Monocyte / Macrophage Activation and Traffic Mediates HIV and SIV – Associated Peripheral Neuropathy

Abstract

Human immunodeficiency virus-associated peripheral neuropathy (HIVPN) continues to be a prevalent comorbidity of HIV infection, despite virologic control due to effective antiretroviral therapy (ART). Symptoms include bilateral tingling, numbness, and pain in distal extremities. Severity of symptoms is associated with a loss of intraepidermal nerve fiber density (IENFD) in the feet. Damage to the dorsal root ganglia (DRG) has also been observed in postmortem tissue analysis from patients with HIV-PN. Treatment options are limited due to a lack of understanding of the disease pathogenesis. Chronic monocyte activation and accumulation of macrophages in peripheral nervous system (PNS) tissues has been reported but few studies have directly demonstrated the role of monocyte/macrophage activation and traffic in the pathogenesis of HIV-PN. The central hypothesis of this thesis is that monocyte activation and traffic mediates PNS neuronal damage. We addressed this hypothesis in several ways. In chapter 2, we describe pathology seen in a rapid disease progression animal model of HIV-PN. We found that an early loss of IENFD preceded a loss of small diameter DRG neurons. In chapter 3, we associated DRG pathology with an accumulation of inflammatory macrophages surrounding DRG neurons. Increased monocyte traffic to the DRG was associated with severity of DRG pathology and with a loss of IENFD. In chapter 4, we directly tested the impact of monocyte traffic on DRG pathology by blocking leukocyte traffic with an anti-VLA-4 antibody, natalizumab. Blocking cell traffic reduced accumulation of macrophages in the DRG and improved pathology. Next we treated animals with methylglyoxal-bisguanylhydrazone (MGBG) to specifically target myeloid cells and reduce their activation. MGBG treatment improved DRG pathology and reduced accumulation of macrophages in tissues. Having demonstrated the role of monocyte traffic and activation, we aimed to identify signaling proteins and inflammatory proteins associated with PNS pathology. We found elevated monocyte chemoattractants in DRG tissue and elevated markers of monocyte activation in plasma that were associated with a loss of IENFD. Together, these studies demonstrate that systemic monocyte activation, macrophage accumulation in DRG tissue, and monocyte traffic plays a major role in SIV-PN pathogenesis. These studies provide novel insight into immune mechanisms that impact neuronal loss during SIV infection. Thus, modulating macrophage activation and reducing monocyte traffic may have therapeutic benefits to patients suffering from or at risk of developing HIV-PN.