Classical Pathway
 

Normally, serum antibodies IgM and subclasses of IgG (IgG1, IgG2, and IgG3)  bind to foreign pathogens, in this case HSV, and initiate a specific host IR. [18] Specifically, they initiate complement mediated lysis (CML)  via the classical pathway (antigen-antibody)  and opsonization, which both aid in the elimination of foreign pathogens.  Commonly, each of these IRs are governed by interactions with the immunoglobulins (Ig) Fc binding domain.  Typically, the Fc binding domain of the Ig will bind to either C1q or to the Fc receptor of a phagocytic cell, effectively initiating CML or functioning as a opsonin, respectively. In evolution, HSV  has acquired the ability to evade these host IRs by blocking their specific Fc interactions. HSV achieves this by using its surface glycoproteins (gp) gE and gI,  these gp form a hetero-oligomer complex that functions as a Fc receptor for IgG. Coincidentally,  HSV's surface glycoprotein gI has sequence homology with the mammalian Fc receptor, leading to the assumption that this ability was acquired from evolutionary recombination. [22][23] HSV's gE/gI receptor complex binds both non-immune and immune IgG. Immune IgG is evaded by bi-polar bridging when the Fab portion of the Ig binds to the HSV antigen (ex. gD) and the gE/gI complex binds the Fc portion. [22][23] This bi-polar bridging of the IgG antibody disrupts the effector functions mediated by the Fc region; including binding of C1q, consequently inhibiting the classical pathway for complement activation, and blocking opsonization. Also revealed is that gE can act alone as a low-affinity IgG Fc receptor for IgG aggregates but not IgG monomers. [23] Currently, it is unknown if HSV gp are incorporated into the host cell membrane to evade antibody-dependent cellular cytotoxicity (ADCC).

Alternative Pathway

    In yet another mechanism, which is not fully understood,  HSV can avoid the complement activation governed by the alternative pathway. In the alternate pathway, serum C3 undergoes slow spontaneous hydrolysis to yield two products, C3a and C3b. [18] C3b has the ability to bind to foreign surface antigens and activate the complement cascade. [18] Unfortunately HSV ­1 glycoprotein C (gC) binds to complement component C3b,  once gC binds complement C3b it blocks the binding of properdin and C5, thereby inhibiting MAC formation (has not been established in vivo). [65]Although the mechanism is not fully understood, it has been discovered that activation is mediated by the amino-terminal end of gC, a separate region than heparan sulfate binding. [22]Subsequently in observation, the protection of gC-1 against antibody plus complement was similar to that against complement alone, indicating that gC-1 is likely to be important in early infection before antibodies develop [22][65]For this reason gC has been distinguished as a virulence factor for HSV. [65] Link--> to BIO 160 Viral Immune Evasion (COMPL_IE)
 

Binding TAP
 

Most cells have the ability to express internal peptides to a "surveillance" immune system, achieved by a process involving a transporter protein TAP (transporter associated with antigen processing). [18] TAP is composed of two subunits, TAP1 and TAP2, which form a heterodimeric membrane complex that serves as a gate keeper for transporting peptides from the cytosol into the RER. The transported peptides are to be coupled to MHC I and then expressed on the cell surface. [18]  After primary penetration, a HSV protein, ICP 47 binds to the  TAP, which blocks peptide binding and peptide translocation by TAP, thereby avoiding the loading of peptide epitopes into the binding clef of MHC-I molecules. [16][20][21][22][63]  The resultant empty MHC class I molecules are retained in the ER which effectively prevents the expression of viral epitopes. [21] Subsequently, by preventing the expression of viral epitopes, ICP47 prevents the immune recognition of virus infected cells by CD 8+ cytotoxic T lymphocytes, which would regularly interact with MHC I.
This interaction of ICP 47 and TAP has been shown to be highly species-specific, since ICP 47 has a 100 fold higher affinity for human TAP than fore murine TAP. The affinity of the human TAP-ICP47 interaction has been estimated to be around 50 nM. [21]  ICP 47 interacts specifically with lipid membranes and surprisingly, it was found that ICP 47-2 fragments showed a significantly reduced activity in blocking peptide binding to TAP compared to ICP 47-1.[20]  A conserved region was identified in both HSV-1 and HSV-2 ICP 47 within residues 14-24 which have a pattern of charged amino acid that is supposed to interact with substrate binding. [20][21] Using overlapping or stepwise truncated fragments of the viral TAP-inhibitor, a 32-mer peptide, ICP47 (3-34), was identified as the active domain. [20] A related study identified ICP47 (2-35)  as the active domain, these similarities allow for confidence to be established for the recognition of the active region of this protein. [20][21] Possibilities:      In order to initiate specific IRs, future vaccines maybe able to incorporate  "ICP47" to prevent MHC 1 expression, if desired. Ex. Allograft.

Avoid Apoptosis

        Apoptosis is critical for the control of viral infections by CTL, inhibition of apoptosis could be important mechanism of immune evasion. Usually, CTL's induced apoptosis either by using components of their lytic granules or by engagement of the target cell Fas ligand. HSV  has shown to be able to inhibit the killing ability of the CD4+ CTLs by an unknown mechanism. [63]  Although the mechanism is unknown, a recent association suggests that HSV may encode anti-apoptotic proteins, although their ability to inhibit CTL-induced apoptosis has not been established. [63] The associated viral protein which is believed to inhibit apoptosis is unique short 3 (US3) which has only proven to inhibit some CTL killing pathways. [63] Further investigation is warranted.

Evolution

     As one can see, HSV is quite diverse in its ability to avoid the host immune system. It has been suggested that HSV has probably evolved in parallel with the mammalian nervous system, which can clarify part of its symbiotic abilities of not only immune evasion but also its vast array of sequence homology( e.g. The gE/gI Fc receptor). These parallels were most likely acquired by evolutionary recombination and not a result of independent formulation, although possible.  By continual integration with with host DNA it is probable that HSV DNA fused and encapsulated new versions of itself,  resulting in an evolutionary advantage over its non-recombined counterpart.  By acquiring these overt systems, HSV has improved its ability to survive within its host, therefore perpetuating its own survival. One smart Bug!
 

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