Primary

       Primary infections are defined as infections which occur in the absence of detectable antibody directed against Herpes Simplex virus (HSV). [77] The initial immune response (IR) is complex and not completely understood but antibodies to HSV antigens can be detected within 4 - 8 days of initial infection. The first antibodies detected are IgM followed by IgG which persists for longer period of time. [77] At the site of of epidermal infection viral antigens are presented on dendritic cells and macrophages to CD4+ Th1 cells. These CD4+ Th1 cells initiate viral clearance by secreting cytokines such as IFN-gamma, stimulating  recruitment and activation of macrophages and natural killer (NK) cells, brooding the IR. The IR effectively induces lysis of the Infected cells expressing viral antigen, by integrated mechanisms involving: CD4+ T-cells, CD8 + T-cells, NK cells and the antibody-dependent cell-mediated cytotoxicity (ADCC). (79)  Also detected is early complement components of the alternate pathway and/or the classical pathway. [77]
        Humoral Immunity  involving IgG1, IgG3 and IgA were detected in all patients with primary and non-primary infections, whereas IgG4 was detected in 74% of persons with non-primary infections and IgG2 was not detected. IgM was detected in 100% of patients with primary infection, and in 68% of non-primary infected patients. IgA showed a peak similar to IgM in patients with primary infection. [77]
 

Secondary IR

      In recurrent lesions, HSV antigen is thought to be taken up by Lagerhan's cells and presented on MHC II effectively stimulating specific resident memory CD4+ Th cells which are also stimulated by IFN-gamma. [4]  Langerhan cells, working in accordance with other sources of cytokines, possibly from keratinocytes, basel epidermal cells, infiltrating macrophages and Langerhan cells themselves, coordinate a proper Th1 immune response (IR). [4][16] Even before restimulation of immune T-cells, an initial cytokine, TNF-alpha, was found  bound to macrophages, keratinocytes, and/or T lymphocytes emphasizing the beginning of the secondary IR in these early stages on recurrent lesions. [4]  Another early detectable cytokine represented in high titers is INF-beta, which is known to be released by fibroblasts, effectively  inhibiting viral replication. [16][18]   However, it is the T-lymphocytes along with macrophages that are the main mediators of the protective immune response against recurrent HSV. [16] Specifically, these are the CD4+ and CD8+  T Lymphocytes, along with macrophages which are predominantly found in the mononuclear infiltrate surrounding infected epidermal cells and keratinocytes. [16][17][62]  The anti-viral functions of these infiltrating T-cells include cytotoxicity, inhibition of viral growth, lymphokine secretion, and support of CD8+ and humoral responses.  The cytotoxicity response is thought to be mediated by early infiltrating CD4+ T lymphocytes which are responsible for the secretion of IFN-Gamma, as with initial infection, associated with the Th-1 IR. [4][16]   The secretion of IFN-gamma may also help to overcome the down regulation of MHC I by TAP (Immune_Evasion), which helps permit lysis by CD8+ cytotoxic T lymphocytes (CTLs). A study performed by Zorka Mikloska and Anthony Cunningham found that  CD8+ T-lymphocyte cytotoxicity was only detectable with IFN-gamma stimulated keratinocytes, highlighting the importance of this CK in an operational IR. [16] Ineffectively, the infiltrating CD8+ T cells were found to exert a very weak cytotoxicity against HSV infected fibroblasts, due to the correlation of decreased expression of MHC I by TAP inhibition {IE}. [16]  On the other hand, IFN-Gamma helps to up-regulates HLA class II on HSV infected keratinocytes to allow recognition by cytolytic CD4+ T cells. [62] Most importantly, IFN-gamma within the lesions stimulates the induction of major histocompatibility complex (MHC) class II antigens (HLA-DR, not HLA-DQ) on the surface of epidermal cells within the first two days of the lesions. [16]  Allowing for recognition by CD4+ T-cells to amplify the Th1 Tc response, deduced by the cytokine profile present in recurrent vesicle fluid. (See Below) This analysis  provides good reason why people with poor or impaired T-cell responses exhibit frequent HSV disease. [63]
 
 

        The role of the humoral immune response has also been examined. It has been determined that B-lymphocytes are scarce in these lesions, so the antibody response is not adequate. However, high levels of pre-existing neutralizing antibody may still play a role in preventing the spread of HSV, as in neonatal herpes and in the prevention of viremia. [16] The reasoning here would be that the HSV specific antibodies will decrease the amount of free virus preventing its spread to adjacent tissues and therefore effectively  reducing the size of the herpetic lesions and amount of viral spread. [4]

T cell Epitopes

        The antigenicity of HSV  specific CD4+ cells is incompletely defined. However, recent advances have shown that the predominate viral proteins recognized by CD4+ T-lymphocyte cytotoxicity are late viral proteins. [16] Specifically,  the Unique Long (UL) 48 gene, which encodes the Tegument protein, VP16, which contains at least 3 T-cell epitopes [62]  Further investigation has detected additional CD4+ T-cell epitopes related to HSV envelope glycoproteins: gB, gC, gD and gH. [62] These findings confirm why CD4+ T-lymphocyte cytotoxicity  is directed toward these major late structural proteins, gB, gD, gC, gH, and occasionally the major tegument protein VP16.  Also, reaction with an additional tegument protein, Unique long 21 (UL21), VP22 coded by UL49 gene and dUTPase coded by UL50 gene, has been confirmed. [62] However, as of now, the exact sequence of HLA-DR epitopes are not known. In comparison, CD8+ T-lymphocyte cytotoxicity was only detectable with IFN-gamma stimulated keratinocytes which predominantly targeted early HSV proteins. [16]

 Immune Responses to individual HSV surface glycoproteins in Mice after vaccination:
 

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