ROLE OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE IN HIV TYPE-1 PRODUCTIONIN-VITRO

The proinflammatory cytokines interleukin (LL)-1 and tumor necrosis fa ctor (TNF) promote HIV type 1 viral replication in vitro. In the prese nt studies, HIV production was increased in the macrophagic U1 cell li ne expressing the HIV genome after exposure to IL-1 beta, osmotic stre ss, or surface adhesion, suggesting a confluence of signaling pathways for proinflammatory cytokines and cell stressors. The p38 mitogen-act ivated protein kinase (MAPK) mediates both cytokine and stress respons es; thus the role of this kinase in HIV production was investigated. H IV production as measured by p24 antigen correlated with changes in th e expression of a specific (non-alpha) isoform of p38 MAPK. In the pre sence of a specific p38 MAPK inhibitor (p38 inh), IL-1 beta-induced HI V production was suppressed by more than 90% and IL-1 beta-induced IL- 8 production was suppressed completely, both with IC50 of 0.01 mu M. p 38 inhibition blocked cell-associated p24 antigen and secreted virus t o a similar extent. The p38 inh also decreased constitutive HIV produc tion in freshly infected peripheral blood mononuclear cells by up to 5 0% (P < 0.05:. Interruption of p38 MAPK activity represents a viable t arget for inhibition of HIV.