Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors.
CD4+ macrophages in tissues such as lung, skin, and lymph nodes, promyelocytic cells in bone marrow, and peripheral blood monocytes serve as important targets and reservoirs for human immunodeficiency virus type 1 (HIV-1) replication. HIV-1-infected myeloid cells are often diminished in their ability to participate in chemotaxis, phagocytosis, and intracellular killing. HIV-1 infection of myeloid cells can lead to the expression of surface receptors associated with cellular activation and/or differentiation that increase the responsiveness of these cells to cytokines secreted by neighboring cells as well as to bacteria or other pathogens. Enhancement of HIV-1 replication is related in part to increased DNA-binding activity of cellular transcription factors such as NF-kappa B. NF-kappa B binds to the HIV-1 enhancer region of the long terminal repeat and contributes to the inducibility of HIV-1 gene expression in response to multiple activating agents. Phosphorylation and degradation of the cytoplasmic inhibitor I kappa B alpha are crucial regulatory events in the activation of NF-kappa B DNA-binding activity. Both N- and C-terminal residues of I kappa B alpha are required for inducer-mediated degradation. Chronic HIV-1 infection of myeloid cells leads to constitutive NF-kappa B DNA-binding activity and provides an intranuclear environment capable of perpetuating HIV-1 replication. Increased intracellular stores of latent NF-kappa B may also result in rapid inducibility of NF-kappa B-dependent cytokine gene expression. In response to secondary pathogenic infections or antigenic challenge, cytokine gene expression is rapidly induced, enhanced, and sustained over prolonged periods in HIV-1-infected myeloid cells compared with uninfected cells. Elevated levels of several inflammatory cytokines have been detected in the sera of HIV-1-infected individuals. Secretion of myeloid cell-derived cytokines may both increase virus production and contribute to AIDS-associated disorders.
Roulston
A
A
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Lin
R
R
Beauparlant
P
P
Wainberg
M A
MA
Hiscott
J
J
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D015696:Gene Products, tat / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000503:physiopathology / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007962:Leukocytes / Q000502:physiology* / Q000821:virology; D008264:Macrophages / Q000502:physiology* / Q000821:virology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D014158:Transcription, Genetic / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D015696:Gene Products, tat; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus