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Neurodegeneration Associated with HIV-1 in the Era of cART

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Handbook of Neurotoxicity

Abstract

Infection with human immunodeficiency virus (HIV)-1 targets not only cells of the immune system and eventually causes AIDS, but also triggers HIV-associated neurocognitive disorders (HAND) that can culminate in frank dementia. Several lines of evidence suggest that HIV-1 strikes at the brain in at least two ways: i) by causing toxicity leading to neuronal injury and death and ii) by impairing neurogenesis. Both pathogenic mechanisms share the involvement of neuroinflammatory mediators and seem to be influenced by host and viral factors, including the interferon response, age, and viral subtypes, as well as treatment and comorbidity factors, such as drug abuse. Despite viral control and life prolonging effects of combination antiretroviral treatments (cART), neuroinflammation and concomitant activation of macrophages and microglia accompany the persistence of HAND in people living with HIV (PLWH). Experimental evidence supports two different, but not exclusive hypotheses of how HIV-1 causes neuronal damage in the brain. The “direct injury” hypothesis proposes that viral proteins directly compromise neurons, whereas the “indirect” or “bystander effect” hypothesis states virus infection and viral components trigger in macrophages, microglia and astrocytes the production of neurotoxins that injure neurons. While the life expectancy of PWH approaches the range of uninfected individuals, the prevalence of HAND and observations in autopsy studies have raised the question, if its development shares pathological mechanisms with Alzheimer’s disease (AD). Converging mechanisms underlying HAND and AD may include neuroinflammation, mitogen-activated protein kinase signaling, altered gene expression, oxidative stress, and compromised autophagy leading to synaptic injury and, ultimately, neuronal apoptosis.

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Abbreviations

Aβ:

Amyloid-beta

AD:

Alzheimer’s disease

AIDS:

Acquired immunodeficiency syndrome

APP:

Amyloid precursor protein

BACE:

Beta-secretase

cART:

Combination antiretroviral therapy

CCL:

C-C motif chemokine ligand

CCR:

C-C motif chemokine receptor

CD:

Cluster of differentiation

Cdk5:

Cyclin-dependent kinase 5

CNS:

Central nervous system

CREB1:

CAMP responsive element binding protein 1

CSF:

Cerebrospinal fluid

CXCL:

C-X-C motif chemokine ligand

CXCR:

C-X-C motif chemokine receptor

ERK:

Extracellular signal-regulated kinase

FIV:

Feline immunodeficiency virus

GABA:

Gamma aminobutyric acid

GFAP:

Glial fibrillary acidic protein

gp120:

HIV envelope glycoprotein gp120

GSK-3β:

Glycogen synthase kinase 3 beta

HAD:

HIV-associated dementia

HAND:

HIV-associated neurocognitive disorders

HIV:

Human immunodeficiency virus

HIVE:

HIV encephalitis

HSV:

Herpes simplex virus

IBA-1:

Ionized calcium binding adaptor molecule 1

IgG:

Immunoglobulin G

JNK:

c-Jun N-terminal kinase

KO:

Knockout

LAV:

Lymphadenopathy-associated virus

LCN2:

Lipocalin-2

LPS:

Lipopolysaccharide

LTD:

Long-term depression

LTP:

Long-term potentiation

MAP-2:

Microtubule-associated protein 2

MAPK:

Mitogen-activated protein kinase

MKP-1:

MAPK phosphatase 1

NFkB:

Nuclear factor kappa B

NFT:

Neurofibrillary tangles

NMDA:

N-Methyl-d-aspartate

p38 MAPK:

p38 mitogen-activated protein kinase

PET/CT:

Positron emission tomography–computed tomography

PS1:

Presenilin-1

pTau:

Phosphorylated Tau

PLWH:

People living with HIV

Syp:

Synaptophysin

SIV:

Simian immunodeficiency virus

tg:

Transgenic

tTau:

Total Tau

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Acknowledgments

M. Kaul is supported by grants from the National Institutes of Health (NIH), MH087332, MH10533, MH104131, and DA052209.

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  1. Division of Biomedical Sciences, School of Medicine, University of California, Los Angeles, CA, USA

    Daniel Ojeda-Juárez, Indira S. Harahap-Carrillo & Marcus Kaul

  2. Department of Pathology, University of California, San Diego, CA, USA

    Daniel Ojeda-Juárez

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    Richard M. Kostrzewa

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Ojeda-Juárez, D., Harahap-Carrillo, I.S., Kaul, M. (2022). Neurodegeneration Associated with HIV-1 in the Era of cART. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_137

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