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Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques

Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host–HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. I...

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Autores principales: Lo, Ming, Zhu, Jia, Hansen, Scott G., Carroll, Timothy, Farr Zuend, Christina, Nöel-Romas, Laura, Ma, Zhong-Min, Fritts, Linda, Huang, Meei-Li, Sun, Sijie, Huang, Ying, Koelle, David M., Picker, Louis J., Burgener, Adam, Corey, Lawrence, Miller, Christopher J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321901/
https://www.ncbi.nlm.nih.gov/pubmed/30333177
http://dx.doi.org/10.1128/JVI.01574-18
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author Lo, Ming
Zhu, Jia
Hansen, Scott G.
Carroll, Timothy
Farr Zuend, Christina
Nöel-Romas, Laura
Ma, Zhong-Min
Fritts, Linda
Huang, Meei-Li
Sun, Sijie
Huang, Ying
Koelle, David M.
Picker, Louis J.
Burgener, Adam
Corey, Lawrence
Miller, Christopher J.
author_facet Lo, Ming
Zhu, Jia
Hansen, Scott G.
Carroll, Timothy
Farr Zuend, Christina
Nöel-Romas, Laura
Ma, Zhong-Min
Fritts, Linda
Huang, Meei-Li
Sun, Sijie
Huang, Ying
Koelle, David M.
Picker, Louis J.
Burgener, Adam
Corey, Lawrence
Miller, Christopher J.
author_sort Lo, Ming
collection PubMed
description Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host–HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 10(7) PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (10(2) to 10(3) DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation. IMPORTANCE Herpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation.
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spelling pubmed-63219012019-01-11 Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques Lo, Ming Zhu, Jia Hansen, Scott G. Carroll, Timothy Farr Zuend, Christina Nöel-Romas, Laura Ma, Zhong-Min Fritts, Linda Huang, Meei-Li Sun, Sijie Huang, Ying Koelle, David M. Picker, Louis J. Burgener, Adam Corey, Lawrence Miller, Christopher J. J Virol Pathogenesis and Immunity Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host–HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 10(7) PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (10(2) to 10(3) DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation. IMPORTANCE Herpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation. American Society for Microbiology 2019-01-04 /pmc/articles/PMC6321901/ /pubmed/30333177 http://dx.doi.org/10.1128/JVI.01574-18 Text en Copyright © 2019 Lo et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pathogenesis and Immunity
Lo, Ming
Zhu, Jia
Hansen, Scott G.
Carroll, Timothy
Farr Zuend, Christina
Nöel-Romas, Laura
Ma, Zhong-Min
Fritts, Linda
Huang, Meei-Li
Sun, Sijie
Huang, Ying
Koelle, David M.
Picker, Louis J.
Burgener, Adam
Corey, Lawrence
Miller, Christopher J.
Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title_full Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title_fullStr Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title_full_unstemmed Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title_short Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques
title_sort acute infection and subsequent subclinical reactivation of herpes simplex virus 2 after vaginal inoculation of rhesus macaques
topic Pathogenesis and Immunity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321901/
https://www.ncbi.nlm.nih.gov/pubmed/30333177
http://dx.doi.org/10.1128/JVI.01574-18
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