Neuroinflammation in the Dorsal Root Ganglia and Dorsal Horn Contributes to Persistence of Nociceptor Sensitization in SIV-infected ART-treated Macaques

Despite the development of antiretroviral therapy (ART), human immunodeficiency virus (HIV)-associated distal sensory polyneuropathy (HIV-DSP) has remained prevalent. Using simian immunodeficiency virus (SIV)-infected rhesus macaques, we examined molecular mechanisms of peripheral and central sensitization to infer chronic pain from HIV infection. 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 show 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 a significantly higher number of CD68+ cells in the dorsal horn of SIV+/ART macaques compared to uninfected animals. In summary, these data demonstrate that neuroinflammation, characteristics of nociceptor sensitization, and central terminal atrophy persists in SIV infection with ART.