Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4

Abstract

CXCR4, a seven transmembrane domain G-protein-coupled receptor for the Cys-X-Cys class of chemokines, is one of several chemokine receptors that can act as a co-receptor with CD4 for the human immunodeficiency virus (HIV-1) glycoprotein gp120 [1-3]. CXCR4 can mediate the entry of HIV-1 strains that specifically infect T cells, such as the IIB strain (see [4] for review). Recent reports indicate that gp120 can signal through CXCR4 [5] and it has been suggested that signal transduction, mediated by the viral envelope, might influence viral-associated cytopathicity or apoptosis [6]. Neuronal apoptosis is a feature of HIV-1 infection in the brain [7,8], although the exact mechanism is unknown. Here, we address the possible role of CXCR4 in inducing apoptosis using cells of the hNT human neuronal cell line; these cells resemble immature post-mitotic cholinergic neurons and have a number of neuronal characteristics [9-15]. We have previously shown that gp120 from the HIV-1 IIIB strain binds with high affinity to CXCR4 expressed on hNT neurons [15]. We now find that both IIIB gp120 and the Cys-X-Cys chemokine SDF-1 alpha can directly induce apoptosis in hNT neurons in the absence of CD4 and in a dose-dependent manner. To our knowledge, this is the first report of a chemokine and an HIV-1 envelope glycoprotein eliciting apoptotic responses through a chemokine receptor.

Microglial and Astrocyte Chemokines Regulate Monocyte Migration through the Blood-Brain Barrier in Human Immunodeficiency Virus-1 Encephalitis

“…63 Binding of viral proteins (gp120) and SDF-1 to CXCR4 expressed on neurons could be a pathway for the neuronal apoptosis, suggesting an additional mechanism for neurodegeneration developed in HAD and HIVE. 63,64 These observations, taken together with those in this report, strongly support the idea that HAD is a metabolic encephalopathy fueled by viral replication and immune activation of macrophages and astrocytes. The heterogeneity in MP secretory functions and their interaction with other glial cells certainly play important roles in the pathogenesis of HAD and its associated encephalitis.…”

Apoptosis in SIV infection

“…144 The HIV envelope protein has also been reported to cause apoptosis by binding to a chemokine coreceptor. [145][146][147][148] Several studies have indicated that macrophages are capable to trigger apoptosis of uninfected bystander CD4 þ and CD8 þ T cells. 149 Apoptosis involve the interaction between several death receptors (Fas, TNF-R, TRAIL-R) and their counterparts, their death ligands.…”

Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology

“…A number of viral and cellular factors produced by infected or activated cells over a long period of time appear to be responsible for the neuronal damage caused by HIV (recent reviews: Gartner and Liu, 2002;Gonzalez-Scarano and MartinGarcia, 2005;Jones and Power, 2006;Mattson et al, 2005). One of these factors is the HIV envelope protein gp120 that binds to chemokine receptors (i.e., CCR5 and CXCR4) on the surface of target cells, including neurons (Gartner and Liu, 2002;GonzalezScarano and Martin-Garcia, 2005;Hesselgesser et al, 1998;Jones and Power, 2006;Mattson et al, 2005). Several in vitro and in vivo studies have shown the neurotoxic potential of the envelope protein and the involvement of chemokine receptors in this process (Gartner and Liu, 2002;Gonzalez-Scarano and Martin-Garcia, 2005;Jones and Power, 2006;Mattson et al, 2005).…”

“…The interaction of the co-receptors with the viral protein only partially resembles the interaction with their natural ligands , suggesting that activation of chemokine receptors may lead to cell death. Indeed, both apoptotic and pro-survival actions of chemokines have been reported (Cartier et al, 2005;Hesselgesser et al, 1998;Kaul and Lipton, 1999;Meucci et al, 1998). Thus, chemokine receptors may mediate both survival and apoptotic pathways in neurons.…”