PMID- 10846077
OWN - NLM
STAT- MEDLINE
DCOM- 20000810
LR  - 20240314
IS  - 0022-538X (Print)
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 74
IP  - 13
DP  - 2000 Jul
TI  - Optimized viral dose and transient immunosuppression enable herpes simplex virus 
      ICP0-null mutants To establish wild-type levels of latency in vivo.
PG  - 5957-67
AB  - The reduced efficiency with which herpes simplex virus type 1 (HSV-1) mutants 
      establish latent infections in vivo has been a fundamental obstacle in efforts to 
      determine the roles of individual viral genes in HSV-1 reactivation. For example, 
      in the absence of the "nonessential" viral immediate-early protein, ICP0, HSV-1 
      is severely impaired in its ability to (i) replicate at the site of inoculation 
      and (ii) establish latency in neurons of the peripheral nervous system. The mouse 
      ocular model of HSV latency was used in the present study to determine if the 
      conditions of infection can be manipulated such that replication-impaired, 
      ICP0-null mutants establish wild-type levels of latency, as measured by viral 
      genome loads in latently infected trigeminal ganglia (TG). To this end, the 
      effects of inoculum size and transient immunosuppression on the levels of acute 
      replication in mouse eyes and of viral DNA in latently infected TG were examined. 
      Following inoculation of mice with 2 x 10(3), 2 x 10(4), 2 x 10(5), or 2 x 10(6) 
      PFU/eye, wild-type virus replicated in mouse eyes and established latency in TG 
      with similar efficiencies at all four doses. In contrast, increasing the inoculum 
      size of the ICP0-null mutants n212 and 7134 from 2 x 10(5) to 2 x 10(6) PFU/eye 
      significantly decreased the levels of infectious virus detected in the tear films 
      of mice from days 4 to 9 postinfection. In an attempt to establish the biological 
      basis for this finding, the effect of viral dose on the induction of the host 
      proinflammatory response was examined. Quantitative reverse transcription-PCR 
      demonstrated that increasing the inoculum of 7134 from 2 x 10(4) to 2 x 10(6) 
      PFU/eye significantly increased the expression of proinflammatory (interleukin 
      6), cell adhesion (intercellular adhesion molecule 1), and phagocyte-associated 
      (CD11b) genes in mouse eyes 24 h postinfection. Furthermore, transient 
      immunosuppression of mice with cyclophosphamide, but not cyclosporin A, 
      significantly enhanced both the levels of acute n212 and 7134 replication in the 
      eye and the levels of mutant viral genomes present in latently infected TG in a 
      dose-dependent manner. Thus, the results of this study demonstrate that acute 
      replication in the eye and the number of ICP0-null mutant genomes in latently 
      infected TG can be increased to wild-type levels for both n212 and 7134 by (i) 
      optimization of inoculum size and (ii) transient immunosuppression with 
      cyclophosphamide.
FAU - Halford, W P
AU  - Halford WP
AD  - Department of Microbiology, University of Pennsylvania School of Medicine, 
      Philadelphia 19104-6076, USA.
FAU - Schaffer, P A
AU  - Schaffer PA
LA  - eng
GR  - AI 10147/AI/NIAID NIH HHS/United States
GR  - P01 NS 35138/NS/NINDS NIH HHS/United States
GR  - P01 NS035138/NS/NINDS NIH HHS/United States
GR  - F32 AI010147-01/AI/NIAID NIH HHS/United States
GR  - F32 AI010147/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Immunosuppressive Agents)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Vmw110 protein, Human herpesvirus 1)
SB  - IM
MH  - Animals
MH  - Chlorocebus aethiops
MH  - Cyclophosphamide/pharmacology
MH  - Cyclosporine/pharmacology
MH  - Disease Models, Animal
MH  - Eye/virology
MH  - Genome, Viral
MH  - Herpes Simplex/*immunology/*virology
MH  - Herpesvirus 1, Human/immunology/physiology
MH  - Immediate-Early Proteins/genetics/*physiology
MH  - Immunosuppression Therapy
MH  - Immunosuppressive Agents/pharmacology
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mutagenesis
MH  - Trigeminal Ganglion/virology
MH  - Ubiquitin-Protein Ligases
MH  - Vero Cells
MH  - Viral Load
MH  - Virus Latency/*physiology
MH  - Virus Replication/drug effects
PMC - PMC112092
EDAT- 2000/06/14 09:00
MHDA- 2000/08/12 11:00
PMCR- 2000/07/01
CRDT- 2000/06/14 09:00
PHST- 2000/06/14 09:00 [pubmed]
PHST- 2000/08/12 11:00 [medline]
PHST- 2000/06/14 09:00 [entrez]
PHST- 2000/07/01 00:00 [pmc-release]
AID - 0214 [pii]
AID - 10.1128/jvi.74.13.5957-5967.2000 [doi]
PST - ppublish
SO  - J Virol. 2000 Jul;74(13):5957-67. doi: 10.1128/jvi.74.13.5957-5967.2000.