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, pro myelocytic cells in bone marrow and peripheral blood monocytes serve a s important targets and reservoirs for human immunodeficiency virus ty pe 1 (HIV-1) replication. HIV-1-infected myeloid cells are often dimin ished in their ability to participate in chemotaxis, phagocytosis, and intracellular killing. HIV-1 infection of myeloid cells can lead to t he expression of surface receptors associated with cellular activation and/or differentiation that increase the responsiveness of these cell s 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 su ch 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 gen e expression in response to multiple activating agents. Phosphorylatio n and degradation of the cytoplasmic inhibitor I kappa B alpha are cru cial regulatory events in the activation of NF-kappa B DNA-binding act ivity. 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 provid es an intranuclear environment capable of perpetuating HIV-1 replicati on. Increased intracellular stores of latent NF-kappa B may also resul t in rapid inducibility of NF-kappa B-dependent cytokine gene expressi on. In response to secondary pathogenic infections or antigenic challe nge, cytokine gene expression is rapidly induced enhanced, and sustain ed over prolonged periods in HIV-1-infected myeloid cells compared wit h uninfected cells Elevated levels of several inflammatory cytokines h ave 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.