HSV shedding

bImmunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2⌬TMR 340-363 ) and a truncated form of infected cell polypeptide 4 (ICP4 383-766 ), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4؉ and CD8 ؉ T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003-or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease. H erpes simplex virus 2 (HSV-2) is one of the most prevalent sexually transmitted diseases, having infected more than 500 million people worldwide, with an estimated 23 million new infections occurring annually (1). HSV-2 infects epithelial cells of the genital mucosa during primary infection, followed by the establishment of latency in neuronal dorsal root ganglia via retrograde transport along nerve axons. Throughout latency, virus can reactivate, causing genital lesions and/or asymptomatic shedding of virus. Although suppressive antiviral therapy has shown promise in reducing both symptomatic recurrent lesions and overall viral shedding, subclinical HSV reactivation persists, likely contributing significantly to the observed continued transmission (2). The development of an efficacious immunotherapeutic vaccine targeting HSV-2 likely represents the best strategy for preventing both lesion outbreaks and the continued spread of virus.Despite considerable effort, all vaccine candidates to date have failed to meet their defined endpoints in clinical trials. The majority of clinical trials to date have focused on prophylactic subunit vaccines, largely using the HSV-2 surface glycoproteins as immunogens. The viral envelope glycoproteins gD and gB are the dominant targets for neutralizing antibody production (3, 4), making them logical candidates for vaccine devel...

Section: Discussionmentioning

confidence: 99%

An Adjuvanted Herpes Simplex Virus 2 Subunit Vaccine Elicits a T Cell Response in Mice and Is an Effective Therapeutic Vaccine in Guinea Pigs

Škoberne

Cardin

Lee

et al. 2013

“…uman herpesviruses can reactivate from latency at internal anatomical sites and be shed from epithelial surfaces long after initial infection and establishment of an adaptive immune response (1)(2)(3)(4)(5)(6)(7)(8). This suggests that the ability to spread from cell to cell in the presence of immune effectors is a conserved property of herpesviruses.…”

mentioning

confidence: 99%

The Herpes Simplex Virus 1 UL51 Protein Interacts with the UL7 Protein and Plays a Role in Its Recruitment into the Virion

Roller

Fetters

2015

The alphaherpesvirus UL51 protein is a tegument component that interacts with the viral glycoprotein E and functions at multiple steps in virus assembly and spread in epithelial cells. We show here that pUL51 forms a complex in infected cells with another conserved tegument protein, pUL7. This complex can form in the absence of other viral proteins and is largely responsible for recruitment of pUL7 to cytoplasmic membranes and into the virion tegument. Incomplete colocalization of pUL51 and pUL7 in infected cells, however, suggests that a significant fraction of the population of each protein is not complexed with the other and that they may accomplish independent functions. IMPORTANCEThe ability of herpesviruses to spread from cell to cell in the face of an immune response is critical for disease and shedding following reactivation from latency. Cell-to-cell spread is a conserved ability of herpesviruses, and the identification of conserved viral genes that mediate this process will aid in the design of attenuated vaccines and of novel therapeutics. The conserved UL51 gene of herpes simplex virus 1 plays important roles in cell-to-cell spread and in virus assembly in the cytoplasm, both of which likely depend on specific interactions with other viral and cellular proteins. Here we identify one of those interactions with the product of another conserved herpesvirus gene, UL7, and show that formation of this complex mediates recruitment of UL7 to membranes and to the virion. Human herpesviruses can reactivate from latency at internal anatomical sites and be shed from epithelial surfaces long after initial infection and establishment of an adaptive immune response (1-8). This suggests that the ability to spread from cell to cell in the presence of immune effectors is a conserved property of herpesviruses. Within the alphaherpesviruses, where this phenomenon has been the most extensively studied, the evidence suggests that cell-to-cell spread (CCS) between epithelial cells in vitro has two mechanistic components. The first of these is a virion trafficking component in which virions are targeted from the site of secondary envelopment to the junctional surfaces of cells, where they have access to adjacent cells in a compartment that is sterically protected from immune effectors in the medium (9-11). The second component is a specialized entry process that may involve gE binding to specific CCS receptors and that also may involve different patterns of receptor usage by the virus entry apparatus (12-15). In alphaherpesviruses, both mechanistic components involve the complex between the envelope glycoproteins gE and gI. However, since gE and gI are encoded only by alphaherpesvirus genomes, any mechanism for CCS that is conserved among all herpesviruses is likely to involve other, more widely conserved viral factors.Virus genome-encoded proteins that are specifically required for epithelial CCS fall into two categories: those required for virus entry into cells regardless of the mode of virus egress and those tha...

“…Currently, 47% of the U.S. population is seropositive for HSV-1 and 16% are seropositive for HSV-2 (3). Many seropositive individuals are asymptomatic, although a number of people shed virus regardless of clinical signs of disease (4). However, the frequency of shedding is greater in those with recurrent clinical outbreaks (5).…”

mentioning

confidence: 99%

Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific

Cairns

Huang

Gallagher

et al. 2015

Herpes simplex virus 1 (HSV-1) and HSV-2 infect many humans and establish a latent infection in sensory ganglia. Although some infected people suffer periodic recurrences, others do not. Infected people mount both cell-mediated and humoral responses, including the production of virus-neutralizing antibodies (Abs) directed at viral entry glycoproteins. Previously, we examined IgGs from 10 HSV-seropositive individuals; all neutralized virus and were directed primarily against gD or gD؉gB. Here, we expand our studies and examine 32 additional sera from HSV-infected individuals, 23 of whom had no recurrent disease. Using an Octet RED96 system, we screened all 32 serum samples directly for both glycoprotein binding and competition with known neutralizing anti-gD and -gB monoclonal Abs (MAbs). On average, the recurrent cohort exhibited higher binding to gD and gB and had higher neutralization titers. There were similar trends in the blocking of MAbs to critical gD and gB epitopes. When we depleted six sera of Abs to specific glycoproteins, we found different types of responses, but always directed primarily at gD and/or gB. Interestingly, in one dual-infected person, the neutralizing response to HSV-2 was due to gD2 and gB2, whereas HSV-1 neutralization was due to gD1 and gB1. In another case, virus neutralization was HSV-1 specific, with the Ab response directed entirely at gB1, despite this serum blocking type-common anti-gD and -gB neutralizing MAbs. These data are pertinent in the design of future HSV vaccines since they demonstrate the importance of both serotypes of gD and gB as immunogens. IMPORTANCEWe previously showed that people infected with HSV produce neutralizing Abs directed against gD or a combination of gD؉gB (and in one case, gD؉gB؉gC, which was HSV-1 specific). In this more extensive study, we again found that gD or gD؉gB can account for the virus neutralizing response and critical epitopes of one or both of these proteins are represented in sera of naturally infected humans. However, we also found that some individuals produced a strong response against gB alone. In addition, we identified type-specific contributions to HSV neutralization from both gD and gB. Contributions from the other entry glycoproteins, gC and gH/gL, were minimal and limited to HSV-1 neutralization. Knowing the variations in how humans see and mount a response to HSV will be important to vaccine development. Herpes simplex virus 1 (HSV-1) and HSV-2 cause human diseases, ranging from benign cold sores to life-threatening infections such as encephalitis and neonatal HSV disease (1, 2). The hallmark of HSV infection is the ability of each serotype to establish a lifelong latent infection in sensory neurons. Reactivation can lead to clinical symptoms such as oral or genital lesions. Currently, 47% of the U.S. population is seropositive for HSV-1 and 16% are seropositive for HSV-2 (3). Many seropositive individuals are asymptomatic, although a number of people shed virus regardless of clinical signs of disease (4). However,...