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.

Keywords:

• brain
• CD45
• cell cycle
• growth
• Ki67
• macrophages

The current address of Melissa Cosenza-Nashat is Department of Science, Borough of Manhattan Community College of the City University of New York, New York, USA.

The authors thank the Einstein Human Fetal Tissue Repository for fetal tissue and the Manhattan HIV Brain Bank (R24 MH59724) for autopsy tissue. This study was supported by R01 MH55477 and the Einstein Center for AIDS Research P30 AI51519. MCN and QS were in part supported by the Neuropathology Training Grant NS07098.