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Christopher Power - One of the best experts on this subject based on the ideXlab platform.
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cxcr3 activation by Lentivirus Infection suppresses neuronal autophagy neuroprotective effects of antiretroviral therapy
The FASEB Journal, 2009Co-Authors: Yu Zhu, Justin C. Mcarthur, David Vergote, Carlos A. Pardo, Farshid Noorbakhsh, Morley D. Hollenberg, Christopher M. Overall, Christopher PowerAbstract:Previous studies have implicated CXCL12 in the neuropathogenesis of HIV Infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P<0.05) and neuronal survival (P<0.05), which recapitulated findings in FIV- and HIV-infected brains (P<0.05). Oral didanosine (ddI) treatment of FIV-infected animals reduced neurobehavioral abnormalities in conjunction with diminished plasma viral load (P<0.05). F4/80 transcript abundance and CXCL12(5-67) immunoreactivity were reduced with restored neuronal LC3 expression in the brains of FIV-infected animals after ddI treatment (P<0.05). ddI treatment also prevented microglial activation and depletion of synaptic proteins in the cortex of FIV-infected animals (P<0.05). These findings indicate that the beneficial effects of ddI might be a consequence of a reduced systemic viral burden and concurrent leukocyte activation, leading to diminished neuroinflammation with preservation of neuronal autophagy by regulating CXCR3 activation.
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CXCR3 activation by Lentivirus Infection suppresses neuronal autophagy: neuroprotective effects of antiretroviral therapy
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009Co-Authors: Yu Zhu, Justin C. Mcarthur, David Vergote, Carlos A. Pardo, Farshid Noorbakhsh, Morley D. Hollenberg, Christopher M. Overall, Christopher PowerAbstract:Previous studies have implicated CXCL12 in the neuropathogenesis of HIV Infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P
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Dual Lentivirus Infection potentiates neuroinflammation and neurodegeneration: viral copassage enhances neurovirulence
Journal of NeuroVirology, 2009Co-Authors: Amir Afkhami-goli, Shu-hong Liu, Yu Zhu, Joseph M. Antony, Hosseinali Arab, Christopher PowerAbstract:Infection by multiple lentiviral strains is recognized as a major driving force in the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, but the neuropathogenic consequences of multivirus Infections remain uncertain. Herein, we investigated the neurovirulence and underlying mechanisms of dual Lentivirus Infections with distinct viral strains. Experimental feline immunodeficiency virus (FIV) Infections were performed using cultured cells and an in vivo model of AIDS neuropathogenesis. Dual Infections were comprised of two FIV strains (FIV-Ch and FIV-PPR) as copassaged or superinfected viruses, with subsequent outcome analyses of host immune responses, viral load, neuropathological features, and neurobehavioral performance. Dual Infections of feline macrophages resulted in greater IL-1β (interleukin-1b), TNF-α (tumor necrosis factor α), and IDO (indoleamine 2,3-dioxygenase) expression and associated neurotoxic properties. FIV coInfection and sequential superInfection in vivo also induced greater IL-1β, TNF-α , and IDO expression in the basal ganglia (BG) and cortex (CTX), compared to the monovirus- and mock-infected groups, although viral loads were similar in single virus and dual virusinfected animals. Immunoblot analyses disclosed lower synaptophysin immunoreactivity in the CTX resulting from FIV super- and coInfections. Cholinergic and GABAergic neuronal injury was evident in the CTX of animals with dual FIV Infections. With increased glial activation and neuronal loss in dual FIV infected brains, immunohistochemical analysis also revealed elevated detection of cleaved caspase-3 in dysmorphic neurons, which was associated with worsened neurobehavioral abnormalities among animals infected with the copassaged viruses. Dual Lentivirus Infections caused an escalation in neuroinflammation and ensuing neurodegeneration, underscoring the contribution of Infection by multiple viruses to neuropathogenesis.
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cd8 lymphocyte mediated injury of dorsal root ganglion neurons during Lentivirus Infection cd154 dependent cell contact neurotoxicity
The Journal of Neuroscience, 2006Co-Authors: Yu Zhu, Shu-hong Liu, Joseph M. Antony, Douglas W. Zochodne, Jose A Martinez, Fabrizio Giuliani, Christopher PowerAbstract:Neuronal damage in dorsal root ganglia (DRGs) with accompanying axonal injury is a key feature of human immunodeficiency virus (HIV)-related distal sensory polyneuropathy (DSP). In a model of HIV-related DSP, we observed numerous CD3+ T lymphocytes ( p < 0.05) in DRGs from feline immunodeficiency virus (FIV)-infected animals, which also exhibited low CD4+ and high CD8+ lymphocyte levels in blood accompanied by a selective loss of small-diameter sural nerve axons ( p < 0.05). FIV-infected lymphocytes cocultured with syngeneic DRGs caused neuronal damage, indicated by neurite retraction, neuronal soma atrophy, and loss ( p < 0.05). In contrast, supernatants from FIV-infected or uninfected lymphocytes were minimally neurotoxic, despite high FIV virion levels. Among lymphocyte subsets cocultured with DRG cultures, CD8+ T cells from both FIV-infected and uninfected lymphocytes selectively caused DRG neuronal injury ( p < 0.05). FIV-infected CD8+ T cells showed markedly increased CD154 expression ( p < 0.05), whereas neurons were the predominant cells expressing CD40 in DRGs. Blocking CD154 on activated CD8+ T cells protected DRG neurons ( p < 0.05). These findings indicated that CD8+ T cells were principal effectors of DRG neuronal injury after FIV Infection through a CD40–CD154 interaction in a cell contact-dependent manner.
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Peripheral neuropathy in Lentivirus Infection: evidence of inflammation and axonal injury.
AIDS (London England), 2004Co-Authors: J Kennedy, Guido Van Marle, James B. Johnston, Yu Zhu, Ahmet Hoke, Claudia Silva, Douglas W. Zochodne, Christopher PowerAbstract:OBJECTIVE As distal sensory polyneuropathy (DSP) is a major neurological complication of HIV-1 Infection, we investigated the extent of peripheral nervous system disease in animals infected with the Lentivirus, feline immunodeficiency virus (FIV), because it causes neurological disease and immunosuppression in cats similar to HIV-1 in humans. METHODS After Infection with a neurovirulent FIV molecular clone, neurobehavioral testing, nerve morphology, viral detection and load measurements were performed. RESULTS Neurobehavioral studies showed delayed withdrawal in response to a noxious stimulus among FIV-infected animals compared with sham-infected controls (P < 0.05). Dorsal root ganglia and sciatic nerves from FIV-infected ammals showed activated macrophages that were increased in number and size compared with controls. In addition, TNF-alpha messenger RNA was detectable in most nerves and spinal cords from the FIV-infected group, but was infrequently detected in controls. Viral RNA copy numbers in plasma and sciatic nerves were detectable in all FIV-infected animals at high levels. Studies of sural nerves identified myelinated fiber atrophy in 12-week FIV-infected animals compared with age-matched control animals, which was accompanied by reduced myelin sheath thickness (P < 0.05). The footpads of FIV-infected animals displayed reduced intraepidermal fiber density compared with control animals (P < 0.01). CONCLUSION FIV Infection results in the rapid onset of peripheral neuropathy, defined by axonal injury and macrophage activation, together with abundant virus within the nerve, indicating that it may serve as a model of HIV-related DSP.
Gregory S. Lewis - One of the best experts on this subject based on the ideXlab platform.
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Reduced Lentivirus Susceptibility in Sheep with TMEM154 Mutations
PLOS Genetics, 2012Co-Authors: Michael P. Heaton, Lynn M. Herrmann-hoesing, Stephen N. White, Gregory P Harhay, Michael L. Clawson, Carol G. Chitko-mckown, Kreg A. Leymaster, Timothy P. L. Smith, Michelle R. Mousel, Gregory S. LewisAbstract:Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent Lentivirus Infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for Lentivirus Infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with Infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of Infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value
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reduced Lentivirus susceptibility in sheep with tmem154 mutations
PLOS Genetics, 2012Co-Authors: Michael P. Heaton, Stephen N. White, Gregory P Harhay, Michael L. Clawson, Kreg A. Leymaster, Timothy P. L. Smith, Michelle R. Mousel, Carol G Chitkomckown, Lynn M Herrmannhoesing, Gregory S. LewisAbstract:Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent Lentivirus Infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for Lentivirus Infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with Infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of Infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of Infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine Lentivirus Infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reInfection.
Barbara Blacklaws - One of the best experts on this subject based on the ideXlab platform.
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Infection of Dendritic Cells by the Maedi-Visna Lentivirus
Journal of Virology, 2000Co-Authors: Susanna Ryan, Laurence Tiley, Ian Mcconnell, Barbara BlacklawsAbstract:The early stages of Lentivirus Infection of dendritic cells have been studied in an in vivo model. Maedi-visna virus (MVV) is a natural pathogen of sheep with a tropism for macrophages, but the Infection of dendritic cells has not been proven, largely because of the difficulties of definitively distinguishing the two cell types. Afferent lymphatic dendritic cells from sheep have been phenotypically characterized and separated from macrophages. Dendritic cells purified from experimentally infected sheep have been demonstrated not only to carry infectious MVV but also to be hosts of the virus themselves. The results of the in vivo Infection experiments are supported by Infections of purified afferent lymph dendritic cells in vitro, in which late reverse transcriptase products are demonstrated by PCR. The significance of the Infection of afferent lymph dendritic cells is discussed in relation to the initial spread of Lentivirus Infection and the requirement for CD4 T cells.
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In vivo depletion of CD8+ cells does not affect primary maedi visna virus Infection in sheep.
Veterinary Immunology and Immunopathology, 1999Co-Authors: Kristina Eriksson, Susanna Ryan, Ian Mcconnell, Elizabeth Mcinnes, Paul Tonks, Barbara BlacklawsAbstract:T-cells have been implicated both, in promoting and reducing viral replication during Lentivirus Infection. CD8+ lymphocytes are believed to be important in controlling viral load through direct killing of virus-infected cells and by secretion of inhibitory chemokines and cytokines. To evaluate the role of CD8+ T-cells in the induction and control of the primary phase of a Lentivirus Infection, we have used a non-T-cell tropic Lentivirus, maedi-visna virus (MVV), to study the initial pathogenesis and subsequent immune responses in sheep depleted in vivo of CD8+ cells. Sheep were depleted of CD8+ cells in both blood and efferent lymph for up to 14 days. No difference in MVV replication was observed in either the draining efferent lymph or lymph node of these sheep. Surprisingly, these animals displayed a normal induction of pCTL whereas the virus-specific proliferative responses were reduced. This could reflect either that a proportion of functional CD8+ lymphocytes remained in these animals, as suggested by the appearance of pCTLs, or that CD8+ cells are not required for control of primary MVV Infection.
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CD4(+) T-cells are required for the establishment of maedi-visna virus Infection in macrophages but not dendritic cells in vivo.
Virology, 1999Co-Authors: Kristina Eriksson, Susanna Ryan, Ian Mcconnell, Elizabeth Mcinnes, Paul Tonks, Barbara BlacklawsAbstract:Abstract The role of CD4 + lymphocytes in the establishment of Lentivirus Infection in macrophages has been studied in an in vivo system of Lentivirus Infection where CD4 + lymphocytes are not the targets for Infection. Using the non-T-cell-tropic Lentivirus, maedi-visna virus (MVV), in CD4-depleted sheep, we have found that CD4 + T cells were required for MVV Infection in macrophages but not dendritic cells. CD4-depleted sheep had significantly lower levels of MVV-infected cells in lymph nodes and efferent lymph after MVV challenge in the drainage area of the lymph node. Due to the absence of virus in combination with the lack of CD4 + T helper cells, virus-specific immune responses were reduced. There was delayed induction of cytotoxic T cell precursors, a marked reduction in virus-specific in vitro proliferative responses, and a delay in the appearance of MVV-specific antibodies. By contrast, CD4 depletion had no effect on the establishment of MVV Infection in afferent lymph dendritic cells migrating from the skin Infection site to the lymph node.
Yu Zhu - One of the best experts on this subject based on the ideXlab platform.
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cxcr3 activation by Lentivirus Infection suppresses neuronal autophagy neuroprotective effects of antiretroviral therapy
The FASEB Journal, 2009Co-Authors: Yu Zhu, Justin C. Mcarthur, David Vergote, Carlos A. Pardo, Farshid Noorbakhsh, Morley D. Hollenberg, Christopher M. Overall, Christopher PowerAbstract:Previous studies have implicated CXCL12 in the neuropathogenesis of HIV Infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P<0.05) and neuronal survival (P<0.05), which recapitulated findings in FIV- and HIV-infected brains (P<0.05). Oral didanosine (ddI) treatment of FIV-infected animals reduced neurobehavioral abnormalities in conjunction with diminished plasma viral load (P<0.05). F4/80 transcript abundance and CXCL12(5-67) immunoreactivity were reduced with restored neuronal LC3 expression in the brains of FIV-infected animals after ddI treatment (P<0.05). ddI treatment also prevented microglial activation and depletion of synaptic proteins in the cortex of FIV-infected animals (P<0.05). These findings indicate that the beneficial effects of ddI might be a consequence of a reduced systemic viral burden and concurrent leukocyte activation, leading to diminished neuroinflammation with preservation of neuronal autophagy by regulating CXCR3 activation.
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CXCR3 activation by Lentivirus Infection suppresses neuronal autophagy: neuroprotective effects of antiretroviral therapy
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009Co-Authors: Yu Zhu, Justin C. Mcarthur, David Vergote, Carlos A. Pardo, Farshid Noorbakhsh, Morley D. Hollenberg, Christopher M. Overall, Christopher PowerAbstract:Previous studies have implicated CXCL12 in the neuropathogenesis of HIV Infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P
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Dual Lentivirus Infection potentiates neuroinflammation and neurodegeneration: viral copassage enhances neurovirulence
Journal of NeuroVirology, 2009Co-Authors: Amir Afkhami-goli, Shu-hong Liu, Yu Zhu, Joseph M. Antony, Hosseinali Arab, Christopher PowerAbstract:Infection by multiple lentiviral strains is recognized as a major driving force in the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, but the neuropathogenic consequences of multivirus Infections remain uncertain. Herein, we investigated the neurovirulence and underlying mechanisms of dual Lentivirus Infections with distinct viral strains. Experimental feline immunodeficiency virus (FIV) Infections were performed using cultured cells and an in vivo model of AIDS neuropathogenesis. Dual Infections were comprised of two FIV strains (FIV-Ch and FIV-PPR) as copassaged or superinfected viruses, with subsequent outcome analyses of host immune responses, viral load, neuropathological features, and neurobehavioral performance. Dual Infections of feline macrophages resulted in greater IL-1β (interleukin-1b), TNF-α (tumor necrosis factor α), and IDO (indoleamine 2,3-dioxygenase) expression and associated neurotoxic properties. FIV coInfection and sequential superInfection in vivo also induced greater IL-1β, TNF-α , and IDO expression in the basal ganglia (BG) and cortex (CTX), compared to the monovirus- and mock-infected groups, although viral loads were similar in single virus and dual virusinfected animals. Immunoblot analyses disclosed lower synaptophysin immunoreactivity in the CTX resulting from FIV super- and coInfections. Cholinergic and GABAergic neuronal injury was evident in the CTX of animals with dual FIV Infections. With increased glial activation and neuronal loss in dual FIV infected brains, immunohistochemical analysis also revealed elevated detection of cleaved caspase-3 in dysmorphic neurons, which was associated with worsened neurobehavioral abnormalities among animals infected with the copassaged viruses. Dual Lentivirus Infections caused an escalation in neuroinflammation and ensuing neurodegeneration, underscoring the contribution of Infection by multiple viruses to neuropathogenesis.
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cd8 lymphocyte mediated injury of dorsal root ganglion neurons during Lentivirus Infection cd154 dependent cell contact neurotoxicity
The Journal of Neuroscience, 2006Co-Authors: Yu Zhu, Shu-hong Liu, Joseph M. Antony, Douglas W. Zochodne, Jose A Martinez, Fabrizio Giuliani, Christopher PowerAbstract:Neuronal damage in dorsal root ganglia (DRGs) with accompanying axonal injury is a key feature of human immunodeficiency virus (HIV)-related distal sensory polyneuropathy (DSP). In a model of HIV-related DSP, we observed numerous CD3+ T lymphocytes ( p < 0.05) in DRGs from feline immunodeficiency virus (FIV)-infected animals, which also exhibited low CD4+ and high CD8+ lymphocyte levels in blood accompanied by a selective loss of small-diameter sural nerve axons ( p < 0.05). FIV-infected lymphocytes cocultured with syngeneic DRGs caused neuronal damage, indicated by neurite retraction, neuronal soma atrophy, and loss ( p < 0.05). In contrast, supernatants from FIV-infected or uninfected lymphocytes were minimally neurotoxic, despite high FIV virion levels. Among lymphocyte subsets cocultured with DRG cultures, CD8+ T cells from both FIV-infected and uninfected lymphocytes selectively caused DRG neuronal injury ( p < 0.05). FIV-infected CD8+ T cells showed markedly increased CD154 expression ( p < 0.05), whereas neurons were the predominant cells expressing CD40 in DRGs. Blocking CD154 on activated CD8+ T cells protected DRG neurons ( p < 0.05). These findings indicated that CD8+ T cells were principal effectors of DRG neuronal injury after FIV Infection through a CD40–CD154 interaction in a cell contact-dependent manner.
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Peripheral neuropathy in Lentivirus Infection: evidence of inflammation and axonal injury.
AIDS (London England), 2004Co-Authors: J Kennedy, Guido Van Marle, James B. Johnston, Yu Zhu, Ahmet Hoke, Claudia Silva, Douglas W. Zochodne, Christopher PowerAbstract:OBJECTIVE As distal sensory polyneuropathy (DSP) is a major neurological complication of HIV-1 Infection, we investigated the extent of peripheral nervous system disease in animals infected with the Lentivirus, feline immunodeficiency virus (FIV), because it causes neurological disease and immunosuppression in cats similar to HIV-1 in humans. METHODS After Infection with a neurovirulent FIV molecular clone, neurobehavioral testing, nerve morphology, viral detection and load measurements were performed. RESULTS Neurobehavioral studies showed delayed withdrawal in response to a noxious stimulus among FIV-infected animals compared with sham-infected controls (P < 0.05). Dorsal root ganglia and sciatic nerves from FIV-infected ammals showed activated macrophages that were increased in number and size compared with controls. In addition, TNF-alpha messenger RNA was detectable in most nerves and spinal cords from the FIV-infected group, but was infrequently detected in controls. Viral RNA copy numbers in plasma and sciatic nerves were detectable in all FIV-infected animals at high levels. Studies of sural nerves identified myelinated fiber atrophy in 12-week FIV-infected animals compared with age-matched control animals, which was accompanied by reduced myelin sheath thickness (P < 0.05). The footpads of FIV-infected animals displayed reduced intraepidermal fiber density compared with control animals (P < 0.01). CONCLUSION FIV Infection results in the rapid onset of peripheral neuropathy, defined by axonal injury and macrophage activation, together with abundant virus within the nerve, indicating that it may serve as a model of HIV-related DSP.
Nichole R Klatt - One of the best experts on this subject based on the ideXlab platform.
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cmv primes functional alternative signaling in adaptive δg nk cells but is subverted by Lentivirus Infection in rhesus macaques
Cell Reports, 2018Co-Authors: Spandan V Shah, Cordelia Manickam, Kyle Kroll, Hannah L Itell, Sallie R Permar, Dan H Barouch, Nichole R Klatt, Keith R ReevesAbstract:Summary Despite burgeoning evidence demonstrating the adaptive properties of natural killer (NK) cells, mechanistic data explaining these phenomena are lacking. Following antibody sensitization, NK cells lacking the Fc receptor (FcR) signaling chain (Δg) acquire adaptive features, including robust proliferation, multifunctionality, rapid killing, and mobilization to sites of virus exposure. Using the rhesus macaque model, we demonstrate the systemic distribution of Δg NK cells expressing memory features, including downregulated Helios and Eomes. Furthermore, we find that Δg NK cells abandon typical γ-chain/Syk in lieu of CD3ζ-Zap70 signaling. FCγRIIIa (CD16) density, mucosal homing, and function are all coupled to this alternate signaling, which in itself requires priming by rhesus cytomegalovirus (rhCMV). Simian immunodeficiency virus (SIV) Infections further expand gut-homing adaptive NK cells but result in pathogenic suppression of CD3ζ-Zap70 signaling and function. Herein, we provide a mechanism of virus-dependent alternative signaling that may explain the acquisition of adaptive features by primate NK cells and could be targeted for future vaccine or curative therapies.
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cmv primes functional alternative signaling in adaptive δg nk cells but is subverted by Lentivirus Infection in rhesus macaques
Cell Reports, 2018Co-Authors: Spandan V Shah, Cordelia Manickam, Daniel R Ram, Kyle Kroll, Hannah L Itell, Sallie R Permar, Dan H Barouch, Nichole R KlattAbstract:Despite burgeoning evidence demonstrating the adaptive properties of natural killer (NK) cells, mechanistic data explaining these phenomena are lacking. Following antibody sensitization, NK cells lacking the Fc receptor (FcR) signaling chain (Δg) acquire adaptive features, including robust proliferation, multifunctionality, rapid killing, and mobilization to sites of virus exposure. Using the rhesus macaque model, we demonstrate the systemic distribution of Δg NK cells expressing memory features, including downregulated Helios and Eomes. Furthermore, we find that Δg NK cells abandon typical γ-chain/Syk in lieu of CD3ζ-Zap70 signaling. FCγRIIIa (CD16) density, mucosal homing, and function are all coupled to this alternate signaling, which in itself requires priming by rhesus cytomegalovirus (rhCMV). Simian immunodeficiency virus (SIV) Infections further expand gut-homing adaptive NK cells but result in pathogenic suppression of CD3ζ-Zap70 signaling and function. Herein, we provide a mechanism of virus-dependent alternative signaling that may explain the acquisition of adaptive features by primate NK cells and could be targeted for future vaccine or curative therapies.