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Rifka rated it it was amazing Jul 21, Diego Nepomnaschy rated it really liked it Aug 02, Melissa Hart rated it really liked it Jun 04, F McDaniel rated it it was amazing May 29, May 01, MrsSamy Leo rated it it was amazing. With a very realistic approach to informing readers about herpes and its possible ways to manage it, this book is already a winner to me. For a subject that was deemed taboo to many societies, the author gave hope to those who are afflicted. I like how he immediately explained from the onset that there are holistic remedies available for this disease and surgery is not necessary.

This triggered my interest to read further. My curiosity was satisfied and I am now more informed about this curable With a very realistic approach to informing readers about herpes and its possible ways to manage it, this book is already a winner to me. My curiosity was satisfied and I am now more informed about this curable disease. This does not promise healing but the information given here provides an alternative therapy. I know this book will help a lot of people.

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Furthermore, in a murine model they demonstrated that maternal IgG accessed and persisted in neonatal TG and was protective not only against disseminated infection but also against neurological disease following neonatal HSV challenge These recent studies provide evidence that maternal immunization could provide protection against neonatal herpes, and that neutralizing antibodies play a critical role in mediating this protection.

Overall, evidence suggests that humoral immunity is likely to play an early beneficial role in primary HSV infection, and may be particularly beneficial in preventing vertical transmission from mother to neonate, but ultimately cell-mediated immunity is necessary for HSV clearance and protection CD4 and CD8 T cells are the key components of the cell-mediated immune response. CD8 T cells have the important role of killing virally infected cells via their cytotoxic components perforin and granzymes, mediated through the engagement of MHC class I molecules on target cells HSV T cell immunity operates at two sites—neuronal ganglia and the mucosa.

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In mice, CD4 and CD8 T cells surround the neurons and adherent satellite cells of trigeminal ganglia TG and control latency and some reactivation. CD8 T cells secrete granzymes which degrade intracellular ICP4 and contribute to this control 83 , Whether these T cells are truly tissue resident memory T RM cells has not been confirmed 85 , From early studies of human recurrent herpes lesions in genital skin and mucosa, we know CD4 T cells infiltrate early and are the predominant T cell subset in the first 12—48 h post onset Similarly, in human recurrent herpetic lesions, CD8 T cells infiltrate later than CD4 T cells 52 , and their recruitment into genital lesions is strongly correlated with viral clearance, confirmed by the selective depletion of CD4 T cells Upon lesion healing, HSV specific CD8 T cells persist at the dermo-epidermal junction adjacent to peripheral nerve endings in small, enriched clusters, and function as sentinels for reactivation in the female genital tract 91 , Resident HSV-specific CD8 T cells encounter HSV quite frequently, and as such express genes for antiviral function, chemotaxis, and recruitment 93 , as well as a lack of chemokine receptor expression for egress and recirculation, and the ability to produce cytolytic granules during clinical quiescence These findings demonstrate that these cells remain active in immunosurveillance after episode clearance.

This homodimer expression has been associated with high affinity antiviral effector T cells Despite CD8 T RM cells remaining in the genital tract as sentinels to protect against recurrences, shedding continues to occur and at variable rates between individuals. The model found that high levels of overall CD8 T cell density did not equate with total control of HSV and that high shedding drove frequent mucosal T cell turnover.

HSV was also found to capitalize on the spatial heterogeneity of local immunity, exploiting the gaps and allowing reactivation to occur Schiffer and colleagues, using a mathematical model, found that HSV infection did not induce sufficient T RM cells in the human genital tract to eliminate reactivation, and that strict spatial distribution is maintained during infection, as was found in murine models.

The spatial distribution and heterogeneity of T RM cells calculated from the mathematical model was also confirmed in histological genital biopsies. Understanding how genital tract T RM cells are spaced in the tissue provides insight as to how reactivation continues to occur, even in their presence They initially clear active lesions, then become T RM cells, immune sentinels, that ensure reactivation is a rare occurrence. These studies on CD8 T cells suggest important insights into why previous vaccines, which have not been able to stimulate CD8 T cell activation, were unsuccessful.

New vaccine designs should incorporate a focus on the stimulation of CD8 T cells and induction of a T RM population that remain in the tissue as sentinels, ready for an encounter with HSV. Tregs are an inherent component of any immunological response as they silence and suppress effector and cytotoxic immune responses to ensure harm does not come to the body. The role Tregs play in HSV lesions is controversial.

Some murine studies have found that Tregs are beneficial either in facilitating an effective immune response or suppressing immunopathology. Tregs are essential for promoting the accumulation of HSV specific CD4 T cells in infected tissue and ensuring DCs traffic to the appropriate draining lymph node from the vaginal mucosa, resulting in effective CD4 T cell priming Furthermore, depletion of Tregs prior to HSV infection significantly decreases skin lesion severity and granulocyte cell numbers at the site of ganglionic spread from flank HSV2 In human genital biopsies from HSV2 recurrent lesions, the density of Tregs directly correlated with HSV2 titers Thus, it may be the balance between effector T cells and Tregs that determines whether Tregs are beneficial or detrimental during HSV infection.

A significant limitation of murine HSV infection models is that HSV does not cause recurrent lesions in mice, and so the role of Tregs in reactivation cannot be assessed. Therefore, it is important to assess the role of human Tregs in response to HSV infection. It is known that high numbers of Tregs infiltrate the site of viral reactivation in genital skin biopsies and persist in proximity to T cells, specifically during reactivation. There is also a correlation between high Treg numbers and increased viral replication, indicating that Tregs may be suppressing immune effectors and allowing virus to proliferate.

This correlates with the observation that Tregs were found to localize with CD4 T cells in the upper dermis Shedding biopsies also had significantly higher ratios of Tregs to other T cells, and this affected the clinical presentation of disease; for example, an increase in Tregs could result in insufficient effector function In the context of human HSV infection, the evidence suggests Tregs could be more detrimental than beneficial, particularly during virus reactivation. Therefore, an additional consideration for new vaccine designs could be the addition of adjuvants that suppress the activation of Treg responses, particularly in immunotherapeutic vaccines that aim to reduce virus reactivation.

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Dendritic cells DCs are the most important bridge between the innate and adaptive immune system. Several subsets of DCs have been identified in various tissue compartments e. These models still must be confirmed in tissue-derived human DCs; a complex process. It has been known for a long time that Langerhans cells LCs are the major DC subtype located in the epidermis.

Whether LCs were important in HSV infection was first shown in the s, where mice whose skin was abraded, leading to the fleeing of LCs, and inoculated with HSV1, had an increase in viral pathogenicity due to the absence of LCs. Additionally, most infected LCs failed to downregulate E-cadherin preventing their emigration and became apoptotic When investigating the role of LCs in humans, one major difference is seen. LCs still become productively infected, mature and become apoptotic, however all infected LCs migrate into the dermis Such differences highlight the importance of examining the immune response to HSV in human skin and in particular the role of subsets of human DCs.

In recent years, the development of technologies such as single cell RNA-sequencing have facilitated the classification of DC subsets. The major dermal DC subset are cDC2s, which have conventional antigen-presenting capacity to stimulate CD4 T cells, but also have some ability to cross-present to CD8 T cells , Single cell analysis has also complicated the definition of what is considered a DC or a macrophage. Several studies have tried to unravel this complexity and define the process in murine models. In our recent human study, we investigated the interaction of HSV-infected LCs with dermal cDC1s in human inner foreskin explants and in biopsies of initial herpes simplex virus lesions.

This has filled an important gap in knowledge of the immunological processes facilitating HSV antigen presentation to T cells. By understanding the roles of specific human DC subsets in response to HSV infection, it should drive vaccine design toward stimulating pathways that induce the same immune responses as natural infection and, in particular, CD8 T cell responses that were not induced by previous vaccine candidates. A summary of the HSV viral relay and localization of immune cell subsets in human skin is shown in Figure 1.

Figure 1. The HSV viral relay and localization of immune cell subsets in human skin. NK cells and ILCs are found both constitutively in skin in low numbers and also infiltrate into the skin during infection or inflammation. There is increasing evidence that at least some of these additional cell types influence the developing immune response to HSV infection in the skin and further illuminating this complex picture would inform vaccine design.

Prophylactic and immunotherapeutic vaccines have different goals and as such there are challenges to overcome in the development of a successful prophylactic vaccine that are not critical for an immunotherapeutic vaccine. Since prophylactic vaccines aim to prevent acquisition of a pathogen, they need to stimulate effective primary immune responses at the site of pathogen entry. Therefore, a successful prophylactic vaccine needs to stimulate the appropriate DCs. In contrast, immunotherapeutic vaccines aim to reduce morbidity by reducing clinical episodes, and reduce transmission by reducing viral shedding.

This may be an easier immunological task than prophylaxis, as it relies on re-stimulating already existing memory T cell responses.

Therefore, a much wider range of immune cells than DCs can act as antigen presenting cells including keratinocytes and monocytes. This also means memory T cell stimulation is more likely to occur in the periphery 91 , There is now compelling evidence that the presence of T RM cells and neutralizing antibodies in the mucosa are critical for protection against release of virus from the DRG and also likely to prevent virus entry into the DRG during initial infection.

It is therefore important to consider how to design a prophylactic vaccine that will induce the development of local T RM cells and mucosal antibody to prevent infection with HSV as recruitment of B and T cells from the blood may be too slow to prevent viral seeding of the nerves.

HSV replication involves the production of rounds of viral proteins for the assembly of the virus, beginning with immediate-early IE , followed by early E then late L structural proteins The immune response is capable of targeting many of these viral components and it is important that a vaccine stimulates responses to antigenic epitopes that have been identified as key targets for neutralizing antibodies, CD4 and CD8 T cells.

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Other glycoproteins, such as gK, have only been investigated in murine models In the Herpevac trial, HSV2 gD was seen to confer protection for genital infection caused by HSV1 but not HSV2 , which correlated with high gD antibody titers, supporting the importance of antibodies in mediating this protection. When investigating the antibody response elicited from this vaccine in guinea pigs, the protection provided against genital disease was due mostly to neutralizing antibodies directed against gD, with various epitopes recognized, such as ID3, DL6, and MC The more epitopes the animals recognized, the better protected they were against genital disease.

Upon investigating the epitope-specific antibody responses in women from the Herpevac trial, it was found that significantly fewer crucial gD epitopes were recognized compared to the guinea pigs Anti-gE is aimed at preventing cell to cell spread. Human antibody responses to this vaccine have not yet been assessed.

Perhaps assessment of the efficacy of this vaccine and any future vaccines should evaluate epitope-specific antibody responses, such as to the gD2 epitopes ID3, DL6, and MC Interestingly, a live attenuated viral vaccine, with a gD deletion, elicited mucosal antibodies with low neutralization activity but high antibody-dependent cellular cytotoxicity ADCC activity, provided sterilizing immunity in murine models and passively transferred immunity against vaginal infection with multiple clinical isolates — It is noteworthy that they authors did not include complement in their neutralization assays, which should be considered as an alternative mechanism to ADCC.

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  • The authors propose that the removal of the immunodominant gD protein may unmask alternative epitopes important in a protective immune response or remove a possible immunosuppressive effect of gD. ADCC activity may warrant further attention in vaccine evaluations. Although the above studies provide evidence for the importance of vaccines eliciting strong neutralizing antibody responses, many of the previous human clinical trial vaccines did induce neutralizing antibodies and yet were unsuccessful , Although it has been suggested that this may be partially explained by a lack of epitope-specific responses, also neutralizing antibodies may not be sufficient by themselves to provide protection against HSV infection.

    CD4 and CD8 T cells are also likely to be required. Therefore, the ability to stimulate them in a vaccine needs to be improved from the previous vaccine candidates. CD4 and CD8 T cells respond to various viral proteins, some of which overlap with those that neutralizing antibodies recognize. The identification and use of conserved and cross-reactive epitopes in new vaccine designs may lead to the possibility of targeting multiple immune cells against multiple herpesviruses in the one vaccine. However, recent evidence indicates that there may be compartmentalization of T-cell receptor TCR repertoires and expansion of particular T cell clones at distinct anatomical sites.

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    This may have important implications for how T cell responses to potential vaccine candidates should be assessed. Furthermore, recent data from the same lab presented at the International Herpesvirus Workshop investigated the overlap of TCR sequences between genital skin and PBMCs in HSV2 infected patients and also in response to an immunotherapeutic vaccine.