HIV-1 induces complement factor C3 synthesis in astrocytes and neurons by modulation of promoter activity.
Virus-induced complement expression and activation in the brain is hypothesized to contribute to the process of neurodegeneration in AIDS-associated neurological disorders. Previous experiments have shown that the human immunodeficiency virus (HIV) upregulates the low basal production of complement factor C3 in astrocytes and neurons. Since inhibition of complement synthesis and activation in the brain may represent a putative therapeutic goal to prevent virus-induced damage, we analysed the mechanism of the HIV-induced modulation of C3 expression. Detailed studies using different C3 promoter constructs revealed that HIV activates the synthesis of C3 by stimulation of the promoter. This HIV-induced promoter activation could be measured both in different astrocytic cell lines and in neurons. Deletion constructs of the C3 promoter defined the IL-6/IL-1beta responsive element within the promoter region as a central element for the responsiveness of the C3 promoter towards the influence of HIV. A binding site for the transcription factor C/EBPdelta was identified as important regulatory domain within the IL-6/IL-1beta responsive element, since a point mutation which eliminates the binding capacity of C/EBPdelta to this site also abolishes the induction by HIV-1. Similarly, the viral proteins Nef and gp41 which had also been shown to stimulate the synthesis of C3, exert their effect via the IL-6/IL-1beta responsive element with binding of the transcription factor C/EBPdelta representing the critical step. Our experiments clearly define the mechanism for the induction of complement factors in the HIV-infected brain and reveal a decisive role of the regulator protein C/EBPdelta for the HIV-induced increase in C3 expression.
Bruder
Cornelia
C
Institute of Hygiene and Social Medicine, University of Innsbruck and Ludwig-Boltzmann-Institute for AIDS Research, Fritz-Pregl-Str. 3, A-6020, Innsbruck, Austria.
Hagleitner
Magdalena
M
Darlington
Gretchen
G
Mohsenipour
Iradj
I
Würzner
Reinhard
R
Höllmüller
Isolde
I
Stoiber
Heribert
H
Lass-Flörl
Cornelia
C
Dierich
Manfred P
MP
Speth
Cornelia
C
D001253:Astrocytes / Q000378:metabolism*; D001483:Base Sequence; D003176:Complement C3 / Q000096:biosynthesis* / Q000235:genetics; D015693:Gene Products, nef / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D054311:nef Gene Products, Human Immunodeficiency Virus
D003176:Complement C3; D015693:Gene Products, nef; D015700:HIV Envelope Protein gp41; D054311:nef Gene Products, Human Immunodeficiency Virus