α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

Abstract

Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine þ MAC387 þ ) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to a4-integrins. SIV-infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine þ (early), MAC387 þ (late), CD68 þ (early and late), and SIVp28 þ (late) macrophages in DRG tissues. The number of CD3 þ T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy. The primary mechanisms of HIV peripheral neuropathy include immune damage secondary to viral infection and mitochondrial toxicity from the antiretrovirals. Because HIV and SIV do not productively infect neurons or Schwann cells, damage to the dorsal root ganglia (DRG) in peripheral neuropathy is believed to be, in part, because of infected and activated macrophages. In vitro and in vivo studies suggest that both viral proteins and systemic inflammation secondary to the viral infection may damage neurons and axons. 1 Using a CD8-depleted SIV-infected rhesus macaque model of peripheral neuropathy, we have shown that accumulation of recruited [bromodeoxyuridine (BrdU) þ MAC387 þ ] monocytes/macrophages was associated with severe DRG pathology. 2 The number of BrdU þ monocytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macrophages play a significant role in DRG pathogenesis.

Mechanisms of CNS Viral Seeding by HIV+CD14+CD16+Monocytes: Establishment and Reseeding of Viral Reservoirs Contributing to HIV-Associated Neurocognitive Disorders

“…CD14 + CD16 + monocytes are key mediators of HIV neuropathogenesis ( 11 , 12 , 21 , 37 , 38 , 46 , 51 – 53 ). They transmigrate across the BBB in response to chemokines, including CCL2, which is one of the proposed mechanisms of viral entry into the CNS ( 21 , 22 , 54 ).…”

Frontline Science: CXCR7 mediates CD14+CD16+ monocyte transmigration across the blood brain barrier: a potential therapeutic target for NeuroAIDS

“…In addition, there are still no therapies that decrease neuroinflammation and neurodegeneration mediated by HIV infection of the CNS. Whereas some therapeutic targets have been suggested, these do not prevent entry of CD14 + CD16 + monocytes specifically into the brain [23,[60][61][62]. We demonstrated in this study that CXCR7 is expressed on the cell surface of CD14 + CD16 + monocytes, that it is higher in expression on CD14 + CD16 + monocytes than on CD14 + CD16 2 monocytes, and that it is increased on the surface of CD14 + CD16 + monocytes from HIV-infected individuals compared with those cells from uninfected people.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Additionally,CD137 signaling regulates trafficking of activated macrophage to dorsal root ganglia, leading to severe loss of intra-epidermal nerve fiber densit [28]. Recently, as a potential therapeutic approach, treatment with α4-integrin antibody has been found to rescue dorsal root ganglia fiber damage by block-ingthetraffickingofactivatedmonocyte/macrophage, but not T-lymphocyte [29]. Similar antibody treatment in another study has been found to decrease cardiac pathology by regulating monocyte/macrophage trafficking to the heart in SIV-infected primate model of HIV-AIDS [30].…”