INTERFERON GAMMA-MEDIATED NEUROINFLAMMATION CONTRIBUTES TO THE PERSISTENCE OF NOCICEPTOR SENSITIZATION IN HIV-ASSOCIATED DISTAL SENSORY POLYNEUROPATHY

Abstract

Despite the development of antiretroviral therapy (ART), human immunodeficiency virus (HIV)-associated distal sensory polyneuropathy (HIV-DSP) has remained prevalent. To recapitulate chronic pain during HIV infection, simian immunodeficiency virus (SIV)-infected rhesus macaques were examined to dissect the molecular mechanisms of peripheral and central sensitization. Previous studies identified atrophy in nociceptive neurons during SIV infection, which was associated with monocyte infiltration into the dorsal root ganglia (DRG). However, the sensory signaling mechanism connecting this pathology to symptomology remains unclear, especially because pain persists after resolution of high viremia and inflammation with ART. We hypothesize that residual DRG and dorsal horn neuroinflammation contributes to nociceptive sensitization. Using three cohorts of macaques (uninfected, SIV-infected, and SIV+/ART), we showed an increase in the cellular and cytokine inflammatory profiles in the DRG of SIV+/ART macaques compared to uninfected animals. We observed significant increased expression of nociceptive ion channels, transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) among DRG neurons in SIV+/ART compared to uninfected animals. SIV-infected and SIV+/ART animals showed reduced innervation of the non-peptidergic nociceptors into the dorsal horn compared to uninfected animals. Finally, there were significantly higher numbers of CD68+ macrophages in the dorsal horn of SIV+/ART macaques compared to uninfected animals. As pain persists in people with HIV (PWH) on ART, mechanisms outside of viral load and DRG pathology were investigated. Here, bulk RNAseq of DRGs from the three cohorts of macaques revealed a significant increase in upstream regulation by interferon γ (IFNγ) and lipopolysaccharide (LPS) with SIV infection. The introduction of ART decreased the signaling of IFNγ and LPS, yet in SIV+/ART animals, there was a significant increase in expression of the IFNγ inducible chemokines, CXCL9 and CXCL10. To assess if CXCL9 and/or CXCL10 influence TRPV1/TRPA1 expression, we utilized an induced pluripotent stem cell-derived peripheral sensory neuron model (IPSC-PSN). Treatment of IPSC-PSNs with CXCL9 and/or CXCL10 induced a significant increase in TRPV1, but not TRPA1 expression. Since macrophages persist in the DRGs of SIV+/ART macaques, monocyte-derived macrophages (MDMs) were treated with IFNγ or LPS. MDMs treated with IFNᵧ but not LPS, significantly increased the release of CXCL9/CXCL10. Conditioned media from MDMs treated with IFNγ, but not LPS, significantly increased expression of TRPV1 in IPSC-PSNs. Inhibition of the CXCL9/CXCL10 receptor, CXCR3, in IPSC-PSNs partially blocked TRPV1 upregulation following treatment with conditioned media from IFNᵧ treated MDMs. In summary, these data demonstrate that neuroinflammation, characteristics of nociceptor sensitization, and central terminal atrophy persists in SIV infection with ART. Mechanistically, these data indicate a potential role of IFNᵧ signaling in the sensitization of nociceptors in HIV-DSP despite ART.