Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus.
The mechanisms regulating human immunodeficiency virus (HIV) persistence in human monocytes/macrophages are partially understood. Persistent HIV infection of U937 monocytic cells results in NF-kappa B activation. Whether virus-induced NF-kappa B activation is a mechanism that favors continuous viral replication in macrophages remains unknown. To further delineate the molecular mechanisms involved in the activation of NF-kappa B in HIV-infected monocytes and macrophages, we have focused on the regulation of the I kappa B molecules. First, we show that persistent HIV infection results in the activation of NF-kappa B not only in monocytic cells but also in macrophages. In HIV-infected cells, I kappa B alpha protein levels are decreased secondary to enhanced protein degradation. This parallels the increased I kappa B alpha synthesis secondary to increased I kappa B alpha gene transcription, i.e., increased RNA and transcriptional activity of its promoter-enhancer. Another protein with I kappa B function, p105, is also modified in HIV-infected cells: p105 and p50 steady-state protein levels are increased as a result of increased synthesis and proteolytic processing of p105. Transcriptional activity of p105 is also increased in infected cells and is also mediated by NF-kappa B through a specific kappa B motif. These results demonstrate the existence of a triple autoregulatory loop in monocytes and macrophages involving HIV, p105 and p50, and MAD3, with the end result of persistent NF-kappa B activation and viral persistence. Furthermore, persistent HIV infection of monocytes and macrophages provides a useful model with which to study concomitant modifications of different I kappa B molecules.
McElhinny
J A
JA
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
MacMorran
W S
WS
Bren
G D
GD
Ten
R M
RM
Israel
A
A
Paya
C V
CV
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000382:microbiology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000382:microbiology*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014158:Transcription, Genetic
D017931:DNA Primers; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D051841:Transcription Factor RelB