Enhanced Expression of Proinflammatory Cytokines in the Central Nervous System Is Associated with Neuroinvasion by Simian Immunodeficiency Virus and the Development of Encephalitis

New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA.
Journal of Virology (Impact Factor: 4.44). 07/2002; 76(11):5797-802. DOI: 10.1128/JVI.76.11.5797-5802.2002
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Inflammatory cytokines are believed to play an important role in the pathogenesis of human immunodeficiency virus type 1-associated encephalitis. To examine this in the simian immunodeficiency virus (SIV)-infected macaque model of neuroAIDS, inflammatory cytokine gene expression was evaluated in the brains of macaques infected with pathogenic SIV(mac251) by reverse transcriptase PCR. Interleukin-1 beta was readily detected in the brains of all animals evaluated, regardless of infection status or duration of infection. Tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) transcripts were undetectable in the brains of uninfected control animals but were upregulated at 7 and 14 days postinoculation. At the terminal stage of infection, TNF-alpha and IFN-gamma transcripts were coexpressed in the brains of four of five animals with SIV encephalitis (SIVE). Within an encephalitic brain, TNF-alpha and IFN-gamma transcripts were detected in six of seven regions with histologic evidence of SIVE, suggesting a direct relationship between neuropathology and altered cytokine gene expression. With combined fluorescent in situ hybridization and immunofluorescence, TNF-alpha-expressing cells were frequently identified as CD68-positive macrophages within perivascular lesions. These observations provide evidence that cytokines produced by activated inflammatory macrophages are an important element in the pathogenesis of SIVE.

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Available from: Andrew A Lackner, Oct 06, 2015
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    • "Human immunodeficiency virus (HIV) gains access to the central nervous system (CNS) soon after the systematic infection (Roberts et al. 2004; Orandle et al. 2002) and causes a variety of neurological dysfunctions, collectively called HIVassociated neurocognitive disorder (HAND) (Kramer- Hammerle et al. 2005; Navia et al. 1986). Despite the success of combination antiretroviral therapy (cART) in suppressing HIV replication in the peripheral blood, improving immune function and prolonging the lifespan of HIV-infected individuals (Cysique et al. 2004; Sacktor et al. 2002), HAND has remained prevalent (Sacktor et al. 2002; Langford et al. 2003; Kandanearatchi et al. 2003). "
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    ABSTRACT: Astrocytes are the most abundant cells in the central nervous system and play important roles in human immunodeficiency virus (HIV)/neuro-acquired immunodeficiency syndrome. Detection of HIV proviral DNA, RNA, and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV infection albeit in a restricted manner. We as well as others have shown that cell-free HIV is capable of entering CD4− astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV reporter viruses and further characterized HIV interaction with astrocytes. First, we found that HIV was successfully transferred to astrocytes from HIV-infected CD4+ T cells in a cell–cell contact- and gp120-dependent manner. In addition, we demonstrated that, compared to endocytosis-mediated cell-free HIV entry and subsequent degradation of endocytosed virions, the cell–cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV was readily recovered from HIV latent astrocytes in a cell–cell contact-mediated manner. Taken together, our studies point to the importance of the cell–cell contact-mediated HIV interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV latent reservoirs in the central nervous system.
    Journal of NeuroVirology 12/2014; 21(1). DOI:10.1007/s13365-014-0304-0 · 2.60 Impact Factor
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    • "Isolation of SIV sequence variants from SIVmac251-infected rhesus macaques SIV gp120 sequence variants were cloned and sequenced from archived samples stored at À 80 1C, available from previous studies of SIVmac251-infected rhesus macaques (Orandle et al., 2002; Williams et al., 2002, 2001) (Table 1). Four macaques (Group I) were infected with SIVmac251 stock from the Desrosiers lab; two were inoculated intravenously and two intravaginally. "
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    ABSTRACT: Macrophages play an important role in HIV/SIV pathogenesis by serving as a reservoir for viral persistence in brain and other tissues. Infected macrophages have been detected in brain early after infection, but macrophage-tropic viruses are rarely isolated until late-stage infection. Little is known about early variants that establish persistent infection in brain. Here, we characterize a unique macrophage-tropic SIV envelope glycoprotein (Env) variant from two weeks post-infection in blood of an SIVmac251-infected macaque that is closely related to sequences in brain from animals with neurological disease. SIVmac251 clones expressing this Env are highly fusogenic, and replicate efficiently in T cells and macrophages. N173 and N481 were identified as novel determinants of macrophage tropism and neutralization sensitivity. These results imply that macrophage-tropic SIV capable of establishing viral reservoirs in brain can be present in blood during early infection. Furthermore, these SIVmac251 clones will be useful for studies on pathogenesis, eradication, and vaccines.
    Virology 06/2014; s 458–459(1):53–68. DOI:10.1016/j.virol.2014.03.024 · 3.32 Impact Factor
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    • "The initiation and development of the neuropathology that leads to either HAND or HAD remains unclear whilst the daily impact on patients and healthcare systems continues despite advances in ART (Ellis et al. 2007; Valcour et al. 2011; Letendre et al. 2010). Accelerated models of SIV infection within rhesus macaques has been used extensively to model largely late stage HIV-associated pathology of the brain and central nervous system (Babas et al. 2003; Flaherty et al. 1997; Orandle et al. 2002: Overholser et al. 2003; Williams et al. 2001) By contrast, the CNS pathology induced following SIV infection of cynomolgus macaques (Macaca fascicularis) progressing at a natural rate has not been extensively described. "
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    ABSTRACT: The neuropathology of simian immunodeficiency (SIV) infection in cynomolgus macaques (Macaca fascicularis) was investigated following infection with either T cell tropic SIVmacJ5, SIVmacC8 or macrophage tropic SIVmac17E-Fr. Formalin fixed, paraffin embedded brain tissue sections were analysed using a combination of in situ techniques. Macaques infected with either wild-type SIVmacJ5 or neurovirulent SIVmac17E-Fr showed evidence of neuronal dephosphorylation, loss of oligodendrocyte and CCR5 staining, lack of microglial MHC II expression, infiltration by CD4⁺ and CD8⁺ T cells and mild astrocytosis. SIVmacJ5-infected animals exhibited activation of microglia whilst those infected with SIVmac17E-Fr demonstrated a loss of microglia staining. These results are suggestive of impaired central nervous system (CNS) physiology. Furthermore, infiltration by T cells into the brain parenchyma indicated disruption of the blood brain barrier (BBB). Animals infected with the Δnef-attenuated SIVmacC8 showed microglial activation and astrogliosis indicative of an inflammatory response, lack of MHC II and CCR5 staining and infiltration by CD8⁺ T cells. These results demonstrate that the SIV infection of cynomolgus macaque can be used as a model to replicate the range of CNS pathologies observed following HIV infection of humans and to investigate the pathogenesis of HIV associated neuropathology.
    Journal of NeuroVirology 03/2012; 18(2):100-12. DOI:10.1007/s13365-012-0084-3 · 2.60 Impact Factor
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