title: Establishment of HSV1 latency in immunodeficient mice facilitates efficient in vivo reactivation.
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.
authors.affiliation: Department of Virology, Beckman Research Institute of City of Hope; Duarte, California, United States of America.
authors.forename: Chandran
authors.initials: C
authors.lastname: Ramakrishna
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Ferraioli
authors.affiliation: Centre de Génétique et Physiologie Moléculaire et Cellulaire CNRS UMR5534, Université de Lyon 1, Lyon, France; Université de Lyon 1, Lyon, France; Laboratoire d'excellence, LabEX DEVweCAN, Lyon, France.
authors.forename: Aleth
authors.initials: A
authors.lastname: Calle
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Thanh K
authors.initials: TK
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, Beckman Research Institute of City of Hope; Duarte, California, United States of America.
authors.forename: Harry
authors.initials: H
authors.lastname: Openshaw
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Patric S
authors.initials: PS
authors.lastname: Lundberg
authors.affiliation: Centre de Génétique et Physiologie Moléculaire et Cellulaire CNRS UMR5534, Université de Lyon 1, Lyon, France; Université de Lyon 1, Lyon, France; Laboratoire d'excellence, LabEX DEVweCAN, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lomonte
authors.affiliation: Department of Virology, Beckman Research Institute of City of Hope; Duarte, California, United States of America; Department of Neurology, Beckman Research Institute of City of Hope; Duarte, California, United States of America; Department of Immunology, Beckman Research Institute of City of Hope; Duarte, California, United States of America.
authors.forename: Edouard M
authors.initials: EM
authors.lastname: Cantin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000276:immunology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000821:virology*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*