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,
*
Department of Pathology, University of Illinois, Chicago, IL 60154; Departments of
Ophthalmology and
Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
§
Department of Cell Biology and Immunology, Free University, Amsterdam, The Netherlands; and
¶
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
After corneal infection, herpes simplex virus type 1 (HSV-1)
invades sensory neurons with cell bodies in the trigeminal ganglion
(TG), replicates briefly, and then establishes a latent infection in
these neurons. HSV-1 replication 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 
TCR+ T
lymphocytes infiltrate the TG, and TNF-
, IFN-, the inducible
nitric oxide synthase (iNOS) enzyme, and IL-12 are expressed. TNF-,
IFN-, and the iNOS product nitric oxide (NO) all inhibit HSV-1
replication in vitro. Macrophage and TCR+ T cell
depletion studies demonstrated that macrophages are the main source of
TNF- and iNOS, whereas TCR+ T cells produce
IFN-. Macrophage depletion, aminoguanidine inhibition of iNOS, and
neutralization of TNF- or IFN- all individually and
synergistically increased HSV-1 titers in the TG after HSV-1 corneal
infection. Moreover, individually depleting macrophages or neutralizing
TNF- or IFN- markedly reduced the accumulation of both
macrophages and TCR+ T cells in the TG. Our findings
establish that after primary HSV-1 infection, the bulk of virus
replication in the sensory ganglia is controlled by macrophages and
TCR+ T lymphocytes through their production of
antiviral molecules TNF-, NO, and IFN-. Our findings also
strongly suggest that cross-regulation between these two cell types is
necessary for their accumulation and function in the infected
TG.
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