Persistent Elevated Expression of Cytokine Transcripts in Ganglia Latently Infected with Herpes Simplex Virus in the Absence of Ganglionic Replication or Reactivation

Abstract

Infection of mouse trigeminal ganglia by herpes simplex virus induces cytokine expression that persists long after infectious virus or viral antigens become undetectable. To examine mechanisms underlying this phenomenon, we used a thymidine kinase mutant, dlsptk, which fails to replicate in ganglia and does not reactivate upon ganglionic explant. Using quantitative reverse transcriptase-polymerase chain reaction assays, we found that levels of interferon-gamma and tumor necrosis factor-alpha transcripts in dlsptk-infected ganglia were lower than those in wild type-infected ganglia, but were significantly (eight- to 10-fold) higher than those in mock-infected ganglia from Day 3 to Day 100 postinfection. We also studied latency-associated transcript (LAT) negative mutants that exhibit increased expression of productive cycle transcripts in ganglia. Ganglia infected with these mutants contained levels of cytokine transcripts similar to those in wild type-infected ganglia; any increases in viral antigen expression mediated by the LAT deletion were not accompanied by increased cytokine expression. Thus, neither viral replication, the ability to reactivate, nor LAT expression in ganglia is required for persistent elevated cytokine expression. The results provide indirect evidence that low-level expression of viral productive cycle genes in neurons can provide signals that elicit cytokine expression.

Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice

“…However, recent studies of latent infection with a reactivation-deficient TK deletion virus (dlstpk) suggest that cytokine expression can be maintained in sensory ganglia in the absence of propagation of infectious virus, albeit at significantly lower levels than KOS-infected controls (38). In the current study, we observed mostly focal, rather than diffuse, inflammatory infiltrates in latently infected ganglia.…”

“…If these neurons do not survive, then the reservoir of latently infected neurons should decrease over time. However, all evidence to date demonstrates that this decrease does not occur (37,38). This finding suggests that either the latent reserve is replenished by means of subsequent latent infection of neurons adjacent to the rare neurons that express viral transcripts or changes in viral load are so small that it is unlikely that they would be detected by the methods that have been used.…”

Acyclovir Reduces the Duration of Fever in Patients with Infectious Mononucleosis-like Illness

“…Studies have reported that HSV enhances the expression of cytokines such as interferon-gamma and tumor necrosis factor-alpha, and that EBV can immortalize B cells activated by cytokines (Wendel-Hansen et al 1994;Chen et al 2000). Interestingly, a previous study has reported that acyclovir blocks the expression of inflammatory cytokines (Halford et al 1997).…”

Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

“…Most of our current knowledge about the role of T cells and their cytokines in preventing ␣-herpesvirus reactivation from sensory neurons has been obtained from mouse studies (9)(10)(11)(12)(13)(14). Because of the species restriction of VZV susceptibility, these studies have been limited to HSV-1.…”