Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in cultured rat astroglial cells but not in cultured rat cortical neurons

Abstract

The alpha chemokine receptor CXCR4 is used as the major coreceptor for the cell entry of T-cell-tropic human immunodeficiency virus-1 (HIV-1) isolates. Activation of this coreceptor by its natural ligand SDF1alpha is associated with an intracellular Ca(2+) increase. Because the HIV-1 glycoprotein 120 (gp120) is shedded from the surface of HIV-1-infected cells and is regarded as an injurious molecule in the pathogenesis of HIV-1-associated encephalopathy (HIVE), we investigated the effects of gp120 on the intracellular Ca(2+) regulation of astrocytes and neurons. After 5 days in vitro (DIV), SDF1alpha (50 nM) elicited a pertussis toxin-sensitive intracellular Ca(2+) increase due to Ca(2+) release from internal stores that was reduced by a blocking monoclonal antibody against the CXCR4 receptor in astrocytes and neurons. Parallel with the development of the SDF1alpha response, cells became sensitive to direct application of gp120 (1.25 microg/ml), which, similarly to SDF1alpha, elicited a transient intracellular Ca(2+) increase. However, short-term incubation with gp120 for 60 to 120 min induced a reduction of glutamate- or ATP-evoked intracellular Ca(2+) responses only in astrocytes and not in neurons, although functional CXCR4 receptors were expressed in both cell types. Therefore, our data strongly suggest that the CXCR4 receptor-mediated intracellular signaling pathway of gp120 differs in astrocytes and neurons.

HIV-1 Viral Envelope Glycoprotein gp120 Triggers an Inflammatory Response in Cultured Rat Astrocytes and Regulates the Functional Expression of P-Glycoprotein

“…Previous studies have shown that the chemokine receptors CXCR4 and CCR5 are expressed in cultured rat astrocytes (Bajetto et al, 1999;Koller et al, 2002). In the present study, we confirmed the expression of both CXCR4 and CCR5 in our primary cultures of rat astrocytes.…”

“…It is interesting that Kong et al (1996) reported cytokine secretion (i.e., TNF-␣, IL-1␤, and IL-6) in cultured murine astrocytes triggered with subtype B gp120 isoforms. In addition, it has been demonstrated that gp120 may interact with rodent CXCR4 and CCR5 orthologs (Wu et al, 1997;Koller et al, 2002). Therefore, the secretion of cytokines may be facilitated by interactions between shed gp120 and CXCR4/CCR5.…”

“…In addition, shed gp120 from HIV-1-infected macrophages and microglia can activate intracellular signaling cascades in CD4-negative cell types by binding directly to CXCR4 and CCR5 (Persidsky and Gendelman, 2003;Kaul et al, 2005). Although astrocytes do not express CD4 (Liu et al, 2004), studies have reported expression of both coreceptors in these cells (Bajetto et al, 1999;Koller et al, 2002). It is interesting that Kong et al (1996) reported cytokine secretion (i.e., TNF-␣, IL-1␤, and IL-6) in cultured murine astrocytes triggered with subtype B gp120 isoforms.…”

“…Corasaniti et al (2005) demonstrated elevated IL-1␤ expression in rat neocortex after gp120 administration, suggesting a relationship between gp120 exposure and increased brain concentrations of cytokines. Studies in cul-tured astrocytes suggest that gp120 binding to cell surface chemokine receptors (e.g., CXCR4 and CCR5) may mediate this inflammatory response (Wu et al, 1997;Koller et al, 2002).…”

X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens

“…HIV-1 gp120 is able to directly interact with chemokine receptors; for example, X4-gp120 has been shown to mediate signaling in murine and rat cells (3,11,28). Although there are no specific reports that indicate that R5 HIV-1 gp120 can trigger murine CCR5, this protein has been shown to bind this chemokine receptor on rat cells (20).…”