Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Abstract

Varicella-zoster virus (VZV) is an alphaherpesvirus with the characteristic neurotropism of this group, but VZV also infects T cells productively and downregulates major histocompatibility complex (MHC) class I expression on infected T cells, as shown in the SCID-hu mouse model. T-cell tropism is likely to be critical for the cell-associated viremia associated with primary VZV infection. In these experiments, we found that VZV infects human tonsillar CD4؉ T cells in culture, with 15 to 25% being positive for VZV proteins as detected by polyclonal anti-VZV immunoglobulin G (IgG) staining and monitored by flow cytometry analysis. RNA transcripts for VZV gE, a late gene product, were detected in T-cell populations that expressed VZV surface proteins, but not in the VZV-negative cell fraction. Exposure to phorbol myristate acetate resulted in an increase in VZV-positive T cells, indicating that viral DNA was present within these cells and that VZV gene expression could be induced by T-cell activation. By immune scanning electron microscopy, VZV virions were detected in abundance on the surfaces of infected tonsillar T cells. The predominant CD4؉ T-lymphocyte subpopulations that became infected were activated CD69 ؉ T cells with the CD45RA ؊ memory phenotype. Subsets of CD4؉ T cells that expressed skin homing markers, cutaneous leukocyte antigen, and chemokine receptor 4 were also infected with VZV. By chemotaxis assay, VZV-infected T cells migrated to SDF-1, demonstrating that skin migratory function was intact despite VZV infection. The susceptibility of tonsil T cells to VZV suggests that these cells may be important targets during the initial VZV infection of upper respiratory tract sites. Viral transfer to migrating T cells in the tonsils may facilitate cell-associated viremia, and preferential infection of CD4 T cells that express skin homing markers may enhance VZV transport to cutaneous sites of replication.Varicella-zoster virus (VZV) is a human alphaherpesvirus that has a linear double-stranded DNA genome consisting of approximately 125,000 bp and encoding at least 69 unique proteins (34). VZV is a highly contagious pathogen. Primary infection leads to varicella (chickenpox) in susceptible individuals and establishment of latency in sensory ganglia; VZV may reactivate as herpes zoster (shingles) (3). Healthy individuals acquire VZV through contact with skin lesions of an infected person, followed by inoculation of respiratory mucosa, or by direct inoculation of virus in respiratory secretions. By analogy with mousepox, VZV has been presumed to be transferred to regional lymph nodes, where it is thought to initiate a primary viremic phase within a few days after inoculation (12). The mechanism of VZV transport from respiratory mucosa to regional lymph nodes is not known. A secondary viremia has been demonstrated to occur at the end of a 10-to 21-day incubation period, accompanied by the appearance of skin lesions. VZV has been recovered from cultured mononuclear cells obtained from 5 days before until 2 days...

Functions of the C-Terminal Domain of Varicella-Zoster Virus Glycoprotein E in Viral Replication In Vitro and Skin and T-Cell Tropism In Vivo

“…Primary VZV infection causes varicella, which is characterized by cell-associated viremia and the formation of vesicular skin lesions that contain high concentrations of cell-free virions (3,19,35). It is believed that VZV is transmitted by aerosolized virions and infected cell material shed from skin and respiratory epithelium, although this process has not been tested in animal models.…”

Differential Requirement for Cell Fusion and Virion Formation in the Pathogenesis of Varicella-Zoster Virus Infection in Skin and T Cells

“…The pathogenesis of primary VZV infection appears to depend upon its tropism for migratory T cells, which may transport the virus from mucosal sites of inoculation, and on its capacity to form skin lesions containing high titers of cell-free infectious virus, which can be transmitted to other susceptible individuals in the population (1,15,19,20,38). This evaluation of the VZV mutant viruses rOka47⌬C and rOka47D-N, expressing kinase-defective forms of ORF47 protein, in SCIDhu mice with T-cell xenografts demonstrated that ORF47 kinase function was essential for VZV infection of human T cells within their differentiated microenvironment in vivo.…”

“…Varicella is characterized by viremia and skin lesions. VZV infects T cells, which may be a mechanism for its transport from respiratory epithelial sites of inoculation to dermal and epidermal cells (1,19,20,38). Thus, T cells as well as skin are critical targets for VZV pathogenesis.…”

Varicella zoster virus infection

“…Primary infection-Following transmission to susceptible hosts, VZV proliferates in the oral pharynx (tonsils), infects T cells that enter the circulation and disseminate virus to the skin and possibly other organs; infection is at first controlled by innate immunity 32,33 .…”

“…VZV DNA can be detected in T cells (viraemia) as early as 10 days prior to the occurrence of a rash and can persist for a week afterwards 35 . Initially, innate immunity delays viral multiplication in the skin, which provides time for adaptive immunity to develop 32 . Eventually, cutaneous innate immune responses are overcome by the virus, and there is substantial viral replication in the skin (and sometimes the viscera), resulting in the characteristic rash of varicella 33 (FIG.…”