Nonproductive Human Immunodeficiency Virus Type 1 Infection of Human Fetal Astrocytes: Independence from CD4 and Major Chemokine Receptors

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection of the brain is associated with neurological manifestations both in adults and in children. The primary target for HIV-1 infection in the brain is the microglia, but astrocytes can also be infected. We tested 26 primary HIV-1 isolates for their capacity to infect human fetal astrocytes in culture. Eight of these isolates, independent of their biological phenotype and chemokine receptor usage, were able to infect astrocytes. Although no sustained viral replication could be demonstrated, the virus was recovered by coculture with receptive cells such as macrophages or on stimulation with interleukin-1beta. To gain knowledge into the molecular events that regulate attachment and penetration of HIV-1 in astrocytes, we investigated the expression of several chemokine receptors. Fluorocytometry and calcium-mobilization assay did not provide evidence of expression of any of the major HIV-1 coreceptors, including CXCR4, CCR5, CCR3, and CCR2b, as well as the CD4 molecule on the cell surface of human fetal astrocytes. However, mRNA transcripts for CXCR4, CCR5, Bonzo/STRL33/TYMSTR, and APJ were detected by RT-PCR. Furthermore, infection of astrocytes by HIV-1 isolates with different chemokine receptor usage was not inhibited by the chemokines SDF-1beta, RANTES, MIP-1beta, or MCP-1 or by antibodies directed against the third variable region or the CD4 binding site of gp120. These data show that astrocytes can be infected by primary HIV-1 isolates via a mechanism independent of CD4 or major chemokine receptors. Furthermore, astrocytes are potential carriers of latent HIV-1 and on activation may be implicated in spreading the infection to other neighbouring cells, such as microglia or macrophages.

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

“…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.…”

“…The HIV-1 coreceptor CCR5 has recently been shown to be expressed in astrocytes in the hippocampus and cerebellum (68). Although CCR5 and CXCR4 have been shown to be utilized for simian immunodeficiency virus and HIV-2 viral entry in the absence of CD4 expression (17,32), the significance of those chemokine receptors in HIV-1 infection of human astrocytes seems to be, at most, minimal (69). In the present study, we demonstrate that the human mannose receptor (hMR) serves as the HIV-1 receptor for CD4-independent infection of astrocytes.…”

Identification of a Subset of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus Strains Able To Exploit an Alternative Coreceptor on Untransformed Human Brain and Lymphoid Cells

“…Low-level CD4-independent infection of brain cultures has been reported for various HIV and SIV strains (15,56). Therefore, we also tested whether fetal and adult astrocytes supported infection by the same panel of HIV and SIV isolates in the absence of adenovirus-mediated CD4 expression.…”

“…Astrocytes do not usually express CD4 and therefore support only an inefficient infection by particular HIV-1 strains (56,74). The chemokine receptor expression profile of astrocytes is controversial, and the role of coreceptors in the observed low-level infection is unclear (8,56). In order to determine if the cultured fetal and adult GFAP-positive cultures express functional coreceptors, we used an Ad-CD4 vector to express CD4 on these cells.…”

Identification of Shared Populations of Human Immunodeficiency Virus Type 1 Infecting Microglia and Tissue Macrophages outside the Central Nervous System

“…None of the findings presented in this paper rule out the possibility for additional restricted or latent infection by HIV of other cell types in the CNS. For example, there may be nonproductive infection of astrocytes (reviewed in reference 11), associated with the expression of nonstructural gene products such as Nef (21,44,65), although whether they contribute significantly to the proviral population detected by PCR awaits more precise quantitative studies based on methods such as in situ PCR (4, 76) which do not rely on gene expression for detection of infected cells.…”