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Progress in Pathological and Therapeutic Research of HIV-Related Neuropathic Pain

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Abstract

HIV-related neuropathic pain (HRNP) is a neurodegeneration that gradually develops during the long-term course of acquired immune deficiency syndrome (AIDS) and manifests as abnormal sock/sleeve-like symmetrical pain and nociceptive hyperalgesia in the extremities, which seriously reduces patient quality of life. To date, the pathogenesis of HRNP is not completely clear. There is a lack of effective clinical treatment for HRNP and it is becoming a challenge and hot spot for medical research. In this study, we conducted a systematic review of the progress of HRNP research in recent years including (1) the etiology, classification and clinical symptoms of HRNP, (2) the establishment of HRNP pathological models, (3) the pathological mechanisms underlying HRNP from three aspects: molecules, signaling pathways and cells, (4) the therapeutic strategies for HRNP, and (5) the limitations of recent HRNP research and the future research directions and prospects of HRNP. This detailed review provides new and systematic insight into the pathological mechanism of HRNP, which establishes a theoretical basis for the future exploitation of novel target drugs.

Graphical Abstract

HIV infection, antiretroviral therapy and opioid abuse contribute to the etiology of HRNP with symmetrical pain in both hands and feet, allodynia and hyperalgesia. The pathogenesis involves changes in cytokine expression, activation of signaling pathways and neuronal cell states. The therapy for HRNP should be patient-centered, integrating pharmacologic and nonpharmacologic treatments into multimodal intervention.

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Data Availability

Not applicable.

Abbreviations

AIDS:

Acquired immune deficiency syndrome

HIV:

Human immunodeficiency virus

WHO:

World health organization

IDP:

Inflammatory demyelinating polyneuropathy

DSN:

Distal symmetric sensory neuropathy

HIV-SN:

HIV-symmetric sensory neuropathy

HRNP:

HIV-related neuropathic pain

HNP:

HIV-induced neuropathic pain

ART-NP:

Antiretroviral therapy-induced neuropathic pain

OPT-NP:

Opioid therapy-exacerbated neuropathic pain

CNS:

Central nervous system

ROS:

Reactive oxygen species

BDNF:

Brain-derived neurotrophic factors

HAART:

Highly active antiretroviral therapy

NRTIs:

Nucleoside reverse transcriptase inhibitors

ddN:

Dideoxynucleoside

BBB:

Blood brain barrier

SDH:

Spinal dorsal horn

NO:

Nitric oxide

IL-6:

Interleukin-6

NOS:

Nitric oxide synthase

TNF-alpha:

Tumor necrosis factor-alpha

IL-1β:

Interleukin-1β

RSA:

Rat serum albumin

DRG:

Dorsal root ganglion

LTR:

Long terminal repeat

Tat:

Transcriptional trans activator

GFAP:

Glial fibrillary acidic protein

FKN:

Fractalkine

HAND syndrome:

HIV-associated neurocognitive disorders

HAART:

Highly active antiretroviral therapy

ART:

Antiretroviral therapy

PKC:

Protein kinase C

BCP:

β-Caryophyllene

CB2:

Cannabinoid type 2

GPR55:

G protein-coupled receptor 55

SDF1:

Stromal cell-derived factor 1

CXCR4:

CXC cytokine receptor 4

CCL2:

Chemokine ligand 2

CCR2:

Chemokine receptor 2

CPEB:

Cytoplasmic polyglycosylation element binding protein

CREB:

Cyclic adenosine monophosphate-response element binding protein

CBP:

Cyclic adenosine monophosphate-response element binding protein-binding protein

COX:

Cyclooxygenase

OIH:

Opioid‑induced hyperalgesia

MOR:

Mu opioid receptor

TLR4:

Toll-like receptor 4

PBN:

Phenyl-N-tert-butylnitrone

DRG:

Dorsal root ganglia

TNFSR:

TNF soluble receptor

nNOS:

Nitric oxide synthase

GAD67:

Glutamic acid decarboxylase 67

SIV:

Simian immunodeficiency virus

nAchRs:

Nicotinic acetylcholine receptors

α7nAchR:

α7 Subunit of nAchRs

Brd4:

Bromodomain-containing protein 4

C/EBPβ:

CCAAT/enhancer binding protein β

SCI:

Spinal cord injury

EPSCs:

Excitatory postsynaptic currents

SP:

Substance P

TLRs:

Toll-like receptors

POD1/12:

Postoperative days 1/12

POD1:

Postoperative days 1

POD14:

Postoperative days 14

SNI:

Spinal nerve injury

PNI:

Peripheral nerve injury

PDTC:

Pyrrolidinedithiocarbamate ammonium

RyR:

Ryanodine receptor

SGCs:

Satellite glial cells

ASs:

Astrocytes

MGs:

Microglia

OLs:

Oligodendrocytes

GSK3β:

P-GSK3β-S9 dephosphorylation

CaMKIIβ:

CaMKIIβ-T287 phosphorylation

PDGFR-α:

Platelet-derived growth factor receptor alpha

PLP:

Proteolipid protein

Env:

Envelope glycoprotein

Th:

CD4 + T helper lymphocytes

Th0:

T lymphocytes

IL-2:

Interleukin

IFN-γ:

Interferon-γ

CTLs:

Cytotoxic T cells

AICD:

Activation-induced cell death

PLCγ:

Phospholipase Cγ

IP3:

Inositol triphosphate

CRAC:

Endoplasmic reticulum calcium channel

PYK2:

Proline-rich tyrosine kinase 2

AP-1:

Activator protein-1

TNFR1:

Tumor necrosis factor receptor superfamily member 1

TRADD:

Death structural domain protein

RIP1:

Receptor interacting protein 1

TAK:

Transforming growth factor β-activated kinase

IKK:

Inhibitory factor kinase

IL-1R1:

Interleukin-1 receptor 1

TOLLIP:

Toll-interacting protein

p-IRAKs:

Phosphorylated interleukin-1 receptor-associated kinases

TRAF6:

Tumor necrosis factor-associated factor 6

TAB1:

TGF-β-activated kinase 1 binding protein 1

NIK:

NF-κB-inducible kinase

EAAT:

Excitatory amino acid transporter protein

GS:

Glutamine synthetase

pro-MEKK1:

Mitogenic extracellular signal-regulated kinase kinase 1 precursor

int-MEKK1:

Mitogenic extracellular signal-regulated kinase kinase 1 intermediate

MEK3:

Mitogenic extracellular signal-regulated kinase 3

MEK6:

Mitogenic extracellular signal-regulated kinase 6

RKIP:

Raf kinase inhibitory protein

F2R:

Frizzled 2 receptor

ERK:

Extracellular regulatory protein kinase

CREB:

CAMP-response element binding protein

AC:

Adenylyl cyclase

PD-1:

Programmed cell death ligand-1

SHP-1:

Tyrosine phosphatase-1

TENS:

Transcutaneous electrical nerve stimulation

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Acknowledgements

We thank AJE (American Journal Experts) company and Dr.Gary Ogin for polishing the text for publication.

Funding

This work was supported by Natural Science Foundation of Zhejiang Province (LY22H090008); Science and Technology Project of Jiaxing city (2021AY30006).

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Author notes

  1. YanLing Hu and JinHong Liu have contributed equally to this work.

Authors and Affiliations

  1. Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China

    YanLing Hu, JinHong Liu, Renjie Zhuang, Fei Lin, Sha Peng & Wenping Zhang

  2. Department of Biological Sciences, University of Denver, Denver, CO, 80210, USA

    Chen Zhang

  3. Department of Orthopedics, Rongjun Hospital, Jiaxing, Zhejiang, China

    Jun Wang

Authors
  1. YanLing Hu
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  2. JinHong Liu
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  3. Renjie Zhuang
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  4. Chen Zhang
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  5. Fei Lin
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  6. Jun Wang
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  7. Sha Peng
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  8. Wenping Zhang
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Contributions

YH, JL, RZ and JW: analyzed and wrote the section of clinical symptoms, etiology and classification of HRNP, HRNP pathological model, pathogenesis of HRNP, HRNP treatment strategy, limitations and future prospects of HRNP research and conclusions. CZ, FL and SP: creates figures and tables. WZ: conceptualized and revised the article.

Corresponding author

Correspondence to Wenping Zhang.

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Hu, Y., Liu, J., Zhuang, R. et al. Progress in Pathological and Therapeutic Research of HIV-Related Neuropathic Pain. Cell Mol Neurobiol 43, 3343–3373 (2023). https://doi.org/10.1007/s10571-023-01389-7

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  • DOI: https://doi.org/10.1007/s10571-023-01389-7

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