Virological and molecular parameters of HIV-1 infection of human embryonic astrocytes

Rienzo, Anna Maria Di; Aloisi, Francesca; Santarcangelo, Anna Claudia; Palladino, Clelia; Olivetta, Eleonora; Genovese, D.; Verani, P; Levi, Giulio

doi:10.1007/s007050050401

Cited by 31 publications

(18 citation statements)

References 40 publications

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“…7A). Similar results have been obtained from studies with chemokines specific for both CXCR4 and CCR5 that fail to inhibit HIV-1 replication in astrocytes (69), and direct infection of astrocytes with both HIV-1 virus strains (16). The ability of hMR to be utilized by both T-and M-tropic HIV-1 viruses corroborated our results from the virus capture assay and the direct gp120 binding assay indicating that the interaction between hMR and HIV-1 viruses was mediated by the carbohydrate moiety of HIV-1 gp120 protein (Fig.…”

Section: Discussionsupporting

confidence: 81%

CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor

Liu

Kim

et al. 2004

J Virol

181

130

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Human immunodeficiency virus type 1 (HIV-1) infection occurs in the central nervous system and causes a variety of neurobehavioral and neuropathological disorders. Both microglia, the residential macrophages in the brain, and astrocytes are susceptible to HIV-1 infection. Unlike microglia that express and utilize CD4 and chemokine coreceptors CCR5 and CCR3 for HIV-1 infection, astrocytes fail to express CD4. Astrocytes express several chemokine coreceptors; however, the involvement of these receptors in astrocyte HIV-1 infection appears to be insignificant. In the present study using an expression cloning strategy, the cDNA for the human mannose receptor (hMR) was found to be essential for CD4-independent HIV-1 infectivity. Ectopic expression of functional hMR rendered U87.MG astrocytic cells susceptible to HIV-1 infection, whereas anti-hMR serum and hMR-specific siRNA blocked HIV-1 infection in human primary astrocytes. In agreement with these findings, hMR bound to HIV-1 virions via the abundant and highly mannosylated sugar moieties of HIV-1 envelope glycoprotein gp120 in a Ca 2؉ -dependent fashion. Moreover, hMR-mediated HIV-1 infection was dependent upon endocytic trafficking as assessed by transmission electron microscopy, as well as inhibition of viral entry by endosomo-and lysosomotropic drugs. Taken together, these results demonstrate the direct involvement of hMR in HIV-1 infection of astrocytes and suggest that HIV-1 interaction with hMR plays an important role in HIV-1 neuropathogenesis.Astrocytes, often identified by glial fibrillary acidic protein expression, constitute a majority of the cells in the brain and are essential for maintaining homeostasis in the brain and, hence, normal brain activities. A number of different and quite diverse functions have been attributed to astrocytes. These include secretion of neurotrophic factors, regulation of the interstitial pH, uptake and metabolism of neurotransmitters, antioxidant defense via scavenging and transforming oxygen free radicals into nontoxic species, modulation of neuronal signals, being an essential structural component of the bloodbrain barrier, and participating in immune responses through production and secretion of cytokines, proteases, protease inhibitors, adhesion molecules, and extracellular matrix components that are key mediators of immunity and inflammation (for recent reviews, see references 6, 13, and 58). Although it is important to note that several of the functions listed above are still controversial, the highly dynamic and reciprocal relationship between astrocytes and neurons suggests that dysfunction of astrocytes could contribute to the pathogenesis of neurological diseases.

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Section: Discussionsupporting

confidence: 81%

CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor

Liu

Kim

et al. 2004

J Virol

181

130

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“…3). Our findings are consistent with other studies of astrocyte infection (6,9,10,41,50,51) and neuroblast infection (13,14); however, this is the first report of HIV-1 infection in a multipotential brain progenitor population.…”

Section: Discussionsupporting

confidence: 93%

Human Immunodeficiency Virus Type 1 Infection of Human Brain-Derived Progenitor Cells

Lawrence

Durham

Schwartz

et al. 2004

J Virol

112

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Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-␣). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-␣ stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5-to 20-fold more infectious virus (27 ng of p24/10 6 cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.

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“…To do this, we used a VSVg-env pseudotyped single-cycle HIV-1 (24). It is well-known that HIV-1 infectivity of astrocytes is low, with minimal production of viable particles (39,40). In contrast, the VSVg-env-mediated entry is efficient resulting in a high percentage of infectivity in our astrocytes permitting us to directly address intracellular antiviral mechanisms.…”

Section: Discussionmentioning

confidence: 99%

TLR3 Ligation Activates an Antiviral Response in Human Fetal Astrocytes: A Role for Viperin/cig5

Rivieccio¹,

Suh²,

Zhao³

et al. 2006

The Journal of Immunology

129

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TLR3 functions as a viral nucleic acid sentinel activated by dsRNA viruses and virus replication intermediates within intracellular vesicles. To explore the spectrum of genes induced in human astrocytes by TLR3, we used a microarray approach and the analog polyriboinosinic polyribocytidylic acid (pIC) as ligand. As expected for TLR activation, pIC induced a wide array of cytokines and chemokines known for their role in inflammatory responses, as well as up-regulation of the receptor itself. The data also showed activation of a broad spectrum of antiviral response genes. To determine whether pIC induced an antiviral state in astrocytes, a pseudotyped HIV viral particle, vesicular stomatitis virus g-env-HIV-1, was used. pIC significantly abrogated HIV-1 replication, whereas IL-1, which also potently activates astrocytes, did not. One of the most highly up-regulated genes on microarray was the protein viperin/cig5. We found that viperin/cig5 expression was dependent on IFN regulatory factor 3 and NF-κB signaling, and that repetitive stimulation with pIC, but not IL-1, further increased expression. Viperin induction could also be substantially inhibited by neutralizing Abs to IFN-β, as could HIV-1 replication. To explore a role for viperin in IFN-β-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, but not a scrambled RNAi, significantly inhibited viperin expression, and also significantly reversed pIC-induced inhibition of HIV-1 replication. We conclude that viperin contributes to the antiviral state induced by TLR3 ligation in astrocytes, supporting a role for astrocytes as part of the innate immune response against infection in the CNS.

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Virological and molecular parameters of HIV-1 infection of human embryonic astrocytes

Cited by 31 publications

References 40 publications

CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor

CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor

Human Immunodeficiency Virus Type 1 Infection of Human Brain-Derived Progenitor Cells

TLR3 Ligation Activates an Antiviral Response in Human Fetal Astrocytes: A Role for Viperin/cig5

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