Inhibition of cytokine-driven human immunodeficiency virus type 1 replication by protease inhibitor

Protease inhibitors block virus maturation and prevent the spread of human immunodeficiency virus (HIV)-1 in vitro, HIV-l-positive persons produce higher levels of proinflammatory cytokines that up-regulate HIV-1 replication. For the protease inhibitor to be effective in vivo, it must be able to suppress cytokine-induced HIV-1 replication. The in vitro efficacy of protease inhibitor to block tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1 alpha, and IL-1 beta induction of HIV-1 was investigated. While 100 U/mL of the respective cytokines induced a 208- to 22-fold increase in HIV-1 p24 production, addition of protease inhibitor completely inhibited this virus induction. The kinetics indicated a sustained HIV-1 inhibition despite high levels of endogenous TNF-alpha induction, Dilution of protease inhibitor led to increased HIV-1 replication. These results show that while protease inhibitor can prevent cytokine induction of HIV-1 replication, a continual effective dose is required for the inhibition to be sustained.