HIV‐1 infection of subcortical astrocytes in the pediatric central nervous system

Abstract

Early reports of pediatric HIV-1-associated neuropathology described the presence of viral particles in some astrocytes, implicating direct infection of the immature nervous system as a contributing factor to the observed neuropathology. Several recent reports suggest that in those astrocytes infected with HIV-1, the level of antigenic expression of the proviral genome is below the sensitivity limits of conventional histochemical techniques. Identification of these astrocytes would instead require the use of a highly sensitive radiolabeled DNA or RNA probe for in situ hybridization to detect the persistent viral nucleic acids. To test this hypothesis, we examined autopsy tissue from 12 infants and children with AIDS-associated encephalopathy for the presence of HIV-1-infected astrocytes using combined isotopic in situ hybridization for the detection of viral-specific nucleic acids and immunohistochemistry for the identification of astrocytes. We detected HIV-1 nucleic acids in astrocytes in subcortical white matter from four pediatric patients with moderate to extensive leukoencephalitis. While gp41 was detectable only on macrophages and multinucleated giant cells, HIV-1 Nef protein was present in cells morphologically identified as astrocytes in two of these patients, further suggesting that HIV-1 establishes a persistent rather than a productive infection in astrocytes. Subcortical astrocytes may therefore be an unrecognized reservoir for HIV-1 in the developing nervous system of some children with AIDS-associated leukoencephalitis.

Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH

“…Since HIV-1 infection of astrocytes is limited, persisting for prolonged periods in a low productive and non-cytolytic state (Shahabuddin et al, 1992;Tornatore et al, 1991Tornatore et al, , 1994a, these results suggest that the parallel e ects observed following infection with HIV-1 and gp120 treatment may re¯ect gene changes resulting as a consequence of signaling events mediated by cell surface interactions. The dysregulation in cellular gene expression may be one route through which HIV-1 infected astrocytes contribute to HAD, despite relatively ine cient viral expression.…”

“…Astrocytes also can be infected with HIV-1 in vitro and in vivo, although with lower e ciency than T cells and macrophages (Dewhurst et al, 1987;Saito et al, 1994;Tornatore et al, 1991Tornatore et al, , 1994areviewed in BrackWerner, 1999). The limited infection of astrocytes has been attributed to various mechanisms, including intracellular restrictions to virus expression (Gorry et al, 1999;Ludwig et al, 1999;Tornatore et al, 1994b) or, as we have shown recently, ine cient virus entry (Bencheikh et al, 1999;Canki et al, 2001).…”

“…There is general agreement, however, that HIV-1 can persist in astrocytes for prolonged periods in a low productive, non-cytolytic state, from which it can be induced by physiologic stimuli such as tumor necrosis factor-a (TNF-a) (Shahabuddin et al, 1992;Tornatore et al, 1991). Surveys of autopsy tissues using in situ PCR and sensitive immunocytochemistry techniques indicate that the frequency of HIV-1 positive astrocytes in selected tissue sections from brains of patients with dementia can achieve 1% (Saito et al, 1994;Takahashi et al, 1996;Tornatore et al, 1994a). Considering that the number of astrocytes in the brain is between 10 11 to 10 12 cells (Verkhratsky et al, 1998), these cells clearly constitute a major target for HIV-1 infection in the brain.…”

HIV-1-induced neuronal injury in the developing brain

“…A recent morphometric study found a statistically significant reduction in the volume of all cortical regions, most of the subcortical gray matter (e.g., caudate nucleus, putamen, globus pallidus, claustrum, and thalamus), and in cerebral white matter [5]. In addition, HIV-1 infection restricted to the production of regulatory gene products in astrocytes has been reported [6,7]. Other prominent pathological findings include widespread activation of microglia, reactive astrocytosis [4], and evidence of neuronal loss and damage to the dendritic arbor [8][9][10][11].…”

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

“…In the brain, microglia/macrophage are the primary targets of HIV-1 infection (128), but in vivo infection of astrocytes has been documented in multiple studies (129)(130)(131)(132)(133)(134)(135)(136). Astrocytes present an abundant CNS target, but the course of infection is generally a long-term latent process.…”