Infection of human fetal dorsal root ganglion glial cells with human immunodeficiency virus type 1 involves an entry mechanism independent of the CD4 T4A epitope

Abstract

Human immunodeficiency virus type 1 (HIV-1) has been implicated in the generation of acquired immunodeficiency syndrome-associated neurological dysfunction, and it is believed that the presence of CD4 in the nervous system may be involved in the susceptibility of selected neural cell populations to HIV-1 infection. We previously demonstrated (B. Wigdahl, R. A. Guyton, and P. S. Sarin, Virology 159:440 445, 1987) that glial cells derived from human fetal dorsal root ganglion (DRG) are susceptible to HIV-1 infection and subsequently express at least a fraction of the virus genome. In contrast to HIV-1 infection of CD4+ lymphocytes, which can be blocked by treatment with monoclonal antibodies directed against the HIV-1-binding region of CD4 (T4A epitope), treatment of human fetal DRG glial cells with similar antibodies resulted in only a slight reduction in HIV-l-specific gag antigen expression. In addition, preincubation of the HIV-1 inoculum prior to infection with HIV-l-neutralizing antiserum did not reduce HIV-1 gag antigen expression in these cells. Furthermore, we were unable to detect the synthesis or accumulation of the CD4 molecule in neural cell populations derived from DRG. However, a protected CD4-specific RNA fragment was detected in RNA isolated from human fetal DRG and spinal cord tissue by an RNase protection assay with a CD4-specific antisense RNA probe. RNA blot hybridization analysis of total cellular RNA isolated from human fetal DRG and spinal cord demonstrated specffic hybridization to an RNA species that comigrated with the mature 3.0-kilobase CD4 mRNA as well as two unique CD4 RNA species with relative molecular sizes of approximately 5.3 and 6.7 kilobases. Furthermore, all three CD4-related RNA species were polyadenylated when isolated from human fetal spinal cord tissue. These data suggest that HIV-1 infection of human fetal DRG glial cells may proceed via a mechanism of viral entry independent of the T4A epitope of CD4.

Infection of brain microglial cells by human immunodeficiency virus type 1 is CD4 dependent

“…In primary human brain cultures containing abundant astrocytes (35) and some oligodendrocytes, we have not observed the productive infection of these glial cells. Similarly, transient and/or low levels of infection were detected in glioma cell lines or fetal dorsal root ganglia cultures (6,9,(17)(18)(19)32), and in these cells virus entry appeared to be CD4 independent (4, 7, 12, 36). Even when glioma cells expressed the CD4 receptor from a transfected gene and could bind HIV-1, these cells were not infected by HIV-1 and cell fusion did not occur when they were mixed with HIV-1-infected lymphocytes (5).…”

Characteristics of HIV‐1 gp120 glycoprotein binding to glycolipids

“…The human immunodeficiency virus (HIV-1) binds to CD4 in T-cells and rnacrophages, but the virus can also infect non-lymphoid cells by CD4 independent mechanisms (Dewhurst et al, 1987;Chiodi et al, 1987;Cheng-Mayer et al, 1989;Weber et al, 1989;Clapham et al, 1989;Adachi et al, 1987;Omary et al, 1991;Tateno et al, 1989;Mellert et al, 1990;Werner et al, 1990;Kunsch et al, 1989;Cao et al, 1990;Xi Ling ct al., 1990). In human placental cells, the gp120 envelope glycoprotein of HIV-1 has been shown to bind to a membrane-associated C-type lectin which might serve as the viral receptor (Curtis et al, 1992).…”

Human immunodeficiency virus type 1 infection of SK-N-MC cells: domains of gp120 involved in entry into a CD4-negative, galactosyl ceramide/3' sulfo-galactosyl ceramide-positive cell line

“…Although microglia, which like macrophages are thought to be CD4 ϩ , are the most highly infected cell type in the brain, recent evidence obtained by using in situ PCR has implicated astrocytes, endothelial cells, neurons, and oligodendrocytes in the pathogenesis of HIV dementia (30,57). As none of these cell types express CD4, understanding CD4-independent entry may become very important in discerning the pathophysiology of HIV dementia.…”

“…The CD4 molecule is the principal receptor for human immunodeficiency virus type 1 (HIV-1) and is responsible for entry of the virus into its main host cells: CD4 ϩ lymphocytes, monocytes, and microglia (18,33,46). However, a number of studies have demonstrated that cell lines of neural, gastrointestinal, fibroblastic, and cervical origin can be infected in vitro by a number of HIV-1 strains, in spite of undetectable levels of CD4 protein or mRNA (11,14,15,25,30,49,52,56). Recent in vivo findings indicate that CD4-negative cells in the brain, including astrocytes, endothelial cells, and neurons, harbor HIV sequences (37,50).…”