Virus reactivation is driven by inflammatory monocytes that are controlled by T cells (VIR9P.1163)

Abstract

Abstract The current dogma is that episodes of transient immunodeficiency triggered by various stressors reactivate herpesviruses that are ubiquitous in the human population. We established a novel model of Herpes simplex virus 1 (HSV) latency in immunodeficient B6.Rag mice inoculated with either a low (LD) or high dose (HD) inoculum by using IVIG and acyclovir to suppress virus replication and promote latency. Remarkably, heat stress induced in vivo reactivation (IVR) of latent HD-Rag mice resulted in uncontrolled HSV replication and fatal encephalitis (HSE) in all mice compared to transient reactivation in LD-Rag mice that all survived. The major difference between the two groups was the massive invasion of inflammatory Ly6Chigh monocytes (IM) into the brainstem (BS) of latent HD-Rag but not LD-Rag mice. T cell transfer prevented IVR induced fatal HSE in HD-Rag recipients by reducing inflammation, especially IM invasion of the BS. Surprisingly, IVR of lethally irradiated latent HD-Rag and wildtype B6 mice induced only transient reactivation resulting in 100% survival; notably, IM were absent in the BS of these mice. Thus, counter intuitively, our data show that IM resident at sites of latency promote rather than suppress HSV reactivation and by modulating IM invasion into the BS, T cells control virus reactivation. This is a novel finding with important clinical implications, especially for treatment of neonates and immunosuppressed cancer patients undergoing transplant therapy.