Herpes simplex. Pathogenesis (Mandell: Principles and Practice of Infectious Diseases)

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Similarly for HSV-2, reactivation in the genital region is 8 to 10 times more frequent than is oral-labial reactivation of HSV-2. [87] In experimental animal systems, both sacral and trigeminal ganglia contain latent virus, but reactivation differs according to the anatomic site of injection. [34] [35] [88] [89] When the region containing the latency-associated transcripts of HSV-2 is inserted into an HSV-1 virus, increasing reactivation in sacral nerve root ganglia has occurred, indicating that viral factors influence reactivation. [35] [38]

Host factors clearly influence rates of reactivation. Immunocompromised patients have both more frequent and more severe reactivation. [90] [91] [92] [93] [94] [95] [96] Alterations in T-cell immunity are critical to viral containment. Although agammaglobulinemic patients appear to handle HSV infection well, widespread local extension and dissemination are common in infants and immunocompromised patients such as organ transplant recipients and human immunodeficiency virus (HIV)-infected persons. [91] [92] [93] [94] [95] [96] Viremic spread of virus to visceral organs can lead to life-threatening disease. [95] [96] [97] Experimental ablation of lymphocytes indicates that T cells play a major role in preventing lethal disseminated disease, although antibodies help reduce viral titer in neural tissue. [98] [99] The surface viral glycoproteins have been shown to be antigens recognized by antibodies mediating neutralization and immune-medicated cytolysis (antibody-dependent cell-mediated cytotoxicity). [100] [101] Monoclonal antibodies specific for each of the known viral glycoproteins have, in experimental infections, conferred protection against subsequent neurologic disease or ganglionic latency. [102] [103] Multiple cell populations, including natural killer cells, macrophages, a variety of T lymphocytes, and lymphokines generated by these cells, play a role in host defenses against HSV infections. [104] In animals, passive transfer of primed lymphocytes confers protection from subsequent challenge. [105] [106] Maximal protection usually requires the activation of multiple T-cell subpopulations, including cytotoxic T cells and T cells responsible for delayed hypersensitivity. The latter cells may confer protection by the antigen-stimulated release of lymphokines (e.g., interferons), which may have a direct antiviral effect or may activate other nonspecific effector cells. Both HSV-1 and HSV-2 encode for proteins that are directed at subverting host T-cell responses. [107] One protein in particular, ICP-47 (infected cell protein No. 47), interacts with the transporter activity protein to prevent the interaction between HSV-specific peptides and HLA class I molecules. [108] This downregulates certain HSV peptides with HLA class I antigen on the cell surface and subverts the host CD8+ cytotoxic T cell response to HSV. [109] [110]

Biopsies of herpetic lesions have shown that initially the predominant infiltrating cell is the CD4+ lymphocyte. [111] [112] Staining of such lesions shows the presence of activation markers on these CD4-bearing cells. These include interleukin-2 receptor, DR+ , ICAM-1+ and large amounts of gamma-interferons within 2 to 4 days, and later the lesions are infiltrated with CD8+ T cells. [113] [114] Clearance of HSV-2 from genital lesions is associated with the ability to detect cytolytic killing to HSV-2 in lesional T cells

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