TY - JOUR
T1 - Genital Herpes simplex virus Type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease
AU - Nixon, Briana
AU - Fakioglu, Esra
AU - Stefanidou, Martha
AU - Wang, Yanhua
AU - Dutta, Monica
AU - Goldstein, Harris
AU - Herold, Betsy C.
N1 - Funding Information:
Financial support. This work was supported by the National Institutes of Health (NIH; grants R01AI065309, U19AI067980, and R01DA033788) and the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center (NIH grant AI-51519). Potential conflicts of interest. All authors: No reported conflicts.
PY - 2014/2/15
Y1 - 2014/2/15
N2 - Background. Epidemiological studies consistently demonstrate synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1). Higher HIV-1 loads are observed in coinfected individuals, and conversely, HIV-1 is associated with more-severe herpetic disease. A small animal model of coinfection would facilitate identification of the biological mechanisms underlying this synergy and provide the opportunity to evaluate interventions.Methods. Mice transgenic for HIV-1 provirus and human cyclin T1 under the control of a CD4 promoter (JR-CSF/hu-cycT1) were intravaginally infected with HSV-2 and evaluated for disease progression, HIV shedding, and mucosal immune responses.Results. HSV-2 infection resulted in higher vaginal HIV loads and genital tissue expression of HIV RNA, compared with HSV-uninfected JR-CSF/hu-cycT1 mice. There was an increase in genital tract inflammatory cells, cytokines, chemokines, and interferons in response to HSV-2, although the kinetics of the response were delayed in HIV-transgenic, compared with control mice. Moreover, the JR-CSF/hu-cycT1 mice exhibited earlier and more-severe neurological disease. The latter was associated with downregulation of secretory leukocyte protease inhibitor expression in neuronal tissue, a molecule with antiinflammatory, antiviral, and neuroprotective properties.Conclusions. JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease.
AB - Background. Epidemiological studies consistently demonstrate synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1). Higher HIV-1 loads are observed in coinfected individuals, and conversely, HIV-1 is associated with more-severe herpetic disease. A small animal model of coinfection would facilitate identification of the biological mechanisms underlying this synergy and provide the opportunity to evaluate interventions.Methods. Mice transgenic for HIV-1 provirus and human cyclin T1 under the control of a CD4 promoter (JR-CSF/hu-cycT1) were intravaginally infected with HSV-2 and evaluated for disease progression, HIV shedding, and mucosal immune responses.Results. HSV-2 infection resulted in higher vaginal HIV loads and genital tissue expression of HIV RNA, compared with HSV-uninfected JR-CSF/hu-cycT1 mice. There was an increase in genital tract inflammatory cells, cytokines, chemokines, and interferons in response to HSV-2, although the kinetics of the response were delayed in HIV-transgenic, compared with control mice. Moreover, the JR-CSF/hu-cycT1 mice exhibited earlier and more-severe neurological disease. The latter was associated with downregulation of secretory leukocyte protease inhibitor expression in neuronal tissue, a molecule with antiinflammatory, antiviral, and neuroprotective properties.Conclusions. JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease.
KW - coinfection
KW - female genital tract
KW - herpes simplex virus-2
KW - human immunodeficiency virus-1
KW - mouse model
KW - sexually transmitted infections
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U2 - 10.1093/infdis/jit472
DO - 10.1093/infdis/jit472
M3 - Article
C2 - 23990571
AN - SCOPUS:84893305227
SN - 0022-1899
VL - 209
SP - 510
EP - 522
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 4
ER -