HIV-Related Neuropathy: Pathophysiology, Treatment and Challenges

Abstract

HIV-sensory neuropathy (HIV-SN) is a debilitating complication in HIV patients with or without anti-retroviral treatment (ART). Common symptoms of HIV-SN include pain, decreased sensation, paresthesias and dysesthesias in a symmetric stocking-glove distribution. While HIV-1 protein such as gp120 is implicated in HIV-SN (e.g. impaired large-diameter fiber), ART itself was recently shown to contribute to HIV-SN in HIV patients and impair thin fiber. Multiple host mechanisms may play roles during the pathogenesis of HIV-SN, including neuron-glia interactions in the spinal dorsal horn (SDH), inflammation, mitochondrial dysfunction and endoplasmic reticulum stress. Concurrent infections, such as tuberculosis, also carry a higher likelihood of HIV-SN as well as environmental or genetic predisposition. Pro-inflammatory cytokines such as IL-1, IL2 receptor-alpha and tumor necrosis factor (TNF) along with abnormal lactate levels have been identified as potential players within the complex pathophysiology of this condition. In this paper, we review the pathophysiology of HIV neuropathy, focusing on the various treatment options available or under investigation. Although several treatment options are available e.g., the capsaicin patch and spinal cord stimulation, symptomatic control of HIV-SN are often challenging. Alternative approaches such as self-hypnosis, resistance exercise, cannabinoids, and acupuncture have all shown promising results, but need further investigation.

Mitochondrial DNA Quantity and Relative Abundance of “Common Deletion” Mutation in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy

“…DSP symptoms include pain, decreased sensation, allodynia, paresthesia, and pain in a symmetric stocking-glove distribution. [8,9] HIV-1 proteins such as gp120 are implicated in HIV-DSP (e.g., impaired large-diameter fibers) [10] [Figure 1]. In addition, it has been shown that some ART have neurotoxic effects, such as efavirenz (EFV), nonnucleoside reverse transcriptase inhibitors (NNRTI) ("D-drugs," principally Stavudine (d4T), Didanosine (ddI), and Zalcitabine (ddC)) which cause neuronal mitochondrial toxicity [11,12].…”

“…In addition, it has been shown that some ART have neurotoxic effects, such as efavirenz (EFV), nonnucleoside reverse transcriptase inhibitors (NNRTI) ("D-drugs," principally Stavudine (d4T), Didanosine (ddI), and Zalcitabine (ddC)) which cause neuronal mitochondrial toxicity [11,12]. Moreover, certain ART has recently been linked to DSP in HIV by impairing thin fiber [9]. For instance, Zidovudine (AZT) causes myopathy; ddC, ddl, and lamivudine (3TC) cause neuropathy; d4T and fialuridine (FIAU) cause 2 neuropathy or myopathy and lactic acidosis [13].…”

Mitochondrial DNA and Electron Transport Chain Protein Levels Are Altered in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy: A Pilot Study

“…HIV-associated distal sensory polyneuropathy (HIV DSP) is a common complication of HIV infection, with prevalence rates ranging from 10% to 45% in PWH [5][6][7]. DSP symptoms include pain, decreased sensation, allodynia, and paresthesia [8,9].…”

“…Neurons depend on ATP for axonal transport and maintaining ionic gradients, which are crucial for generating action potentials and facilitating synaptic activity [10]. Both ART and HIV proteins (ex: gp120) have been implicated in HIV-DSP [9,11], likely through mechanisms that involve mitochondrial function [12][13][14]. HIV infection impairs mitochondrial respiration, electron transport chain (ETC) activity, and mitochondrial DNA (mtDNA) replication [15,16].…”

Preparation of Primary Mixed Glial Cell Cultures from Adult Mouse Spinal Cord Tissue

“…Glial‐mediated neuroinflammation and oxidative stress have been found to contribute to the development of these diseases while neuroprotective effects from subtypes of glial cells have also been identified. In recent decades, similar central mechanisms have been widely identified as critical contributors to the development of neuropathologies of diseases and disorders involving the peripheral nervous system (PNS), including various types of peripheral neuropathies such as peripheral nerve injury‐induced neuropathic pain, diabetic neuropathy, postherpetic neuralgia, and HIV‐associated sensory neuropathy (Fumagalli et al., 2020; Hao, 2013; Jazebi et al., 2021; Ji et al., 2016; Kong et al., 2020; Pottorf et al., 2022; Shayea et al., 2020; Tsuda, 2016). Investigation of the complex contributions of specific cell populations, including glial cells, to the central mechanisms of these peripherally‐manifested diseases often necessitates examining spinal cord glial cells at cellular/molecular levels in vitro.…”