Peripheral neuropathy is the most common neurological complication of HIV infection with the prevalence of neuropathy as high as 69.4% in HIV-infected patients. Increasing reports from humans highlight the contribution of macrophage activation and dorsal root ganglia (DRG) inflammation to the persistence of pathological pain in peripheral neuropathy, but the demonstration of macrophage traffic and DRG macrophages as a viral reservoir is not known. The pathogenesis of peripheral neuropathy is incompletely understood, but it is likely macrophage-mediated. In this application, we will use a SIV rhesus macaque model of AIDS to determine if: 1) continual monocyte traffic to DRGs drives peripheral neuropathy pathogenesis and effective anti-retroviral therapy (ART) will minimize this effect, 2) the ratio of M1/M2 regulatory predicts early versus chronic peripheral nerve lesions and effective ART will alter this ratio, 3) clinically relevant biomarkers (sCD163, BrdU, IENF) are linked to DRG pathology, and 4) DRG macrophages are viral reservoirs with and without ART. Successful completion of studies in this application will allow us to define: 1) monocyte/ macrophage mechanisms of DRG pathology, 2) monocyte/macrophage immune regulation during PNS disease, 3) clinical markers of peripheral nerve disease and 4) DRG macrophages as active sites of viral replication and as viral reservoirs. The overall hypothesis of the application is continual monocyte/macrophage traffic drives DRG pathogenesis and clinically relevant biomarkers and IENF effectively predict peripheral nerve pathology with and without ART. Studies in aim 1 will define the role of monocyte traffic and macrophage turnover driving PNS pathogenesis and establish a correlation between DRG damage and IENF loss with the hypothesis that monocyte traffic to DRGs mediates damage and correlates to PNS pathology. A subaim will address the hypothesis that the ratio of M1/M2 macrophages predicts early versus chronic PNS lesions. Additionally, DRG macrophages as active sites of viral replication and/or as latent viral reservoirs will be defined in this aim. Studies in aim 2 will define the role of systemic viral suppression to: 1) stop or slow PNS disease;2) stop or slow macrophage recruitment to DRGs and 3) to clear DRG viral reservoirs. The hypothesis driving aim 2 is that systemic viral suppression by ART will slow PNS disease progression by inhibiting monocyte traffic to the DRGs and potentially clear DRG viral reservoirs. The studies described in this application provide an exciting opportunity to define the role of monocyte/macrophage traffic and macrophage activation in PNS disease and neuronal injury and the role of systemic viral immune suppression. The studies proposed here will provide new avenues of investigation into the development of therapies targeting the monocyte/macrophage in HIV peripheral neuropathy.

Public Health Relevance

HIV-associated peripheral neuropathy is the most common neurological complication of HIV infection with prevalence as high as 69.4% in HIV-infected patients. In this application, we will use a SIV rhesus macaque model of AIDS to define the role of monocyte traffic driving peripheral nerve pathogenesis, to predict the formation of early versus chronic peripheral nerve lesions using the ratio of M1/M2 regulatory macrophages and to examine clinical biomarkers (sCD163, BrdU, IENF) linked to DRG pathology. Studies in this application will allow us to define mechanisms of DRG pathology, monocyte/macrophage immune regulation during peripheral nerve system disease and the ability of effective antiretroviral therapy to stop monocyte traffic and to clear DRG macrophage reservoirs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS082116-01
Application #
8467482
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Wong, May
Project Start
2012-09-30
Project End
2017-06-30
Budget Start
2012-09-30
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$419,767
Indirect Cost
$103,749
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Lakritz, Jessica R; Thibault, Derek M; Robinson, Jake A et al. (2016) 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. Am J Pathol 186:1754-61
Lakritz, Jessica R; Robinson, Jake A; Polydefkis, Michael J et al. (2015) Loss of intraepidermal nerve fiber density during SIV peripheral neuropathy is mediated by monocyte activation and elevated monocyte chemotactic proteins. J Neuroinflammation 12:237
Poudrier, Johanne; Soulas, Caroline; Chagnon-Choquet, Josiane et al. (2015) High expression levels of BLyS/BAFF by blood dendritic cells and granulocytes are associated with B-cell dysregulation in SIV-infected rhesus macaques. PLoS One 10:e0131513
Soulas, Caroline; Autissier, Patrick J; Burdo, Tricia H et al. (2015) Distinct phenotype, longitudinal changes of numbers and cell-associated virus in blood dendritic cells in SIV-infected CD8-lymphocyte depleted macaques. PLoS One 10:e0119764
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Walker, Joshua A; Beck, Graham A; Campbell, Jennifer H et al. (2015) Anti-α4 Integrin Antibody Blocks Monocyte/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS. J Am Heart Assoc 4:
Lakritz, Jessica R; Bodair, Ayman; Shah, Neal et al. (2015) Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy. Am J Pathol 185:1912-23
Lamers, Susanna L; Nolan, David J; Rife, Brittany D et al. (2015) Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques. J Virol 89:8484-96
Walker, Joshua A; Sulciner, Megan L; Nowicki, Katherine D et al. (2014) Elevated numbers of CD163+ macrophages in hearts of simian immunodeficiency virus-infected monkeys correlate with cardiac pathology and fibrosis. AIDS Res Hum Retroviruses 30:685-94

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