Varicella-Zoster Virus Productively Infects Mature Dendritic Cells and Alters Their Immune Function

Abstract

Varicella-zoster virus (VZV) is a highly species-specific herpesvirus that infects up to 90% of the human population (6). During primary infection, VZV is responsible for the predominantly childhood disease varicella (chicken pox). Following resolution of primary infection by the host immune system, the virus establishes a lifelong, latent infection in the dorsal root ganglia of the host. Reactivation from this site may occur many years later, resulting in herpes zoster (shingles), a condition which can be complicated by prolonged pain associated with postherpetic neuralgia (6, 37).The induction of VZV-specific T-cell immunity is critical for host recovery from varicella, and both major histocompatibility complex (MHC) class I-restricted CD8 ϩ T lymphocytes and MHC class II-restricted CD4 ϩ T lymphocytes are sensitized to viral antigens during primary infection (5). The role of VZVspecific T lymphocytes in maintaining the equilibrium between the host and virus during latency is implied by the association between a decline in the frequency of circulating VZV-specific T lymphocytes and an increased risk of VZV reactivation, causing herpes zoster (26). However, like several other herpesviruses, VZV has the capacity to interfere with the expression of MHC class I and MHC class II molecules (2, 3). VZV-encoded immunomodulatory mechanisms that limit the presentation of VZV peptides by MHC class I or MHC class II pathways to effector T lymphocytes are likely to play an important role in the pathogenesis of VZV disease and persistence of the virus in the human population (1).Several human viruses have evolved alternative strategies of evading immune recognition by selectively infecting and altering the function of specialized immune cells involved in host immune surveillance. For example, T lymphocytes play a critical role in adaptive immunity, and viruses such as human immunodeficiency virus (HIV) and measles virus can infect and destroy these cells, which may result in significant immunosuppression of the host (7,16,17).Dendritic cells (DCs) are potent antigen-presenting cells critical for the initiation of a successful antiviral immune response through the stimulation of immunologically naïve T lymphocytes (8,34). DCs located in the periphery exist as immature cells, expressing low levels of MHC class I and MHC class II molecules and costimulatory molecules such as CD80 and CD86. Immature DCs readily take up antigen and are induced to migrate to the secondary lymphoid organs, where they undergo maturation and present processed antigens to antigen-specific T lymphocytes (8,34,35). Maturation of DCs results in the downregulation of antigen uptake and processing properties and the upregulation of MHC class I and MHC class II molecules; increased surface expression of costimulatory molecules CD80, CD86, and CD40 and the maturation molecule CD83; and upregulation of adhesion molecules such as ICAM-1 (CD54) (8,14,36,(39)(40)(41)(42). The ability of mature DCs to efficiently activate naïve T lymphocytes which subsequently e...

Memory CD8+ T Cells Require CD28 Costimulation

“…For example, the measles virus is able to infect DC and inhibit CD40 ligand-dependent maturation, thereby inhibiting the up-regulation of CD80 and CD86 costimulatory ligands (66). Varicella zoster virus establishes productive infection of immature DC and is able to selectively down-regulate expression of CD80 and CD86 (67). HIV-1 Nef and Vpr proteins have also been shown to impair CD80 and CD86 expression to evade host immune responses (68,69).…”

Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

“…However, we show that programming of the activated virusspecific CD8 + T cells in the LN is not sufficient to maintain their expansion and survival at the periphery or the effector site, which is the lungs in the case of influenza A infections. The DC and CD28 requirement of effector CD8 + T cells has important implications for antiviral and antitumor effector CD8 + T cell responses as one of the immune evasion mechanisms used by viruses (19)(20)(21)(22) and tumors (23,24) is the suppression of DC maturation and inhibition of expression of CD28 costimulatory ligands CD80 and CD86. This requirement for CD28 signaling by effector cells may also contribute to the immune dysfunction found in chronic infections such as HIV infection and aging, where CD28…”

Langerhans cells and viral immunity

“…However, VZV infection of DC does result in apoptosis and passage of the virus to T cells. In contrast to HSV, VZV productively infects both immature and mature monocyte-derived DC but only induces downregulation of co-stimulatory molecules in the latter [87]. VZV can be transferred from both DC states to infect CD4 and CD8 lymphocytes, similar to HIV.…”