Spread Of HSV-2 Research Articles

IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection.

HSV-2 is a neurotropic virus that causes a persistent, lifelong infection that increases risk for other sexually transmitted infections. The vaginal epithelium is the first line of defense against HSV-2 and coordinates the immune response through the secretion of immune mediators, including the proinflammatory cytokine IL-36γ. Previously, we showed that IL-36γ treatment promoted transient polymorphonuclear cell infiltration to the vaginal cavity and protected against lethal HSV-2 challenge. In this report, we reveal that IL-36γ specifically induces transient neutrophil infiltration but does not impact monocyte and macrophage recruitment. Using IL-36γ-/- mice in a lethal HSV-2 challenge model, we show that neutrophil counts are significantly reduced at 1 and 2 d postinfection and that KC-mediated mature neutrophil recruitment is impaired in IL-36γ-/- mice. Additionally, IL-36γ-/- mice develop genital disease more rapidly, have significantly reduced survival time, and exhibit an increased incidence of hind limb paralysis that is linked to productive HSV-2 infection in the brain stem. IL-36γ-/- mice also exhibit a significant delay in clearance of the virus from the vaginal epithelium and a more rapid spread of HSV-2 to the spinal cord, bladder, and colon. We further show that the decreased survival time and increased virus spread observed in IL-36γ-/- mice are not neutrophil-dependent, suggesting that IL-36γ may function to limit HSV-2 spread in the nervous system. Ultimately, we demonstrate that IL-36γ is a key regulator of neutrophil recruitment in the vaginal microenvironment and may function to limit HSV-2 neuroinvasion.

HSV-2 glycoprotein gD targets the CC domain of tetherin and promotes tetherin degradation via lysosomal pathway.

BackgroundHSV-2 is the major cause of genital herpes. We previously demonstrated that the host viral restriction factor tetherin restricts HSV-2 release and is antagonized by several HSV-2 glycoproteins. However, the mechanisms underlying HSV-2 glycoproteins mediated counteraction of tetherin remain unclear. In this study, we investigated whether tetherin restricts the cell-to-cell spread of HSV-2 and the mechanisms underlying HSV-2 gD mediated antagonism of tetherin.MethodsInfectious center assays were used to test whether tetherin could affect cell-to-cell spread of HSV-2. Coimmunoprecipitation assays were performed to map the tetherin domains required for HSV-2 gD-mediated downregulation. Immunoflurence assays were performed to detect the accumulation of tetherin in lysosomes or proteasomes. All experiments were repeated for at least three times and the data were performed statistical analysis.Results1) Tetherin restricts cell-to-cell spread of HSV-2; 2) HSV-2 gD specifically interacts with the CC domain of tetherin; 3) HSV-2 gD promotes tetherin to the lysosomal degradation pathway.ConclusionsTetherin not only restricts HSV-2 release but also its cell-to-cell spread. In turn, HSV-2 gD targets the CC domain of tetherin and promotes its degradation in the lysosome. Findings in this study have increased our understanding of tetherin restriction and viral countermeasures.

Modelling the effects of sexting on the transmission dynamics of HSV-2 amongst adolescents

Prior studies have indicated that adolescents who are into sexting are likely to engage in risky sexual behaviours. In this paper, a mathematical model to assess the impact of sexting and peer influence on the spread of HSV-2 amongst adolescents is developed. The threshold parameters of the model are determined and stabilities are analysed. The impact of filtering and awareness campaigns is explored. Results from the study suggest that HSV-2 prevalence is high amongst adolescents who are into sexting as compared to those who do not. Further, we applied optimal control theory to the proposed model. The controls represent filtering and awareness campaigns. The objective is based on minimising the susceptible sexting adolescents, infected non-sexting adolescents and the infected sexting adolescents. The optimal control is characterised and numerically solved. Overall, the application of optimal control theory suggests that more effort should be devoted to both controls, filtering and awareness campaigns.

HSV-2 and Substance Abuse amongst Adolescents: Insights through Mathematical Modelling

Herpes simplex virus infection is mostly spread and occurs more commonly among substance abusing adolescents as compared to the nonsubstance abusing. In this paper, a mathematical model for the spread of HSV-2 within a community with substance abusing adolescents is developed and analysed. The impacts of condom use and educational campaigns are examined. The study suggests that condom use is highly effective among adolescents, when we have more of them quitting than becoming substance abusers. Measures such as educational campaigns can be put in place to try and reduce adolescents from becoming substance abusers. Further, we applied optimal control theory to the proposed model. The controls represent condom use and educational campaigns. The objective is based on maximising the susceptible nonsubstance abusing adolescents, while minimising the susceptible substance abusing adolescents, the infectious nonsubstance abusing adolescents, and the infectious substance abusing adolescents. We used Pontrygin’s maximum principle to characterise the optimal levels of the two controls. The resulting optimality system is solved numerically. Overall, the application of the optimal control theory suggests that more effort should be devoted to condom use as compared to educational campaigns.

Herpesvirus Entry Mediator and Nectin-1 Mediate Herpes Simplex Virus 1 Infection of the Murine Cornea

Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that enters cells by the receptor-mediated fusion of the viral envelope with a host cell membrane. The envelope glycoprotein gD of HSV must bind to one of its receptors for entry to take place. Recent studies using knockout (KO) mice demonstrated that the gD receptors herpesvirus entry mediator (HVEM) and nectin-1 are the primary entry receptors for HSV-2 in the mouse vagina and brain. Nectin-1 was most crucial for the neuronal spread of HSV-2, particularly in the brain. HVEM was dispensable for infection in these models, but when both HVEM and nectin-1 were absent, infection was completely prevented. We sought to determine the receptor requirements of HSV-1 in an ocular model of infection using knockout mice. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double-KO mice were infected via corneal scarification and monitored for clinical signs of infection and viral replication in various tissues. We report that either HVEM or nectin-1 must be present for HSV-1 infection of the cornea. Additionally, we observed that the infection was attenuated in both HVEM KO and nectin-1 KO mice. This is in contrast to what was reported for studies of HSV-2 in vagina and brain and suggests that receptor requirements for HSV vary depending on the route of inoculation and/or serotype.

The adjuvant CLDC increases protection of a herpes simplex type 2 glycoprotein D vaccine in guinea pigs

Herpes simplex virus (HSV) infections are common but there is no vaccine available. We evaluated cationic liposome–DNA complexes (CLDC) as an adjuvant for an HSV gD2 vaccine and compared it to an MPL/Alum adjuvant in a guinea pig model of genital herpes. The addition of CLDC to the gD2 vaccine significantly decreased acute and recurrent disease and most importantly the number of days with recurrent virus shedding compared to gD2 alone. Reductions in these outcomes were also detected when gD2+CLDC was compared to gD2+MPL/Alum. When the vaccine and adjuvants were evaluated as therapeutic vaccines, they were ineffective. CLDC enhanced protection compared to MPL/Alum and is the first vaccine to reduce recurrent virus shedding, a key to decreasing the spread of HSV-2.

Inhibition of Herpes Simplex Virus Types 1 and 2 In Vitro Infection by Sulfated Derivatives of Escherichia coli K5 Polysaccharide

Herpes simplex virus type 1 (HSV-1) and HSV-2 are neurotropic viruses and common human pathogens causing major public health problems such as genital herpes, a sexually transmitted disease also correlated with increased transmission and replication of human immunodeficiency virus type 1 (HIV-1). Therefore, compounds capable of blocking HIV-1, HSV-1, and HSV-2 transmission represent candidate microbicides with a potential added value over that of molecules acting selectively against either infection. We report here that sulfated derivatives of the Escherichia coli K5 polysaccharide, structurally highly similar to heparin and previously shown to inhibit HIV-1 entry and replication in vitro, also exert suppressive activities against both HSV-1 and HSV-2 infections. In particular, the N,O-sulfated [K5-N,OS(H)] and O-sulfated epimerized [Epi-K5-OS(H)] forms inhibited the infection of Vero cells by HSV-1 and -2, with 50% inhibitory concentrations (IC(50)) between 3 +/- 0.05 and 48 +/- 27 nM, and were not toxic to the cells at concentrations as high as 5 muM. These compounds impaired the early steps of HSV-1 and HSV-2 virion attachment and entry into host cells and reduced the cell-to-cell spread of HSV-2. Since K5-N,OS(H) and Epi-K5-OS(H) also inhibit HIV-1 infection, they may represent valid candidates for development as topical microbicides preventing sexual transmission of HIV-1, HSV-1, and HSV-2.

Growth of herpes simplex virus in epidermal keratinocytes determines cutaneous pathogenicity in mice

Herpes simplex viruses (HSV)-1 and -2 isolated from genital lesions were examined for cutaneous pathogenicity and its correlation with cellular tropism. HSV-1 caused vesiculation, erosion/ulcer, and zosteriform lesions successively, but skin lesions of HSV-2 developed without vesiculation in some mice, and with statistically significantly less frequent vesiculation than HSV-1. Thus, the virological type of HSV was correlated with its cutaneous pathogenicity. The growth characteristics of HSV-1 and -2 were compared in cultured human embryonic lung (HEL) fibroblasts, human lung cancer A549 cells, human neonatal epidermal keratinocytes, human neonatal dermal fibroblasts, HeLa cells, and Vero cells. HSV-2 produced plaques that were 72% times the size of HSV-1 plaques in epidermal keratinocytes but 230%-500% the size in the other cells. The difference between HSV-1 and -2 in the ratio of plaque size to virus yield in epidermal keratinocytes was much larger (502 times) than the ratio of the other cells (5.57-28.8 times). Keratinocytes are the major constituent of the epidermal layer of the skin and the cells in which vesiculation and erosion/ulceration occur histologically. Therefore, the smaller spread of HSV-2 in keratinocytes of the epidermal layer and the greater spread in other cells of the dermal layer might reflect its lesser invasiveness in the epidermal layer despite larger invasiveness in the dermal layer, which is reflected in the low incidence of erosion/ulcer of the skin compared to HSV-1. Thus, the growth of HSV in epidermal keratinocytes appeared to correlate with the cutaneous pathogenicity causing vesiculation in the skin.

Seroprevalence of sexually transmitted viruses in Korean populations including HIV-seropositive individuals.

In order to investigate the prevalence of sexually transmitted viruses (STVs) in Korean populations, the prevalence of specific antibodies to herpes simplex type 2 (HSV-2) and hepatitis C virus (HCV) and surface antigen to hepatitis B virus (HBsAg) was evaluated in blood donors (n = 200), voluntary visitors for STI testing in public health centre (n = 204), HIV seropositive individuals (n = 200) and commercial sex workers (CSWs) (n = 200). All blood samples were tested using commercial enzyme-linked immunosorbent assay (ELISA) kits that detect type-specific IgG to HSV-2 and HBsAg and anti-HCV. The prevalence of type-specific IgG to HSV-2 among the above four groups was 5.0%, 21.9%, 65.0% and 71.0%, respectively. The seroprevalence of HBsAg was 0% in blood donors, 7.0% of visitors for STI, 7.5% of HIV infected individuals and 1.2% in CSWs. That of anti-HCV was 0%, 2.5%, 5.0% and 10.3%, respectively. This study underlines the very high seroprevalence of STVs, especially HSV-2, in the group at high risk of STI. The prevalences of HCV in CSWs and HIV infected individuals were two to three times higher than STI patients. It means sexual transmission might be a possible route of transmission of HCV, because HIV infection is closely related with sexual behaviour in Korea. The spread of HSV-2 is dependent on sexual transmission and that the presence of antibody to HSV-2 may be suitable for use as a serological marker of the degree at risk of STI.