Varicella-Zoster Virus Pathogenesis and Immunobiology: New Concepts Emerging from Investigations with the SCIDhu Mouse Model

Varicella-zoster virus (VZV) is an alphaherpesvirus with a genome of ∼125,000 bp encoding at least 70 unique open reading frames (ORFs) (3, 9, 10, 15). Primary VZV infection is associated with a cell-associated viremia and a diffuse cutaneous rash recognized as varicella, or chickenpox. VZV appears to cause viremia by infecting lymphocytes. VZV establishes latency in sensory ganglia and causes herpes zoster upon reactivation. VZV is sustained in the human population, which is its only natural reservoir, primarily by direct contact with infectious virus in varicella or zoster skin lesions or in respiratory secretions. Investigating the molecular mechanisms of VZV pathogenesis has been difficult because of VZV's restricted infectivity for nonhuman species in vivo and the highly cell-associated nature of VZV replication in vitro. These obstacles have been addressed by the development of the SCIDhu mouse model to examine VZV pathogenesis and immunobiology in vivo (5-7, 19, 30-34, 37, 40-42) and by the making of genetically altered VZV recombinants from VZV cosmids (11, 20, 28). Cosmid mutagenesis can be useful to define essential regions of the VZV genome if infectious virus cannot be recovered without genetic complementation. When genetic changes are not lethal, VZV mutants can be evaluated in vitro and in human T-cell and skin xenografts in SCID mice to determine how particular VZV gene products contribute to virulence in differentiated human cells within their unique tissue microenvironments in vivo. The purpose of this review is to highlight new insights about VZV pathogenesis and immunobiology that have emerged from analyses of VZV infection in the SCIDhu mouse model and from examination of the differential effects of mutations targeting ORF47, which encodes a viral kinase/tegument protein, on VZV tropism for skin and T cells. Clinical observations indicate that primary VZV infection begins with respiratory mucosal inoculation and that the characteristic chickenpox rash develops after an incubation period of 10 to 21 days (3, 9). In the absence of experimental data, early events in VZV pathogenesis have been compared to mousepox (16). According to this model, VZV is presumed to infect mononuclear cells in regional lymph nodes, causing a primary viremia that carries the virus to reticuloendothelial organs, such as the liver, for a phase of viral amplification, which is followed by a secondary viremia in the late incubation period that results in VZV transport to skin. Instead, our recent experiments with the SCIDhu mouse model support the concept that infected T cells have the potential to mediate VZV transfer to skin immediately after entering the circulation during primary viremia and suggest that the prolonged interval between exposure and the appearance of varicella skin lesions reflects the time required for VZV to overcome previously unrecognized but potent innate immune barriers, especially alpha interferon (IFN-α) production, mounted directly by epidermal cells in vivo (27). Experiments analyzing VZV recombinants with disrupted ORF47 protein kinase activity point to differences in the minimal requirements for cell fusion and virion formation in the pathogenesis of VZV infection of skin and T cells in vivo (7). In a broader context, these observations about VZV pathogenesis and immunobiology point to accommodations between VZV and the host that have allowed the virus to persist in the human population so successfully. Virus-host interactions that ensure the gradual formation of cutaneous lesions containing infectious virus at the skin surfaces should function to avoid an otherwise incapacitating infection of the host that would limit opportunities for VZV transmission to other susceptible individuals. New information about events in VZV pathogenesis and differences in the genetic requirements for VZV replication in skin and T cells also suggest that the design of “second-generation” live attenuated varicella vaccines might focus on preserving infectivity in skin and blocking T cell tropism.