Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism

Fakioglu, Esra; Wilson, Sarah S.; Mesquita, Pedro M. M.; Hazrati, Ehsan; Cheshenko, Natalia; Blaho, John A.; Herold, Betsy C.

doi:10.1128/jvi.00603-08

Cited by 72 publications

(86 citation statements)

References 55 publications

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“…UV inactivation prevents viral gene expression (including GFP expression; Fig. 1E) after viral entry (19). Exposure to UV-inactivated virus induced a modest, but significant increase in CD83 expression relative to mock-treated cells (48.5% versus 25.5%) (P ϭ 0.05) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…All viral stocks were stored at Ϫ80°C. Virus was inactivated by exposure to UV light at a distance of 10 cm from the light source for 7 min (19). Recombinant influenza virus bearing hemagglutinin and neuraminidase from the strain A/Brisbane/ 59/2007 (the CDC-recommended vaccine strain for the 2008/2009 and 2009/2010 seasons) and the rest of the genomic segments from A/Puerto Rico/08/1934 (BB.PR8) was kindly provided by Adolfo Garcia-Sastre.…”

Section: Methodsmentioning

confidence: 99%

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Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy

Stefanidou

Ramos

Casullo

et al. 2013

J Virol

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bHerpes simplex virus 2 (HSV-2) may cause frequent recurrences, highlighting its ability to evade host defense. This study tested the hypothesis that HSV-2 interferes with dendritic cell (DC) function as an escape mechanism, which may contribute to enhanced HIV replication in coinfected populations. Immature monocyte-derived human DCs were exposed to live or UV-inactivated HSV-2 or lipopolysaccharide. Little or no increase in the maturation marker CD83 was observed in response to HSV-2 and HSV-2 exposed DCs were impaired in their ability to present antigen (influenza) to T cells. Exposure to UV-inactivated virus stimulated a modest, but significant increase in CD83, suggesting that viral gene expression contributes to the block in DC maturation. The functional impairment of HSV-2-exposed DCs could be partially attributed to the induction of apoptosis. Live and inactivated HSV-2 triggered an increase in the number of early and late apoptotic cells in both the infected and bystander cell populations; apoptosis was associated with a decrease in cellular FLICE-inhibitory protein (c-FLIP). Paradoxically, HSV-2 induced Akt phosphorylation, which typically promotes DC maturation and survival. Despite these aberrant responses, live and inactivated HSV-2 induced the release of cytokines into culture supernatants, which were sufficient to activate HIV-1 replication in latently infected U1 cells. Together, these findings suggest that in the presence of overt or subclinical HSV-2, the function of mucosal DCs would be impaired. These responses may allow HSV to escape immune surveillance but may also promote HIV infection and contribute to the epidemiological link between HIV and HSV.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy

Stefanidou

Ramos

Casullo

et al. 2013

J Virol

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“…Although neuronal and immune cells can be infected, epithelial cells and keratinocytes are the primary HSV-2 target cells (5). It has been well documented from epidemiological studies that HSV-2 infection increases the risk of HIV-1 acquisition and transmission (6)(7)(8)(9). Several mechanisms for this increased susceptibility have been proposed.…”

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confidence: 99%

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

Huang

Luo

et al. 2012

The Journal of Immunology

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Recruitment of CD4+ T cells to infection areas after HSV-2 infection may be one of the mechanisms that account for increased HIV-1 sexual transmission. Lymphocytes recruited by chemokine CXCL9 are known to be important in control of HSV-2 infection in mice, although the underlying mechanism remains to be addressed. Based on our observation that CXCL9 expression is augmented in the cervical mucus of HSV-2–positive women, in this study we demonstrate that HSV-2 infection directly induces CXCL9 expression in primary cervical epithelial cells and cell lines, the principal targets of HSV-2, at both mRNA and protein levels. Further studies reveal that the induction of CXCL9 expression by HSV-2 is dependent upon a binding site for C/EBP-β within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-β via p38 MAPK pathway, leading to binding of C/EBP-β to the CXCL9 promoter. Chemotaxis assays indicate that upregulation of CXCL9 expression at the protein level by HSV-2 infection enhances the migration of PBLs and CD4+ T cells, whereas neutralization of CXCL9 or inhibition of p38-C/EBP-β pathway can significantly decrease the migration. Our data together demonstrate that HSV-2 induces CXCL9 expression in human cervical epithelial cells by activation of p38-C/EBP-β pathway through promoting the binding of C/EBP-β to CXCL9 promoter, which may recruit activated CD4+ T cells to mucosal HSV-2 infection sites and potentially increase the risk of HIV-1 sexual transmission.

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“…Interestingly, a similar downregulatory evasion strategy was described for the papillomavirus protein E6 and Tr expression (71), as well as for HSV-2 and SLPI expression due to viral earlygene expression (47) and for HSV-2 and type I IFNs due to the expression of the HSV-2 virion host shutoff (Vhs) protein (58,72). The latter two studies support our earlier findings showing that Vhs, in a dose-dependent way, inhibited innate immune sensing, IRF3 activation, and IFN-␤ expression in human vaginal ECs (73).…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Trappin-2 and Elafin In Vitro and In Vivo against Genital Herpes

Drannik

Nag

Sallenave

et al. 2013

J Virol

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Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism

Cited by 72 publications

References 55 publications

Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy

Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

Antiviral Activity of Trappin-2 and Elafin In Vitro and In Vivo against Genital Herpes

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