Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system

After corneal infection, herpes simplex virus type 1 (HSV-1) invades sensor y neurons with cell bodies in the trigeminal ganglion (TG), replicates brie fly, and then establishes a latent infection in these neurons. HSV-1 replic ation in the TG can be detected as early as 2 days after corneal infection, reaches peak titers by 3-5 days after infection, and is undetectable by 7- 10 days. During the period of HSV-1 replication, macrophages and gamma delt a TCR+ T lymphocytes infiltrate the TG, and TNF-alpha, IFN-gamma, the induc ible nitric oxide synthase (iNOS) enzyme, and IL-12 are expressed. TNF-alph a, IFN-gamma, and the iNOS product nitric oxide (NO) all inhibit HSV-1 repl ication in vitro. Macrophage and gamma delta TCR+ T cell depletion studies demonstrated that macrophages are the main source of TNF-alpha and iNOS, wh ereas gamma delta TCR+ T cells produce IFN-gamma, Macrophage depletion, ami noguanidine inhibition of iNOS, and neutralization of TNF-alpha or IFN-gamm a all individually and synergistically increased HSV-1 titers in the TG aft er HSV-1 corneal infection. Moreover, individually depleting macrophages or neutralizing TNF-alpha or IFN-gamma markedly reduced the accumulation of b oth macrophages and gamma delta TCR+ T cells in the TG, Our findings establ ish that after primary HSV-1 infection, the bulk of virus replication in th e sensory ganglia is controlled by macrophages and gamma delta TCR+ T lymph ocytes through their production of antiviral molecules TNF-alpha, NO, and I FN-gamma. Our findings also strongly suggest that cross-regulation between these two cell types is necessary for their accumulation and function in th e infected TG.