Efficacy of a Recombinant Glycoprotein D Subunit Vaccine on the Development of Primary and Recurrent Ocular Infection with Herpes Simplex Virus Type 1 in Mice

Ocular herpes simplex virus type 1 (HSV-1) infection elicits a strong inflammatory response that is associated with production of the β chemokines CCL3 and CCL5, which share a common receptor, CCR5. To gain insight into the role of these molecules in ocular immune responses, the corneas of wild-type (WT) and CCR5-deficient (CCR5−/−) mice were infected with HSV-1 and inflammatory parameters were measured. In the absence of CCR5, the early infiltration of neutrophils into the cornea was diminished. Associated with this aberrant leukocyte recruitment, neutrophils in CCR5−/− mice were restricted to the stroma, whereas in WT mice, these cells trafficked to the stroma and epithelial layers of the infected cornea. Virus titres and cytokine/chemokine levels in the infected tissue of these mice were similar for the first 5 days after infection. However, by day 7 post-infection, the CCR5−/− mice showed a significant elevation in the chemokines CCL2, CCL5, CXCL9 and CXCL10 in the trigeminal ganglion and brainstem, as well as a significant increase in virus burden. The increase in chemokine expression was associated with an increase in the infiltration of CD4 and/or CD8 T cells into the trigeminal ganglion and brainstem of CCR5−/− mice. Surprisingly, even though infected CCR5−/− mice were less efficient at controlling the progression of virus replication, there was no difference in mortality. These results suggest that, although CCR5 plays a role in regulating leukocyte trafficking and control of virus burden, compensatory mechanisms are involved in preventing mortality following HSV-1 infection.

Download Full-text

A Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutant with Increased Virulence and Reduced Spontaneous Reactivation

Journal of Virology ◽

10.1128/jvi.73.2.920-929.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 920-929 ◽

Cited By ~ 40

Author(s):

Guey-Chuen Perng ◽

Susan M. Slanina ◽

Ada Yukht ◽

Barbara S. Drolet ◽

William Keleher ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Wild Type ◽

Simplex Virus ◽

Spontaneous Reactivation ◽

Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is essential for efficient spontaneous reactivation of HSV-1 from latency. We previously reported that insertion of the LAT promoter and just the first 1.5 kb of the 8.3-kb LAT gene into an ectopic location in the virus restored wild-type spontaneous reactivation to a LAT null mutant. This mutant, LAT3.3A (previously designated LAT1.5a), thus showed that the expression of just the first 1.5 kb of LAT is sufficient for wild-type spontaneous reactivation. We also showed that in the context of the entire LAT gene, deletion of LAT nucleotides 76 to 447 (LAT mutantdLAT371) had no effect on spontaneous reactivation or virulence. We report here on a LAT mutant designated LAT2.9A. This mutant is similar to LAT3.3A, except that the ectopic LAT insert contains the same 371-nucleotide deletion found in dLAT371. We found that LAT2.9A had a significantly reduced rate of spontaneous reactivation compared to marker-rescued and wild-type viruses. This was unexpected, since the combined results of dLAT371 and LAT3.3A predicted that spontaneous reactivation of LAT2.9A would be wild type. We also found that LAT2.9A was more virulent than wild-type or marker-rescued viruses after ocular infection of rabbits. This was unexpected, since LAT null mutants and LAT3.3A have wild-type virulence. These results suggest for the first time (i) that regions past the first 1.5 kb of LAT can compensate for deletions in the first 1.5kb of LAT and may therefore play a role in LAT dependent spontaneous reactivation and (ii) that regions of LAT affect viral virulence.

Download Full-text

Effect of undernourishment on Herpes Simplex Virus Type 1 ocular infection in the Wistar rat model

International Journal of Experimental Pathology ◽

10.1046/j.1365-2613.2002.00212.x ◽

2002 ◽

Vol 83 (2) ◽

pp. 57-66 ◽

Cited By ~ 1

Author(s):

FABIÁN BENENCIA ◽

GISELA GAMBA ◽

RUBÉN BENEDETTI ◽

MARÍA C. COURRÈGES ◽

HERNÁN CAVALIERI ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Rat Model ◽

Herpes Simplex Virus Type ◽

Wistar Rat ◽

Ocular Infection ◽

Simplex Virus

Download Full-text

A Cationic Peptide, TAT-Cd0, Inhibits Herpes Simplex Virus Type 1 Ocular Infection In Vivo

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.12-10250 ◽

2013 ◽

Vol 54 (2) ◽

pp. 1070 ◽

Cited By ~ 11

Author(s):

Gilbert G. Jose ◽

Inna V. Larsen ◽

Joshua Gauger ◽

Erica Carballo ◽

Rebecca Stern ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Cationic Peptide ◽

Simplex Virus

Download Full-text

Induction of Mucosal Immunity against Herpes Simplex Virus Type 1 in the Mouse Protects against Ocular Infection and Establishment of Latency

The Journal of Infectious Diseases ◽

10.1086/515302 ◽

1998 ◽

Vol 177 (6) ◽

pp. 1451-1457 ◽

Cited By ~ 20

Author(s):

C. M. Richards ◽

C. Shimeld ◽

N. A. Williams ◽

T. J. Hill

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Mucosal Immunity ◽

Ocular Infection ◽

Simplex Virus

Download Full-text

Better Neutralization of Herpes Simplex Virus Type 1 (HSV-1) Than HSV-2 by Antibody From Recipients of GlaxoSmithKline HSV-2 Glycoprotein D2 Subunit Vaccine

The Journal of Infectious Diseases ◽

10.1093/infdis/jiu177 ◽

2014 ◽

Vol 210 (4) ◽

pp. 571-575 ◽

Cited By ~ 37

Author(s):

Sita Awasthi ◽

Robert B. Belshe ◽

Harvey M. Friedman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Subunit Vaccine ◽

Simplex Virus ◽

Hsv 1

Download Full-text

The Latency-Associated Transcript Gene Enhances Establishment of Herpes Simplex Virus Type 1 Latency in Rabbits

Journal of Virology ◽

10.1128/jvi.74.4.1885-1891.2000 ◽

2000 ◽

Vol 74 (4) ◽

pp. 1885-1891 ◽

Cited By ~ 79

Author(s):

Guey-Chuen Perng ◽

Susan M. Slanina ◽

Ada Yukht ◽

Homayon Ghiasi ◽

Anthony B. Nesburn ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Fluorescent Protein ◽

Ocular Infection ◽

Latently Infected ◽

Simplex Virus ◽

Hsv 1

ABSTRACT The latency-associated transcript (LAT) gene the only herpes simplex virus type 1 (HSV-1) gene abundantly transcribed during neuronal latency, is essential for efficient in vivo reactivation. Whether LAT increases reactivation by a direct effect on the reactivation process or whether it does so by increasing the establishment of latency, thereby making more latently infected neurons available for reactivation, is unclear. In mice, LAT-negative mutants appear to establish latency in fewer neurons than does wild-type HSV-1. However, this has not been confirmed in the rabbit, and the role of LAT in the establishment of latency remains controversial. To pursue this question, we inserted the gene for the enhanced green fluorescent protein (EGFP) under control of the LAT promoter in a LAT-negative virus (ΔLAT-EGFP) and in a LAT-positive virus (LAT-EGFP). Sixty days after ocular infection, trigeminal ganglia (TG) were removed from the latently infected rabbits, sectioned, and examined by fluorescence microscopy. EGFP was detected in significantly more LAT-EGFP-infected neurons than ΔLAT-EGFP-infected neurons (4.9% versus 2%, P < 0.0001). The percentages of EGFP-positive neurons per TG ranged from 0 to 4.6 for ΔLAT-EGFP and from 2.5 to 11.1 for LAT-EGFP (P = 0.003). Thus, LAT appeared to increase neuronal latency in rabbit TG by an average of two- to threefold. These results suggest that LAT enhances the establishment of latency in rabbits and that this may be one of the mechanisms by which LAT enhances spontaneous reactivation. These results do not rule out additional LAT functions that may be involved in maintenance of latency and/or reactivation from latency.

Download Full-text