Regulation of HIV-1 infection in astrocytes: expression of Nef, TNF-alpha and IL-6 is enhanced in coculture of astrocytes with macrophages.
'Restricted' human immunodeficiency virus type (HIV-1) infection of astrocytes is recognized in vivo in some pediatric and adult AIDS brains and in vitro in a small proportion of transfected primary fetal astrocytes. We investigated the extent of HIV-1JR-FL expression in fetal astrocytes and macrophages cultivated alone or together. Peak HIV-1 p24 antigen titres in supernatant fluids of macrophage cultures were increased with monocyte/macrophages from certain donors and were higher when macrophages were cocultivated with astrocytes. Structural HIV-1 gene (gp 41 and pol) products (protein and mRNA) were observed only in macrophages. Ten days after HIV-1JR-FL infection, astrocytes in a monoculture were stained negative or only weakly positive (1-2+) for Nef, whereas in a coculture up to 100% of astrocytes displayed Nef staining (up to 4+) in the cytoplasm. The streptavidine-biotine-peroxidase technique with certain monoclonal antibodies to Nef (Ovod et al, 1992) was specific for infected astrocytes. The intensity of Nef staining was higher in astrocytes cultivated with monocyte/macrophages from certain donors. In the coculture, tumor necrosis factor-alpha (TNF-alpha) was expressed in the astrocyte cytoplasm earlier after coinfection with HIV-1 and cytomegalovirus (CMV) compared to infection with HIV-1 alone. Interleukin-6 (IL-6) was secreted spontaneously and transiently in uninfected cocultures, but in a prolonged fashion following HIV-1 and HIV-1/CMV infections. The interactions between HIV-1- and CMV-infected macrophages and astrocytes lead to upregulation of TNF-alpha and IL-6 and enhancement of productive HIV-1 infection of macrophages and of 'restricted' HIV-1 infection of astrocytes with implications for the pathogenesis of AIDS dementia.
Fiala
M
M
Department of Neurology, UCLA School of Medicine 90024, USA.
Rhodes
R H
RH
Shapshak
P
P
Nagano
I
I
Martinez-Maza
O
O
Diagne
A
A
Baldwin
G
G
Graves
M
M
D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000821:virology*; D002478:Cells, Cultured / Q000737:chemistry / Q000821:virology; D003587:Cytomegalovirus / Q000378:metabolism; D004279:DNA, Viral / Q000032:analysis; D015693:Gene Products, nef / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D015693:Gene Products, nef; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus