Background & Aims
A significant proportion of people living with HIV (PLWH) experience chronic neuropathic pain (NP) driven by neuroinflammation due to direct effects of HIV as well as an adverse effect of antiretroviral drugs [1]. Studies of host genetic factors predisposing to NP in PLWH are limited. Only a few candidate gene studies and a single small-scale genome-wide association study (GWAS) have been published to date [2]. Two transcriptomic studies have been conducted in the rodent models of HIV-induced neuropathic pain [3,4], but no such studies have been published in humans. A greater understanding of transcriptomic differences in those with and without pain related to neuropathy could aid the understanding of pain generating mechanisms and reveal potential therapeutic targets. Herewith, we report the results of a pilot transcriptomic study of painful sensory neuropathy in PLWH.
Methods
We recruited male PLWH from outpatient clinic and by public advertisement in the United Kingdom as part of the HIV POGO Study [5]. Quantitative sensory testing (QST) using the German Network for Neuropathic Pain Research protocol [6] was performed and each participant was assigned to one of four QST-derived sensory profiles (“healthy”, thermal hyperalgesia, mechanical hyperalgesia, sensory loss) using a previously published algorithm [7]. RNA samples were extracted from peripheral blood of the participants who were categorised into three groups based on response to validated pain questionnaires, the Clinical HIV Associated Neuropathy Tool and nerve conduction studies: painful sensory neuropathy (PSN), painless sensory neuropathy (NPSN), and participants without pain and neuropathy (Controls). Total RNA sequencing was carried out using Illumina NovaSeq 6000 platform at Novogene company. Differential expression analysis was carried out in R using DESeq2 package.
Results
Twenty three participants were recruited (PSN=8, NPSN=7, Controls=8). We found ADGRG7 and ATP2B3 genes to be differentially expressed in PSN group compared with two other groups (FDR < 0.05). Also, DUSP4 gene was underexpressed in PSN vs Controls and exhibited a low p-value in the comparison between PSN and NPSN (p = 5.2e-5, FDR > 0.05). ADGRG7 gene was found to be underexpressed in individuals with mechanical hyperalgesia and sensory loss compared with the “healthy” and thermal hyperalgesia QST profiles. While none of these genes has been reported in context of pain research, literature queries highlighted their potential roles in biologically plausible pain-generating mechanisms including the development of NP pain via a CNS-related mechanism, control of load of viral infection, and immune regulation of neuroinflammation. Interestingly, DUSP4 is the critical regulator of FOXP3, a protein that has demonstrated therapeutic potential to attenuate neuropathic pain in mice [8].
Conclusions
Despite being underpowered, this pilot transcriptomic study allowed the identification of novel genes, with biological plausibility, that are potentially involved in the development of painful sensory neuropathy in PLWH. To the best of our knowledge, this is the first transcriptomic study in humans relating to NP in HIV-associated neuropathy. Further studies of this kind are warranted to obtain better understanding of the mechanisms of painful neuropathy in PLWH and expand the range of therapeutic targets.
References
1. Evans SR, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25(7):919-28; 2. Mbenda HGM, et al. Genetics of HIV-associated sensory neuropathy and related pain in Africans. J Neurovirol. 2017;23(4):511-519; 3. Huang J, et al. From Initiation to Maintenance: HIV-1 Gp120-induced Neuropathic Pain Exhibits Different Molecular Mechanisms in the Mouse Spinal Cord Via Bioinformatics Analysis Based on RNA Sequencing. J Neuroimmune Pharmacol. 2022;17(3-4):553-575; 4. Maratou K, et al, Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain. Eur J Pain. 2009;13(4):387-398; 5. Kemp HI, et al. A Comparison of Self-reported Pain Measures Between Sensory Phenotypes in HIV-associated Sensory Neuropathy. J Pain. 2023;24(1):112-127; 6. Rolke R, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials Eur J Pain. 2006;10(10):77-88; 7. Vollert J, et al. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. PAIN. 2017;n158(8):1446-55. 8. Shin J, et al. Foxp3 plasmid-encapsulated PLGA nanoparticles attenuate pain behavior in rats with spinal nerve ligation. Nanomedicine. 2019;18:90-100.
Presenting Author
Harriet Kemp
Poster Authors
Topics
- Genetics