Persistent elevated expression of cytokine transcripts in ganglia latently infected with herpes simplex virus in the absence of ganglionic replication or reactivation.
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.
Chen
S H
SH
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Garber
D A
DA
Schaffer
P A
PA
Knipe
D M
DM
Coen
D M
DM
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000276:immunology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D008297:Male; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics; D012668:Trigeminal Ganglion / Q000276:immunology / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D016207:Cytokines; D004279:DNA, Viral; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013937:Thymidine Kinase