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Victoria A Laast,
Beom Shim,
Lisa M Johanek,
Jamie L Dorsey,
Peter E Hauer,
Patrick M Tarwater,
Robert J Adams,
Carlos A Pardo,
Justin C McArthur,
Matthias Ringkamp,
Joseph L Mankowski
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ABSTRACT: Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over one-third of infected individuals, including those treated with antiretroviral therapy. To study the pathogenesis of HIV-induced peripheral nervous system disease, we established a model in which SIV-infected macaques developed changes closely resembling alterations reported in components of the sensory pathway in HIV-infected individuals. Significant declines in epidermal nerve fiber density developed in SIV-infected macaques, similar to that of HIV-infected individuals with neuropathy. Changes in dorsal root ganglia (DRG) included macrophage infiltration, SIV replication in macrophages, immune activation of satellite cells, and neuronal loss. To determine whether dorsal root ganglion damage was associated with altered nerve function, we measured unmyelinated C-fiber conduction velocities (CV) in nerves of SIV-infected macaques and compared CV changes with DRG alterations. Twelve weeks postinoculation, SIV-infected macaques had significantly lower C-fiber conduction velocity in sural nerves than uninfected animals and the magnitude of conduction velocity decline correlated strongly with extent of DRG macrophage infiltration. Thus, injury to neurons in the DRG-mediated by activated macrophages-preceded altered conduction of unmyelinated nerve fibers in SIV-infected macaques, suggesting that macrophage-mediated DRG damage may be the initiating event in HIV-induced sensory neuropathy.
American Journal Of Pathology 09/2011; 179(5):2337-45. · 4.89 Impact Factor
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ABSTRACT: To characterize the regenerative pattern of cutaneous nerves in simian immunodeficiency virus (SIV)-infected and uninfected macaques, excisional axotomies were performed in nonglabrous skin at 14-day intervals. Samples were examined after immunostaining for the pan-axonal marker PGP 9.5 and the Schwann cell marker p75 nerve growth factor receptor. Collateral sprouting of axons from adjacent uninjured superficial dermal nerve bundles was the initial response to axotomy. Both horizontal collateral sprouts and dense vertical regeneration of axons from the deeper dermis led to complete, rapid reinnervation of the epidermis at the axotomy site. In contrast to the slower, incomplete reinnervation previously noted in humans after this technique, in both SIV-infected and uninfected macaques epidermal reinnervation was rapid and completed by 56 days postaxotomy. p75 was densely expressed on the Schwann cells of uninjured nerve bundles along the excision line and on epidermal Schwann cell processes. In both SIV-infected and uninfected macaques, Schwann cell process density was highest at the earliest timepoints postaxotomy and then declined at a similar rate. However, SIV-infection delayed epidermal nerve fiber regeneration and remodeling of new sprouts at every timepoint postaxotomy, and SIV-infected animals consistently had lower mean epidermal Schwann cell densities, suggesting that Schwann cell guidance and support of epidermal nerve fiber regeneration may account for altered nerve regeneration. The relatively rapid regeneration time and the completeness of epidermal reinnervation in this macaque model provides a useful platform for assessing the efficacy of neurotrophic or regenerative drugs for sensory neuropathies including those caused by HIV, diabetes mellitus, medications, and toxins.
The Journal of Comparative Neurology 06/2009; 514(3):272-83. · 3.81 Impact Factor
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ABSTRACT: Peripheral neuropathy is the most frequent neurologic complication associated with human immunodeficiency virus (HIV) infection, yet its pathogenesis remains poorly understood. To study the mechanisms causing HIV-induced peripheral nervous system disease, we examined trigeminal ganglia obtained from simian immunodeficiency virus (SIV)-inoculated macaques. SIV-infected macaques developed multifocal trigeminal ganglionitis of varying severity characterized by multifocal mononuclear infiltrates, neuronophagia, and neuronal loss resembling reports of HIV-associated changes present in dorsal root ganglia. Neuronal density, measured by calculating the fractional area of trigeminal ganglia occupied by neurons, was significantly lower in SIV-infected macaques versus uninfected macaques (p = 0.001). To characterize the inflammatory cell population and measure productive viral infection in ganglia, trigeminal ganglia from SIV-infected macaques were immunostained for macrophage or cytotoxic lymphocyte markers and for SIV gp41. The extent of macrophage infiltration in trigeminal ganglia was inversely correlated with neuronal loss (p = 0.001), whereas cytotoxic lymphocyte infiltration was not associated with neuronal loss. These studies demonstrate that alterations in the somatosensory ganglia of SIV-infected macaques closely parallel those observed in HIV-infected individuals and show that study of SIV-infected macaques may help elucidate the pathophysiology of HIV-induced peripheral neuropathy.
Journal of Neuropathology and Experimental Neurology 02/2007; 66(1):26-34. · 4.26 Impact Factor
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ABSTRACT: Lentiviral diseases of animals have been recognized for over a century, long before HIV was recognized as the cause of AIDS. All lentiviruses cause neurological disease and productive virus replication in the CNS occurs exclusively in cells of macrophage lineage. The ability to molecularly engineer the inoculum virus, to sample the brain at many different time points from acute through terminal infection and to correlate in vivo with in vitro findings are significant advantages of animal models of HIV CNS disease. The lentiviruses can be divided into two pathogenetic groups--those that cause immunosuppression, including the lentiviruses of humans (HIV), non-human primates (SIV), cats (FIV), and cattle (BIV), and those that cause immunoproliferation, including the lentiviruses of horses (EIAV), sheep (OvLV) and goats (CAEV). Despite extensive study, no rodent lentivirus has been identified, prompting development of alternate strategies to study lentiviral pathogenesis using rodents. The immunosuppressive lentiviruses most closely recapitulate the disease manifestations of HIV infection, and both SIV and FIV have contributed significantly to our understanding of how HIV causes both central and peripheral nervous system disease.
Current HIV Research 08/2006; 4(3):293-305. · 1.75 Impact Factor
