Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro.
The proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) promote HIV type 1 viral replication in vitro. In the present studies, HIV production was increased in the macrophagic U1 cell line expressing the HIV genome after exposure to IL-1beta, osmotic stress, or surface adhesion, suggesting a confluence of signaling pathways for proinflammatory cytokines and cell stressors. The p38 mitogen-activated protein kinase (MAPK) mediates both cytokine and stress responses; thus the role of this kinase in HIV production was investigated. HIV production as measured by p24 antigen correlated with changes in the expression of a specific (non-alpha) isoform of p38 MAPK. In the presence of a specific p38 MAPK inhibitor (p38 inh), IL-1beta-induced HIV production was suppressed by more than 90% and IL-1beta-induced IL-8 production was suppressed completely, both with IC50 of 0.01 microM. p38 inhibition blocked cell-associated p24 antigen and secreted virus to a similar extent. The p38 inh also decreased constitutive HIV production in freshly infected peripheral blood mononuclear cells by up to 50% (P < 0.05). Interruption of p38 MAPK activity represents a viable target for inhibition of HIV.
Shapiro
L
L
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Heidenreich
K A
KA
Meintzer
M K
MK
Dinarello
C A
CA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases; D009997:Osmotic Pressure; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases
D016655:HIV Core Protein p24; D007375:Interleukin-1; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases