Pre-print: Ex vivo expression of chemokine receptors on cells surrounding cutaneous nerves in patients with HIV-associated sensory neuropathy. DOI: 10.1097/QAD.0000000000001714

Abstract: Objective: HIV-associated sensory neuropathy (HIV-SN) remains common in HIV+ individuals receiving anti-retroviral therapy (ART), even though neurotoxic anti-retroviral drugs (e.g. stavudine) have been phased out of use. Accumulating evidence indicates that the neuropathy is immune-mediated. We hypothesise that chemokines produced locally in the skin promote migration of macrophages and T-cells into the tissue, damaging cutaneous nerves causing HIV- SN. Design: We assessed chemokine receptor expression on infiltrating CD14+ and CD3+ cells around cutaneous nerves in standardised skin biopsies from HIV-SN+ patients (n=5), HIV-SN- patients (n=9) and healthy controls (n=4). Methods: The AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen was used to assess Indonesian HIV+ patients receiving ART without stavudine (case definition: bilateral presence of at least one symptom and at least one sign of neuropathy). Distal leg skin biopsies were stained to visualise chemokine receptors; CCR2, CCR5, CXCR3, CXCR4, CX3CR1, infiltrating CD3+ and CD14+ cells and protein-gene-product 9.5 on nerves, using immunohistochemistry and 4-colour confocal microscopy. Results: Intraepidermal nerve fibre density was variable in patients without HIV-SN and generally lower in those with HIV-SN. CX3CR1 was more evident on CD14+ cells whereas CCR2, CCR5, CXCR3 and CXCR4 were more common on CD3+ cells. Expression of CX3CR1, CCR2 and CCR5 was more common in HIV-SN+ patients than those without HIV-SN. CXCR3 and CXCR4 were upregulated in all HIV+ patients, compared with healthy controls. Conclusion: Inflammatory macrophages expressing CX3CR1 and T-cells expressing CCR2 and CCR5 may participate in peripheral nerve damage leading to HIV-SN in HIV+ patients treated without stavudine. Further characterisation of these cells is warranted.