Human immunodeficiency virus infection inhibits granulocyte-macrophage colony-stimulating factor–induced microglial proliferation

Abstract

It is well known that infection by the human immunodeficiency virus (HIV) dysregulates cell physiology, but little information is available on the consequences of HIV infection in primary macrophages and microglia. The authors examined the relationship between cell proliferation and HIV infection in primary cultures of microglia and in human central nervous system (CNS). In cultures infected with HIV (ADA and BaL), granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated cell proliferation was reduced in productively infected (p24+) cells as compared to p24- cells. The reduction was observed with both Ki67 and BrdU labeling, suggesting a G1/S block. The reduction was insignificant when microglia were infected with a Vpr- mutant virus. In human CNS, proliferating (Ki67+) cells were rare but were increased in the HIV+ and HIV encephalitis (HIVE) groups compared to the HIV- group. A positive correlation between GM-CSF immunoreactivity and Ki67 counts, implicating GM-CSF as a growth factor in human CNS was found. The relationship between total macrophage (CD68+) proliferation and infected macrophage (p24+) proliferation was assessed in HIVE by double labeling. Whereas 1.2% of total CD68+ cells were Ki67+, only 0.5% of HIV p24+ cells were Ki67+ (P < .05). Furthermore, staining for CD45RB (as opposed to CD68) facilitated the identification of Ki67+ microglia, indicating that CD68 could underestimate proliferating microglia. The authors conclude that although there is increased expression of GM-CSF and increased cell proliferation in the CNS of HIV-seropositive individuals, cell proliferation in the productively infected population is actually suppressed. These data suggest that there might be a viral gain in the suppressed host cell proliferation.

Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: Identification of novel inflammatory markers with implications for pathogenesis

“…GM‐CSF and macrophage colony‐stimulating factor are principal microglial growth factors; their expression (along with that of their cognate receptors) is upregulated in the injured or diseased CNS [Giulian and Ingeman, ; Raivich et al, ; Lee et al, ; Cosenza‐Nashat et al, ]. Here, GM‐CSF levels were slightly lower in sera from TBE patients than in that from control subjects, which is puzzling and requires further study.…”

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

“…HIVE sections for study were chosen based on the presence of multinucleated giant cells (MGCs) and microglial nodules on haematoxylin and eosin (H&E) and/or presence of HIV gag p24 expression by IHC. The details with regards to age and sex for all but one of the cases from the NNTC have been previously reported [23,24]. The additional section (case 38) was from a 47‐year‐old black woman.…”

Microglial response to viral challenges: Every silver lining comes with a cloud

“…This study focuses on the preventive measures taken by the microglia to contain viral replication within the CNS. It was further observed that the infection with Vpr mutant virus did not arrest this GMCSF induced proliferation indicating a role of this protein in maintaining HIV reservoirs upon suppression of host cell proliferation (59).…”

“…In a study carried out by Cosenza-Nashat et. al., Granulocyte Macrophage Colony Stimulating Factor (GMCSF), which elevates during HIV-1 infection within the CNS, reduces the proliferation of productively infected primary microglia by arresting them in the G1/M phages of the cell cycle at least in vitro (59). This study focuses on the preventive measures taken by the microglia to contain viral replication within the CNS.…”