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
Source: PubMed


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 SIVmac251 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-α) and gamma interferon (IFN-γ) 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-α and IFN-γ transcripts were coexpressed in the brains of four of five animals with SIV encephalitis
(SIVE). Within an encephalitic brain, TNF-α and IFN-γ 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-α-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.

Download full-text


Available from: Andrew A Lackner
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2014 · Journal of NeuroVirology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2014 · Virology
  • Source
    • "To study the effects of downstream activation on astrocytes subsequent to stellation, we stimulated stellated astrocytes with TNF-α as described in Figure 1. This proinflammatory cytokine has been observed in viral encephalitides (Orandle et al., 2002), bacterial infection (Phulwani et al., 2008), and stroke (Tuttolomondo et al., 2012). By treating with TNF-α with and without transient acidification we are able to model a broad-spectrum of disease states. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The foot processes of astrocytes cover over 60% of the surface of brain microvascular endothelial cells, regulating tight junction integrity. Retraction of astrocyte foot processes has been postulated to be a key mechanism in pathology. Therefore, movement of an astrocyte in response to a proinflammatory cytokine or even limited retraction of processes would result in leaky junctions between endothelial cells. Astrocytes lie at the gateway to the CNS and are instrumental in controlling leukocyte entry. Cultured astrocytes typically have a polygonal morphology until stimulated. We hypothesized that cultured astrocytes which were induced to stellate would have an activated phenotype compared with polygonal cells. We investigated the activation of astrocytes derived from adult macaques to the cytokine TNF-α under resting and stellated conditions by four parameters: morphology, intermediate filament expression, adhesion, and cytokine secretion. Astrocytes were stellated following transient acidification; resulting in increased expression of GFAP and vimentin. Stellation was accompanied by decreased adhesion that could be recovered with proinflammatory cytokine treatment. Surprisingly, there was decreased secretion of proinflammatory cytokines by stellated astrocytes compared with polygonal cells. These results suggest that astrocytes are capable of multiple phenotypes depending on the stimulus and the order stimuli are applied. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Jun 2013 · Journal of Cellular Physiology
Show more