Abstract
The establishment of latent infections in sensory neurons is a remarkably effective immune evasion strategy that accounts for the widespread dissemination of life long Herpes Simplex Virus type 1 (HSV1) infections in humans. Periodic reactivation of latent virus results in asymptomatic shedding and transmission of HSV1 or recurrent disease that is usually mild but can be severe. An in-depth understanding of the mechanisms regulating the maintenance of latency and reactivation are essential for developing new approaches to block reactivation. However, the lack of a reliable mouse model that supports efficient in vivo reactivation (IVR) resulting in production of infectious HSV1 and/or disease has hampered progress. Since HSV1 reactivation is enhanced in immunosuppressed hosts, we exploited the antiviral and immunomodulatory activities of IVIG (intravenous immunoglobulins) to promote survival of latently infected immunodeficient Rag mice. Latently infected Rag mice derived by high dose (HD), but not low dose (LD), HSV1 inoculation exhibited spontaneous reactivation. Following hyperthermia stress (HS), the majority of HD inoculated mice developed HSV1 encephalitis (HSE) rapidly and synchronously, whereas for LD inoculated mice reactivated HSV1 persisted only transiently in trigeminal ganglia (Tg). T cells, but not B cells, were required to suppress spontaneous reactivation in HD inoculated latently infected mice. Transfer of HSV1 memory but not OVA specific or naïve T cells prior to HS blocked IVR, revealing the utility of this powerful Rag latency model for studying immune mechanisms involved in control of reactivation. Crossing Rag mice to various knockout strains and infecting them with wild type or mutant HSV1 strains is expected to provide novel insights into the role of specific cellular and viral genes in reactivation, thereby facilitating identification of new targets with the potential to block reactivation.
Highlights
Herpes simplex virus type 1 and 2 (HSV1 and HSV2) have colonized roughly 90% and 45% the of US population respectively and are important constituents of the human virome
We established a threshold inoculum dose that was higher for B6- compared to 129-Rag mice, which determined whether Herpes Simplex Virus type 1 (HSV1) could be efficiently reactivated in vivo resulting in encephalitis
We showed directly that memory T cells are required to control spontaneous and induced reactivation in mice inoculated at high dose but are dispensable for maintaining latency in low dose inoculated mice
Summary
Herpes simplex virus type 1 and 2 (HSV1 and HSV2) have colonized roughly 90% and 45% the of US population respectively and are important constituents of the human virome. But often asymptomatic, reactivation events result in virus shedding in bodily fluids, which promotes further dissemination of infection in the population. Reactivated HSV1 is the cause of much human suffering and several diseases including most frequently recurrent oral infections and eye infections, that are a major cause of blindness in the USA. A recent epidemiological study suggests that HSV1 has replaced HSV2 as the most common cause of genital infections [6]. Though less likely to recur, genital HSV-1 is a significant cause of serious neonatal infections including encephalitis, which may well increase in the future
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