HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

A Corrigendum to this article was published on 15 April 2016

This article has been updated

Key Points

  • Despite entering the era of combination antiretroviral therapy (CART), HIV-associated neurocognitive disorder (HAND) remains prevalent; however, less severe forms of HAND now predominate, and the most severe form, HIV-associated dementia, is rare

  • In individuals treated with CART, the risk of HAND increases with age and in the presence of cardiovascular disease risk factors

  • Latent HIV can persist in the brain even when systemic virological control is achieved with CART, thereby hampering efforts to eradicate HIV

  • Animal models of CNS HIV infection — such as macaques infected with simian immunodeficiency virus — develop severe HAND, viral encephalitis and neuronal apoptosis, and are central to understanding the immunopathogenesis of HIV-induced CNS damage

  • A growing body of work indicates that mild HAND can be modelled in immunocompetent mice infected with chimeric HIV (a model known as EcoHIV), and in chronically HIV-infected immunodeficient mice reconstituted with human immune systems

  • To date, clinical trials of HAND therapies have been unsuccessful, but further trials for the treatment of HAND are forthcoming, including a trial of intranasal insulin

Abstract

In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies — treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism — are needed to reverse or improve HAND-related neurological dysfunction.

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Figure 1: Timeline of advances in neuro-AIDS research.
Figure 2: More-effective therapies have reduced the severity of HIV-associated the severity of HIV-associated neurocognitive disorders.
Figure 3: Neuropathogenic mechanisms that contribute to HIV-associated neurocognitive disorders.

Change history

  • 15 April 2016

    The initially published version of this article included an incorrect grant number. The correct number of the NIH grant for David J. Volsky is MH104145. This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

Victoria Maranto and Heather Thomas assisted with the preparation of this manuscript by collating references and assisting with preparation of figures. The authors of this manuscript have been supported by NIH grants: 2P30MH075673 (to J.C.M, B.S., N.H., A.B., N.S.); 1P01MH105280 (J.C.M, N.H., N.S.); 271201000036C-5-0-1, MH22005 and R21MH083465 (J.C.M., A.B.); 5R01MH099733, U01AI035042, NS081196 and MH107345 (N.S.); 5R01DA040390, 2R01MH077542, 1R01MH096636 and R03MH103985 (N.H.); DA037611, DA017618 and MH104145 (D.J.V.); AG034852, R21NS07062 and R03DA032470 (B.S.); R01MH083728 (M.P.); P50MH-094268 (M.H.), P01 MH070306 (J.M.); R01NS077869 and R01NS089482 (J.M.). J.C.M. and A.B. are supported by Johns Hopkins University Center for AIDS Research (P30AI094189). M.P. is supported by the Stanley Medical Research Institute, Chevy Chase, Maryland, USA.

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D.S. and A.M.D. contributed equally to this manuscript. All authors researched the literature for the article and contributed to discussion of the content. D.S., A.M.D., N.H., B.S., M.P., A.B., D.V. and J.C.M. wrote the manuscript. D.S., A.M.D., N.S., N.H., D.V., J.C.M. reviewed and/or edited the manuscript.

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Correspondence to Justin C. McArthur.

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PowerPoint slides

Glossary

Sterilizing cure

Elimination of all HIV-infected cells from the individual.

Asymptomatic neurocognitive impairment

(ANI). Cognitive impairment involving at least two cognitive domains that does not interfere with everyday functioning.

Mild neurocognitive disorder

(MND). Cognitive impairment involving at least two cognitive domains that produces at least mild interference in daily functioning.

CSF viral escape

Presence of detectable HIV in the cerebrospinal fluid (CSF) despite undetectable HIV RNA levels in the plasma.

HIV-associated dementia

(HAD). Marked cognitive impairment involving at least two cognitive domains that substantially interferes with daily functioning.

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Saylor, D., Dickens, A., Sacktor, N. et al. HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment. Nat Rev Neurol 12, 234–248 (2016). https://doi.org/10.1038/nrneurol.2016.27

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