The transcriptional activation domain of VP16 is required for efficient infection and establishment of latency by HSV-1 in the murine peripheral and central nervous systems.
The herpes simplex virus (HSV) transactivator VP16 is a structural component of the virion that activates immediate-early viral gene expression. The HSV-1 mutant in1814, which contains a 12-bp insertion that compromises the transcriptional function of VP16, replicated to a low level if at all in the trigeminal ganglia of mice (I. Steiner, J. G. Spivack, S. L. Deshmane, C. I. Ace, C. M. Preston, and N. W. Fraser (1990). J. Virol. 64, 1630-1638; Valyi-Nagy et al., unpublished data). However, in1814 did establish a latent infection in the ganglia after corneal inoculation from which it could be reactivated. In this study, several HSV-1 strains were constructed with deletions in the VP16 transcriptional activation domain. These viruses were viable in cell culture, although some were significantly reduced in their ability to initiate infection. A deletion mutant completely lacking the activation domain of VP16 (RP5) was unable to replicate to any detectable level or to efficiently establish latent infections in the peripheral and central nervous systems of immunocompetent mice. However, similar to in1814, RP5 formed a slowly progressing persistent infection in immunocompromised nude mice. Thus RP5 is severely neuroattenuated in the murine model of HSV infection. However, the activation domain of VP16 is not essential for replication in the nervous system, since we observed a slow progressive infection persisting in the absence of an immune response.
Tal-Singer
R
R
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Pichyangkura
R
R
Chung
E
E
Lasner
T M
TM
Randazzo
B P
BP
Trojanowski
J Q
JQ
Fraser
N W
NW
Triezenberg
S J
SJ
D000818:Animals; D002490:Central Nervous System / Q000821:virology*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006561:Herpes Simplex / Q000503:physiopathology / Q000821:virology*; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D017933:Peripheral Nervous System / Q000821:virology*; D015533:Transcriptional Activation; D017735:Virus Latency / Q000235:genetics*
D017405:Herpes Simplex Virus Protein Vmw65