Robust expression of TNF-alpha, IL-1 beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus

Cytokine (TNF-alpha/beta, IL-1 beta, IL-6, IL-18, IL-10, and IFN-alpha/beta /gamma) and chemokine (IL-8, IP-10, MCP-1, MIP-1 alpha/beta, and RANTES) pr oduction during herpes simplex virus (HSV) 1 infection of human brain cells was examined. Primary astrocytes as well as neurons were found to support HSV replication, but neither of these fully permissive cell types produced cytokines or chemokines in response to HSV. In contrast, microglia did not support extensive viral replication; however, ICP4 was detected by immunoch emical staining, demonstrating these cells were infected. Late viral protei n (nucleocapsid antigen) was detected in < 10% of infected microglial cells . Microglia responded to nonpermissive viral infection by producing conside rable amounts of TNF-alpha, IL-1 beta, IP-10, and RANTES, together with sma ller amounts of IL-6, IL-8, and MIP-1 alpha as detected by RPA and ELISA. S urprisingly, no interferons (alpha, beta, or gamma) were detected in respon se to viral infection. Pretreatment of fully permissive astrocytes with TNF -alpha prior to infection with HSV was found to dramatically inhibit replic ation, resulting in a 14-fold reduction of viral titer. In contrast, pretre atment of astrocytes with IL-1 beta had little effect on viral replication. When added to neuronal cultures, exogenous TNF-alpha or IL-1 beta did not suppress subsequent HSV replication. Exogenously added IP-10 inhibited HSV replication in neurons (with a 32-fold reduction in viral titer), however, similar IP-10 treatment did not affect viral replication in astrocytes. The se results suggest that IP-10 possesses direct antiviral activity in neuron s and support a role for microglia in both antiviral defense of the brain a s well as amplification of immune responses during neuroinflammation.