Relationship of Nef‐positive and GFAP‐reactive astrocytes to drug use in early and late HIV infection

Abstract

Reactive astrocytosis is a well-documented feature of HIV encephalitis (HIVE), but it is unclear whether restricted infection of astrocytes contributes to this phenomenon. In addition, the part played by reactive and/or infected astrocytes in AIDS-related dementia is not fully understood. In this study of patients at different stages of the human immunodeficiency virus (HIV) infection, who had been treated at most with one antiretroviral drug, reactive astrocytes were identified by immunopositivity for glial fibrillary acidic protein (GFAP) and infected astrocytes by positivity for HIV Nef protein. Results were compared for drug-using AIDS patients with (n=9) and without (n=7) HIVE, for presymptomatic HIV-positive drug users (n=12) and for control HIV-negative subjects (n=20), including a group who used drugs (n=10). GFAP-reactive astrocytes in both grey and white matter were significantly more numerous in HIVE subjects than in each of the other groups but did not correlate with viral load. Nef-positive astrocytes were confined to HIVE cases and to white matter, but were numerous in only one subject who was treatment-naive. Nef-positive microglia were identified in all HIVE cases and in occasional AIDS and presymptomatic subjects who did not have HIVE. The results suggest that astrocytes may form an additional viral reservoir in late HIV infection and may contribute to HIVE. However, the number of GFAP-positive astrocytes was neither increased in pre-AIDS nor in drug abuse, in contrast with microglia which we have shown previously to be up-regulated in both states.

Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

“…Figure 4 demonstrates that repeated stimulation of astrocytes with PIC increases the expression of IDO and viperin (secondary response genes), as well as IFN-␤ (primary response gene) and TLR3. These results, together with the demonstration that PIC-induced gene transcription was suppressed by the inhibitor of endosomal acidification NH 4 Cl (data not shown), implicate receptor (TLR3) upregulation as the underlying mechanism for the increased gene expression (also see Discussion). IL-1, on the other hand, induced smaller amounts of genes, with repeated stimulation providing no benefit.…”

Control of HIV replication in astrocytes by a family of highly conserved host proteins with a common Rev-interacting domain (Risp)

“…Our data suggest that Risp proteins limit HIV production by interfering with Rev (4) and promoting accumulation of Rev in the cytoplasm (7). activity in infected astrocytes in vivo is suggested by the fact that the HIV markers detected in astrocytes in vivo consist mainly of viral RNAs and early viral proteins like Nef, whereas viral structural proteins are only rarely detected [14,[38][39][40][41][42][43][44]. Recent data indicate that HIV infection of astrocytes may occur much more frequently than previously anticipated [45].…”

Impact of HIV on Regional & Cellular Organisation of the Brain

“…In late stage HIV infection, brain infection is manifested by the expression of HIV proteins, often in perivascular microglia/macrophages but also in parenchymal microglia [7,19,47,48,77,82]. HIV proteins including p24, gp41, gp120 and Nef are detectable immunohistochemically in productively infected cells [4,7,19,47,48,69,77,82]. HIV can target both lymphocytes and macrophages in the systemic compartment by means of viral variants which possess envelope sequences appropriate to these two cell types and their varying chemokine receptors [21].…”