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Glycoproteins that exhibit strong immunological responses in patients with herpes infection are targets for diagnostic as well as therapeutic utility.
Bio-Rad has taken advantage of some minor antigenic variation in glycoprotein G (also referred as gG) between the two subtypes in order to develop type-specific polypeptide probes for detecting IgG antibodies to HSV-1 and HSV-2. If you are an educator at the high school or college level, visit our Education Discount Policy page to establish an education account number.
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Herpes simplex virus type 2 (HSV-2), a globally sexually transmitted virus, and also one of the main causes of genital ulcer diseases, increases susceptibility to HIV-1. Put simply, blood tests can show that you are positive for the antibodies, but they cannot show that you are negative for the virus itself. Antibodies are substances produced by your immune system to fight off infections or antigens (such as herpes).
This method of testing has the advantage that it can be done even when a person has no symptoms, so it is a very effective way to detect an established herpes presence. A number of similar tests are produced for research purposes and commercial products are gradually becoming more available. The HSV Western Blot detects HSV-1 and HSV-2 proteins which have been separated by size so that type-specific antibody profiles can be recognized with a specificity of >99% .
Centre of Disease Control guidelines stipulate that only type-specific serologies based on glycoprotein G be used.
The Herpes Simplex Envelope contains at least 11 glycoproteins that exhibit significant protein and DNA (50%) homology between the two herpes immunological variants, type 1 (HSV-1) and type 2 (HSV-2). This was achieved by constructing the HSV-1 specific recombinant antigen and HSV-2* specific synthetic peptide conjugated to BSA. To support this effort, the company has implemented a discount policy that allows high school and college teaching laboratories to purchase kits, instruments, reagents, and other equipment at preferred prices. Effective vaccines to prevent HSV-2 infection are not yet available, but are currently being developed. IntroductionHerpes simplex virus type 2 (HSV-2), a linear double-stranded DNA virus of the Herpesviridae family and a major cause of genital ulcer diseases, is transmitted by sexual contact or via the maternal-neonatal relationship. Route of ImmunizationWidely used routes of delivery for HSV-2 vaccines include subcutaneous, intramuscular, intraperitoneal, intranasal, intravaginal (IVAG), intradermal, ocular and intravenous delivery.
It is regarded as more precise than the (ELISA) and is sometimes used to check the validity of ELISA tests. If the herpes antibodies are found in the blood, it means that your body was exposed to the herpes simplex virus at some point in your life and created antibodies in response. Blood tests do not require swabbing a lesion, so they can be done long after symptoms have faded. This method may be used to distinguish maternal from infant antibody profiles and to distinguish serum and cerebrospinal fluid profiles of HSV antibodies. Even commercial, FDA-cleared tests like the HerpeSelect ELISA from Focus Diagnostics-Quest may have false positive results, especially in samples with low positive readings.
To facilitate this process, the latest progress in development of these vaccines is reviewed in this paper. Despite multiple measures adopted to control the diseases, this virus still infects at least 500 million people around the world [1]. Innate Immune Response: An Immediate Nonspecific ProtectionA powerful and robust immune response to HSV-2 requires both the innate immune response and the adaptive immune response. The route of immunization has an impact on the efficacy of HSV-2 vaccine via different immune responses at different sites. It is now recommended that clinicians avoid serology tests unless they are type-specific tests. This test has been exhaustively validated in studies of well-characterized patient populations.
A summary of the most promising HSV-2 vaccines tested in animals in the last five years is presented, including the main factors, and new ideas for developing an effective vaccine from animal experiments and human clinical trials. HSV-2 reaches a latent state in the sensory nerve root ganglia and reactivates when the immune function of the body declines, causing recurrent episodes (Figure 1) [2]. The combination of gD with HVEM triggers immediate innate immune response, which leads to subsequent adaptive immune response.


Most studies deal with adaptive immune response due to its function for viral clearance and generation of long-term memory. The different immune responses induced by immunization routes are determined by the unique nature of delivery sites.
It is the current gold standard HSV serology and provides a highly accurate confirmatory test for positive results by ELISA.
Experimental results indicate that future HSV-2 vaccines may depend on a strategy that targets mucosal immunity. However, some recent studies provide the findings that the innate immune response induces immediate nonspecific protection against HSV-2, indicating its important role in response to HSV-2 [25].The interaction between virus and innate immune cells initiates the innate immune response via pattern recognition receptors (PRR) that recognize pathogen-associated molecular patterns (PAMP) like viral DNA and RNA. As the findings of some studies indicate, when challenged IVAG with HSV-2 MS, mice immunized with gE2-del virus by the intramuscular route all survived, in contrast with a survival rate of 60% for the mice immunized subcutaneously [75]. Furthermore, estradiol, which increases the effectiveness of vaccines, may be considered as an adjuvant. The major PRRs, Toll-like receptors (TLR), are expressed by innate immune cells inclusive of mononuclear phagocytes, dendritic cells (DC) and NK T cells. In addition, no mice immunized intramuscularly contracted diseases while some of the mice immunized subcutaneously developed diseases [75]. Therefore, this review is expected to provide possible strategies for development of future HSV-2 vaccines.
The function of TLRs, such as TLR9 [26], TLR3 [27] and TLR2 [28], has been demonstrated to induce the immune response. These data provide evidence that the intramuscular route is better than the subcutaneous route when live attenuated HSV-2 vaccine is administered. The potential biological mechanisms by which HSV-2 increases risk of HIV-1 infection include disruption of the genital epithelium, recruiting activated target cells for HIV-1, decreasing innate mucosal immunity and inducing a mucosal inflammatory response [7].
In a recent study, ligand for TLR5 inhibited HSV-2 replication in genital epithelial cells, indicating that TLR5 may be associated with the immune response against HSV-2 [29]. However, as reported in another study, when the HSV-2 DNA vaccine encoding gD2 was injected via intramuscular or footpad route in mice, intramuscular immunization induced higher levels of antibody in sera, while footpad subcutaneous immunization triggered a higher HSV-specific cytotoxicity response [82]. HSV-2-infected monocyte-derived dendritic cells (moDCs) increase retinoic acid production and high ?4?7 expression on CD4+ T cell, which can be spotted by HIV-1 [8]. After viral recognition and TLR activation, immune cells produce type I interferon (IFN), resulting in the antiviral state. The reason is not fully understood why different routes of immunization lead to different types of response.Recently, mucosal immunity has become a preferred method due to its crucial role to prevent STIs. HSV-2 can also damage the protective function of mucosal Langerhans cells (LCs) through abrogating the function of langerin, which enhances the susceptibility of HIV-1 [9].The most effective and economical way to overcome HSV-2 is to develop a vaccine.
The antiviral state is achieved through the activation of RNA-dependent protein kinase (PKR) by the IFN-?1 transgene, which is a major pathway to induce the antiviral state [30]. With most STIs via mucosa such as HIV and HSV, the mucosa is the first line of defence [83]. With much work done towards this end, great progress has been made in the development of an HSV-2 vaccine in the past several decades [10]. The resultant antivirus state in the vagina can be regulated by four major antigen-presenting cell (APC) subsets including langerhans cells (LCs), CD14? lamina propria-dendritic cells (LP-DCs), CD14+ LP-DCs and macrophages polarize CD4+ T cells, which elicit Th1, Th2 and Th22 responses by inducing theexpression of migration receptors [31]. Thus, the mucosal delivery of vaccine not only imitates the natural process of virus infection, but also induces mucosal innate immune response, which shows the potential ability to develop an optimal vaccine.
Now, the mucosal route of HSV-2 vaccine immunization includes intranasal, intravaginal, ocular and oral delivery. In order to facilitate the discovery process of effective vaccines against HSV-2, this review analyzes the key factors of developing effective vaccines and the latest progress in HSV-2 vaccine under the categories of HSV-2 pathogenesis, immune response to HSV-2, vaccine formulation, route of immunization, adjuvant and influence of sex hormones. The ocular delivery of live attenuated virus (HSV-2 ICP0?) induced HSV-specific IgG antibody response and protected against later virus challenge [55].
However, the ocular immunization incurs the difficulty in controlling in humans, a problem that needs to be solved in the future. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. In contrast, the intranasal immunization, widely used in HSV-2 vaccine research, proved to be an effective method. Another alternative, the oral delivery of the vaccine, passes through mucosa of the stomach, small intestine and large intestine.


As a convenient, fast, and painless option, it is easily accepted by people, suggesting a bright future. Besides, rectal immunization of HSV-2 TK? induced HSV-specific cellular and humoral immune responses as well as protection against virus challenge [84].
However, there is a debate on whether the oral delivery is better than the intranasal delivery. Adaptive Immune ResponseThe adaptive immune response, triggered by the innate immune response, consists of cellular and humoral immunity. The main effect of the adaptive immune response is eliminating the virus and inducing long-term memory. According to the findings of many studies, B cells were dispensable against HSV-2 infection [33]. Furthermore, some human clinical trials also showed that the vaccine was invalid though it induced significant HSV-2-specific antibodies [46,47]. On the other hand, another experimental result indicated that antibodies induced by the HSV-2 vaccine were associated with protection against HSV-1 [47].
In addition, B cells triggered CD4+ T cells to produce IFN-? in the presence of dendritic cells [48].
Influence of Sex HormoneFemale sex hormones have demonstrated their influence on acquiring STIs including HSV-2 [102,103]. It was also demonstrated that pre-challenge levels of pan-HSV-2 IgG (the IgG antibodies response to all of HSV-2 antigens) quantitatively correlated with reduction in HSV-2 challenge virus shedding and increased survival rate following HSV-2 challenge [49]. Though the female sex hormones, both estrogen and progesterone, are secreted endogenously via ovaries or provided by hormonal products like hormonal contraceptives, the two types of hormones differ in their response to different variables. The mice exposed to Depo-Provera (a long-acting progestational formulation) failed to generate protection against HSV-2 following intravaginal administration of attenuated HSV-2 [104].
An interesting immunization strategy that consists of fusing gD2 to an IgG Fc fragment induced efficient mucosal and systemic immune response, and provided long-term protection against HSV-2 [52].
In the subsequent studies, the administration of Depo-Provera or a saline suspension of progesterone in mice increased the susceptibility to genital HSV-2 infections by 100-fold or 10-fold, respectively [105]. A recent study found that HSV specific IgG, though not protective for HSV disease, was the major determinant of viral inhibition in cerebrospinal fluid (CSF), preventing virus recovery in cell cultures [53].
The administration of estradiol in ovariectomized mice induced protection against HSV-2 infection without showing any vaginal pathology or viral shedding [106,107], with both intranasal and subcutaneous administration of estradiol leading to the same results in a genital herpes infection model [108]. Therefore, more research needs to be done in regard to the new function of the two types of humoral immunity. As shown in recent studies in mice, intramuscular administration of gD2 subunit vaccine with estradiol induced higher protection by the vaccine, indicating that estradiol also enhances the efficacy of subunit vaccine [109]. However, immunity induced by rectal immunization with HSV-2 TK? is via a MyD88-dependent manner rather than through a sex hormone influence [84]. Thus, more research should be conducted into the reason why progesterone increases the susceptibility of HSV-2 while estradiol increases protection against HSV-2.The studies mentioned above clearly indicate the importance of female sex hormones in HSV-2 infection and immune response.
Progesterone increases the susceptibility of HSV-2 while estradiol increases protection against HSV-2, which influences the efficacy of HSV-2 vaccine. In addition, cervicovaginal lavage (CVL) obtained from 26 women showed the potential ability to inhibit HSV infection [110]. In CVL, human neutrophil peptides 1–3, IL-8, lactoferrin, lysozyme, IgA and IgG were found to correlate with antiviral activity [110]. Also, even in the absence of secondary lymphoid organs, intravaginal administration of HSV-2 TK? induced efficient memory immune responses at genital mucosa [111]. The data strongly suggest that, like the female sex hormones, the female genital tract microenvironment, also plays an important role in immune response and HSV infection, and deserves more research. Furthermore, compared with female sex hormones, the effects of male sex hormones on HSV-2 vaccine efficacy have rarely been studied, which is another research direction for the future studies.



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