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

^*Department of Microbiology and Immunology, University of California Medical Center, Los Angeles, CA 90024; ^†F. I. Proctor Foundation, University of California Medical Center, San Francisco, CA 94143-0944; and ^¶Food and Drug Administration/Center for Biologics Evaluation and Research, Bethesda, MD 20892-4555

Edited by Bernard Roizman, University of Chicago, Chicago, IL, and approved November 26, 2001 (received for review June 14, 2001)

Abstract

Infection of the mouse trigeminal ganglia (TG) is the most commonly used model for the study of herpes simplex virus type 1 (HSV-1) latency. Its popularity is caused, at least in part, by the perception that latent infection can be studied in this system in the absence of spontaneous viral reactivation. However, this perception has never been rigorously tested. To carefully study this issue, the eyes of Swiss–Webster mice were inoculated with HSV-1 (KOS), and 37–47 days later the TG were dissected, serial-sectioned, and probed for HSV-1 ICP4, thymidine kinase, glycoprotein C, and latency-associated transcript RNA by in situ hybridization. Serial sections of additional latently infected TG were probed with HSV-1-specific polyclonal antisera. Analysis of thousands of probed sections revealed abundant expression of viral transcripts, viral protein, and viral DNA replication in about 1 neuron per 10 TG tested. These same neurons were surrounded by a focal white cell infiltrate, indicating the presence of an antigenic stimulus. We conclude that productive cycle viral genes are abundantly expressed in rare neurons of latently infected murine TG and that these events are promptly recognized by an active local immune response. In the absence of detectable infectious virus in these ganglia, we propose the term “spontaneous molecular reactivation” to describe this ongoing process.

Footnotes

↵ ‡ Present address: BitTech, Inc., 725-H Lakefield Road, Westlake Village, CA 91361.
↵ § Present address: Tularik, Inc., 2 Corporate Drive, South San Francisco, CA 94080.
↵ ‖ To whom reprint requests should be addressed. E-mail: tpms{at}itsa.ucsf.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

TG,

trigeminal ganglia;

HSV-1,

herpes simplex virus type 1;

LAT,

latency-associated transcript;

TK,

thymidine kinase;

gC,

glycoprotein C;

ISH,

in situ hybridization