.

Morris water maze

A behavioural assessment procedure designed to assess spatial memory in mice or rats.

HIV-associated dementia

(HAD). Documented moderate to severe impairment in two or more cognitive areas (usually the impairment is severe and pervasive) with marked decline in everyday functioning.

Asymptomatic neurocognitive impairment

(ANI). Documented mild impairment in two or more cognitive areas without a clear effect on everyday functioning.

Mild neurocognitive disorder

(MND). Documented mild to moderate impairment in two or more cognitive areas with mild to moderate decline in everyday functioning.

FSTC circuits

Frontal-striato-thalamo-cortical brain circuits. Reciprocal loops that interconnect neurons in the prefrontal cortex, striatum and thalamus, and that subserve complex cognitive abilities such as planning and execution of multi-step tasks in the context of ongoing distractions and new information.

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Ellis, R., Langford, D. & Masliah, E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8, 33–44 (2007). https://doi.org/10.1038/nrn2040

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