M C Zink

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (121)560.64 Total impact

  • AIDS research and human retroviruses 04/2014; 30(4):333-4. · 2.18 Impact Factor
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    ABSTRACT: We recently demonstrated direct evidence of increased monoamine oxidase (MAO) activity in the brain of an SIV model of HIV CNS disease, consistent with previously reported dopamine deficits in both SIV and HIV infection. In this study, we explored potential mechanisms behind this elevation. MAO B mRNA was highest in macaques with the most severe SIV CNS lesions and positively correlated with levels of CD68 and GFAP transcripts in the striatum. MAO B mRNA also correlated with viral loads in the CNS of SIV-infected macaques and with oxidative stress. Furthermore, in humans, striatal MAO activity was elevated in individuals with HIV encephalitis compared to seronegative controls. These data suggest that the neuroinflammation and oxidative stress caused by SIV CNS infection may provide the impetus for increased transcription of MAO B and also suggest that MAO, and more broadly, oxidative stress, have significant potential as therapeutic targets in HIV CNS disease.
    The Journal of Infectious Diseases 03/2014; · 5.85 Impact Factor
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    ABSTRACT: HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
    Journal of NeuroVirology 01/2014; · 2.85 Impact Factor
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    ABSTRACT: HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo.
    PLoS ONE 01/2014; 9(4):e94375. · 3.53 Impact Factor
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    ABSTRACT: The increasing use of the common marmoset (Callithrix jacchus) in research makes it important to diagnose spontaneous disease that may confound experimental studies. Bone disease and gastrointestinal disease are two major causes of morbidity and mortality in captive marmosets, but currently no effective antemortem tests are available to identify affected animals prior to the terminal stage of disease. In this study we propose that bone disease and gastrointestinal disease are associated disease entities in marmosets and aim to establish the efficacy of several economical antemortem tests in identifying and predicting disease. Tissues from marmosets were examined to define affected animals and unaffected controls. Complete blood count, serum chemistry values, body weight, quantitative radiographs, and tissue-specific biochemical markers were evaluated as candidate biomarkers for disease. Bone and gastrointestinal disease were associated, with marmosets being over seven times more likely to have either concurrent bone and gastrointestinal disease or neither disease as opposed to lesions in only one organ system. When used in tandem, serum albumin <3.5 g/dL and body weight <325 g identified 100% of the marmosets affected with concurrent bone and gastrointestinal disease. Progressive body weight loss of 0.05% of peak body weight per day predicted which marmosets would develop disease prior to the terminal stage. Bone tissue-specific tests, such as quantitative analysis of radiographs and serum parathyroid hormone levels, were effective for distinguishing between marmosets with bone disease and those without. These results provide an avenue for making informed decisions regarding the removal of affected marmosets from studies in a timely manner, preserving the integrity of research results.
    PLoS ONE 01/2013; 8(12):e82747. · 3.53 Impact Factor
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    ABSTRACT: Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.
    Journal of Virology 08/2012; 86(20):11368-72. · 5.08 Impact Factor
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    ABSTRACT: Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes express the CD14(++)CD16(-)CCR2(+) phenotype and migrate to inflammatory sites by quickly responding to CCL2 signaling. Here, we identified and characterized the expansion of a novel monocyte subset during HIV and SIV infection, which were undistinguishable from classical monocytes, based on CD14 and CD16 expression, but expressed significantly lower surface CCR2. Transcriptome analysis of sorted cells demonstrated that the CCR2(low/neg) cells are a distinct subpopulation and express lower levels of inflammatory cytokines and activation markers than their CCR2(high) counterparts. They exhibited impaired phagocytosis and greatly diminished chemotaxis in response to CCL2 and CCL7. In addition, these monocytes are refractory to SIV infection and suppress CD8(+) T cell proliferation in vitro. These cells express higher levels of STAT3 and NOS2, suggesting a phenotype similar to monocytic myeloid-derived cells, which suppress expansion of CD8(+) T cells in vivo. They may reflect an antiproliferative response against the extreme immune activation observed during HIV and SIV infections. In addition, they may suppress antiviral responses and thus, have a role in AIDS pathogenesis. Antiretroviral therapy in infected macaque and human subjects caused this population to decline, suggesting that this atypical phenotype is linked to viral replication.
    Journal of leukocyte biology 02/2012; 91(5):803-16. · 4.99 Impact Factor
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    ABSTRACT: CCAAT/enhancer binding protein (C/EBP)β, and C/EBP binding sites in the HIV/SIV- long terminal repeat (LTR) are crucial for regulating transcription and for IFNβ-mediated suppression of virus replication in macrophages, the predominant source of productive virus replication in the brain. We investigated sequence variation within the SIV-LTR C/EBP sites that may be under selective pressure in vivo and therefore associated with disease progression. Using the SIV-macaque model, we examined viral LTR sequences derived from the spleen, a site of macrophage and lymphocyte infection, and the brain from macaques euthanized at 10, 21, 42, 48 and 84 days postinoculation (p.i.). A dominant variant, DS1C/A, containing an adenine-to-guanine substitution and a linked cytosine-to-adenine substitution in the downstream (DS1) C/EBP site, was detected in the spleen at 10 days p.i. The DS1C/A genotype was not detected in the brain until 42 days p.i., after which it was the predominant replicating genotype in both brain and spleen. Functional characterization of the DS1C/A containing SIV showed increased infectivity with or without IFNβ treatment over the wild-type virus, SIV/17E-Fr. The DS1C/A C/EBP site had higher affinity for both protein isoforms of C/EBPβ compared to the wild-type DS1 C/EBP site. Cytokine expression in spleen compared to brain implicated IFNβ and IL-6 responses as part of the selective pressures contributing to emergence of the DS1C/A genotype in vivo. These studies demonstrate selective replication of virus containing the DS1C/A genotype that either emerges very early in spleen and spreads to the brain, or evolves independently in the brain when IFNβ and IL-6 levels are similar to that found in spleen earlier in infection.
    PLoS ONE 01/2012; 7(8):e42801. · 3.53 Impact Factor
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    ABSTRACT: HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21 days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis.
    Journal of Neuroimmune Pharmacology 12/2011; 7(2):454-64. · 3.80 Impact Factor
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    ABSTRACT: Interferon-β induction occurs during acute simian immunodeficiency virus (SIV) infection in the brain. We have examined expression and function of cytosolic RNA sensors, retinoic acid inducible gene I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5), in vivo in the brain of our consistent, accelerated SIV-macaque model and in vitro in SIV-infected macaque macrophages to identify the pathway of type I interferon (IFN) induction. MDA5 messenger RNA (mRNA) and protein were expressed at higher levels in the brain than RIG-I, with protein expression correlating with the severity of disease from 42 until 84 days post-inoculation. The siRNA experiments reveal that mRNA expression of IFN-inducible gene MxA is dependent on MDA5, but not RIG-I. Finally, we demonstrate that SIV infection leads to the production of double-stranded RNA in vivo, which may act as the MDA5 ligand. We have shown for the first time to our knowledge the functional role of MDA5 in the innate immune response to SIV infection.
    The Journal of Infectious Diseases 10/2011; 204(7):1104-14. · 5.85 Impact Factor
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    ABSTRACT: In response to pressure exerted by major histocompatibility complex (MHC) class I-mediated CD8(+) T cell control, human immunodeficiency virus (HIV) escape mutations often arise in immunodominant epitopes recognized by MHC class I alleles. While the current standard of care for HIV-infected patients is treatment with highly active antiretroviral therapy (HAART), suppression of viral replication in these patients is not absolute and latently infected cells persist as lifelong reservoirs. To determine whether HIV escape from MHC class I-restricted CD8(+) T cell control develops during HAART treatment and then enters latent reservoirs in the periphery and central nervous system (CNS), with the potential to emerge as replication-competent virus, we tracked the longitudinal development of the simian immunodeficiency virus (SIV) Gag escape mutation K165R in HAART-treated SIV-infected pigtailed macaques. Key findings of these studies included: (i) SIV Gag K165R escape mutations emerged in both plasma and cerebrospinal fluid (CSF) during the decaying phase of viremia after HAART initiation before suppression of viral replication, (ii) SIV K165R Gag escape mutations were archived in latent proviral DNA reservoirs, including the brain in animals receiving HAART that suppressed viral replication, and (iii) replication-competent SIV Gag K165R escape mutations were present in the resting CD4(+) T cell reservoir in HAART-treated SIV-infected macaques. Despite early administration of aggressive antiretroviral treatment, HIV immune escape from CD8(+) T cell control can still develop during the decaying phases of viremia and then persist in latent reservoirs, including the brain, with the potential to emerge if HAART therapy is interrupted.
    Journal of Virology 06/2011; 85(17):9167-75. · 5.08 Impact Factor
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    ABSTRACT: HIV infection of the CNS is an early event after primary infection, resulting in neurological complications in a significant number of individuals despite antiretroviral therapy (ART). The main cells infected with HIV within the CNS are macrophages/microglia and a small fraction of astrocytes. The role of these few infected astrocytes in the pathogenesis of neuroAIDS has not been examined extensively. Here, we demonstrate that few HIV-infected astrocytes (4.7 ± 2.8% in vitro and 8.2 ± 3.9% in vivo) compromise blood-brain barrier (BBB) integrity. This BBB disruption is due to endothelial apoptosis, misguided astrocyte end feet, and dysregulation of lipoxygenase/cyclooxygenase, BK(Ca) channels, and ATP receptor activation within astrocytes. All of these alterations in BBB integrity induced by a few HIV-infected astrocytes were gap junction dependent, as blocking these channels protected the BBB from HIV-infected astrocyte-mediated compromise. We also demonstrated apoptosis in vivo of BBB cells in contact with infected astrocytes using brain tissue sections from simian immunodeficiency virus-infected macaques as a model of neuroAIDS, suggesting an important role for these few infected astrocytes in the CNS damage seen with HIV infection. Our findings describe a novel mechanism of bystander BBB toxicity mediated by low numbers of HIV-infected astrocytes and amplified by gap junctions. This mechanism of toxicity contributes to understanding how CNS damage is spread even in the current ART era and how minimal or controlled HIV infection still results in cognitive impairment in a large population of infected individuals.
    Journal of Neuroscience 06/2011; 31(26):9456-65. · 6.91 Impact Factor
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    ABSTRACT: Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV-macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals.
    Journal of Neuroimmune Pharmacology 05/2011; 7(2):401-11. · 3.80 Impact Factor
  • Gina Guillaume, Kenneth W Witwer, M Christine Zink
    Experimental Biology, Washington, DC; 04/2011
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    ABSTRACT: The CNS remains vulnerable to HIV-induced damage despite highly active antiretroviral therapy (HAART). Using a rigorous simian immunodeficiency virus (SIV) macaque model of HAART that combines three classes of antiretroviral drugs (a protease inhibitor, a reverse transcriptase inhibitor, and an integrase inhibitor), we examined immune responses and virus replication in the plasma and cerebrospinal fluid (CSF) following HAART initiation during acute infection (4 days postinoculation (p.i.)). HAART-treated macaques did not experience the level of acute CD4+ and CD8+ T cell and NK cell count suppression in the peripheral blood normally observed during acute infection. Initiation of HAART produced a rapid four-log decline in viral load in plasma and a slower two-log decline of viral RNA in the CSF over the subsequent 17 days of infection. Despite a dramatic reduction of viral RNA levels in the brain at 21 days p.i., viral DNA levels were not different between the two groups. Expression of most cytokine mRNA in brain of HAART-treated macaques did not significantly differ from untreated controls. Expression of the IFN responsive gene MxA was significantly reduced in the brain of HAART-treated macaques, suggesting control of hyperactive immune responses. Control of virus replication likely was enhanced by significant increases in CD4+ and CD8+ T cell trafficking in the brain of infected animals on HAART therapy and the concomitant increase in levels of IFNγ. Collectively, these data indicate preserved innate and adaptive immune activity in the brain following HAART initiation during acute SIV infection in this macaque model, suggesting profound benefits following acute treatment of SIV.
    Journal of NeuroVirology 02/2011; 17(1):120-30. · 2.85 Impact Factor
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    ABSTRACT: Here, simian immunodeficiency virus (SIV) macaque models are examined for their strengths in identifying in-vivo sites of HIV latency and persistent virus replication during highly active antiretroviral treatment (HAART). The best characterized HIV reservoir in HAART-treated persons is resting CD4 T cells in blood, although residual virus also comes from other reservoirs. Nonhuman primate/SIV models of HAART have been developed to characterize potential HIV reservoirs, particularly the central nervous system (CNS) and stem cells in bone marrow, known and potential reservoirs of latent virus that are difficult to study in humans. Few SIV macaque models of HAART have examined plasma and cerebrospinal fluid virus decay, the number of resting CD4 T cells harboring replication-competent latent SIV, HAART-treatment effect on the CNS, or residual viral replication or viral DNA levels in that tissue. Using a consistent, accelerated SIV macaque model, we characterized peripheral viral reservoirs, including those in the CNS, among HAART-treated macaques. The SIV model reproduces latency in memory CD4 T cells throughout the body and indicates that the CNS contains a stable SIV DNA reservoir. An SIV macaque model of HAART recapitulating viral latency, particularly in the CNS, is required to study therapeutic approaches for a functional HIV cure.
    Current opinion in HIV and AIDS 01/2011; 6(1):37-42. · 4.75 Impact Factor
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    ABSTRACT: Of the 33 million people infected with the human immunodeficiency virus (HIV) worldwide, 40-60% of individuals will eventually develop neurocognitive sequelae that can be attributed to the presence of HIV-1 in the central nervous system (CNS) and its associated neuroinflammation despite antiretroviral therapy. PrP(C) (protease resistant protein, cellular isoform) is the nonpathological cellular isoform of the human prion protein that participates in many physiological processes that are disrupted during HIV-1 infection. However, its role in HIV-1 CNS disease is unknown. We demonstrate that PrP(C) is significantly increased in both the CNS of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. PrP(C) is released into the cerebrospinal fluid, and its levels correlate with CNS compromise, suggesting it is a biomarker of HIV-associated neurocognitive impairment. We show that the chemokine (c-c Motif) Ligand-2 (CCL2) increases PrP(C) release from CNS cells, while HIV-1 infection alters PrP(C) release from peripheral blood mononuclear cells. Soluble PrP(C) mediates neuroinflammation by inducing astrocyte production of both CCL2 and interleukin 6. This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease.
    American Journal Of Pathology 10/2010; 177(4):1848-60. · 4.60 Impact Factor
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    ABSTRACT: During the era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated central nervous system (CNS) disease has increased despite suppression of plasma viremia. In a simian immunodeficiency virus (SIV) model system in which all animals develop AIDS and 90% develop CNS disease by 3 months after inoculation, pigtailed macaques were treated with a regimen of tenofovir disoproxil fumarate, saquinavir, atazanavir, and an integrase inhibitor starting at 12 days after inoculation and were euthanized at approximately 175 days after inoculation. Plasma and cerebrospinal fluid (CSF) viral loads declined rapidly after the initiation of HAART. Brain viral RNA was undetectable at necropsy, but viral DNA levels were not different from those in untreated SIV-infected macaques. CNS inflammation was significantly reduced, with decreased brain expression of major histocompatibility complex class II and glial fibrillary acidic protein and reduced levels of CSF CCL2 and interleukin 6. Brain from treated macaques had significantly lower levels of interferon beta, type 1 interferon-inducible gene myxovirus (influenza) resistance A, and indolamine 2,3-dioxygenase messenger RNA, suggesting that immune hyperactivation was suppressed, and fewer CD4(+) and CD8(+) T cells, suggesting that trafficking of T cells from peripheral blood was reduced. Brain levels of CD68 protein and tumor necrosis factor alpha and interferon gamma RNA were reduced but were not significantly lower, indicating continued CNS inflammation. These data, generated in a rigorous, high-viral-load SIV-infected macaque model, showed that HAART provided benefits with respect to CNS viral replication and inflammation but that no change in the level of viral DNA and continued CNS inflammation occurred in some macaques.
    The Journal of Infectious Diseases 07/2010; 202(1):161-70. · 5.85 Impact Factor
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    ABSTRACT: The treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART), a combination of three or more antiretroviral drugs, suppresses viremia below the clinical limit of detection (50 HIV-1 RNA copies/ml), but latently infected resting CD4(+) T cells serve as lifelong reservoirs, and low-level viremia can be detected with special assays. Recent studies have provided evidence for additional reservoirs that contribute to residual viremia but are not present in circulating cells. Identification of all the sources of residual viremia in humans may be difficult. These discoveries highlight the need for a tractable model system to identify additional viral reservoirs that could represent barriers to eradication. In this study, simian immunodeficiency virus (SIV)-infected pig-tailed macaques (Macaca nemestrina) were treated with four antiretroviral drugs to develop an animal model for viral suppression during effective HAART. Treatment led to a biphasic decay in viremia and a significant rise in levels of circulating CD4(+) T cells. At terminal infection time points, the frequency of circulating resting CD4(+) T cells harboring replication-competent virus was reduced to a low steady-state level similar to that observed for HIV-infected patients on HAART. The frequencies of resting CD4(+) T cells harboring replication-competent virus in the pooled head lymph nodes, gut lymph nodes, spleen, and peripheral blood were reduced relative to those for untreated SIV-infected animals. These observations closely parallel findings for HIV-infected humans on suppressive HAART and demonstrate the value of this animal model to identify and characterize viral reservoirs persisting in the setting of suppressive antiretroviral drugs.
    Journal of Virology 08/2009; 83(18):9247-57. · 5.08 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. · 3.66 Impact Factor

Publication Stats

3k Citations
560.64 Total Impact Points

Institutions

  • 1987–2014
    • Johns Hopkins University
      • • Department of Molecular and Comparative Pathobiology
      • • Department of Neurology
      • • Department of Medicine
      • • Department of Psychiatry and Behavioral Sciences
      • • Department of Pathology
      • • Department of Molecular Biology and Genetics
      Baltimore, Maryland, United States
    • University of Guelph
      • Department of Pathobiology
      Guelph, Ontario, Canada
  • 2012
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2011
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 1998–2011
    • Johns Hopkins Bloomberg School of Public Health
      Baltimore, Maryland, United States
  • 1988–2011
    • Johns Hopkins Medicine
      • • Department of Molecular and Comparative Pathobiology
      • • Department of Psychiatry and Behavioral Sciences
      Baltimore, MD, United States
  • 2007
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1995
    • United States Agency for International Development (USAID)
      Washington, Washington, D.C., United States
    • University of Maryland, Baltimore
      • Division of Infectious Diseases
      Baltimore, MD, United States
  • 1993
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
    • New York State
      New York City, New York, United States
  • 1990
    • Colorado State University
      Fort Collins, Colorado, United States