The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 InfectionIn VivoDifferently than the Absence of Other HVEM Cellular Ligands

Abstract

Previously, we reported that the absence of herpesvirus entry mediator (HVEM) decreases latency but not primary infection in ocularly infected mice. Recently, we reported that similar to the absence of HVEM, the absence of HVEM ligands (i.e., LIGHT, CD160, and B and T lymphocyte attenuator [BTLA]) also decreased latency but not primary infection. Similar to LIGHT, CD160, and BTLA, another member of tumor necrosis factor (TNF) superfamily, lymphotoxin-␣ (LT␣), also interacts with HVEM. To determine whether LT␣ decreases latency in infected mice, we ocularly infected LT␣ Ϫ/Ϫ mice with latency-associated transcript-positive [LAT(ϩ)] and LAT(Ϫ) viruses using similarly infected wild-type (WT) mice as controls. In contrast to WT C57BL/6 mice, LT␣ Ϫ/Ϫ mice were highly susceptible to ocular herpes simplex virus 1 (HSV-1) infection, independent of the presence or absence of LAT. Survival was partially restored by adoptive transfer of CD4 ϩ , CD8 ϩ , or total T cells. Infected LT␣ Ϫ/Ϫ mice had significantly higher corneal scarring than WT mice, and adoptive T cell transfer did not alter the severity of eye disease. In contrast to results in WT mice, the amount of latency was not affected by the absence of LAT. The amount of LAT RNA in LT␣ Ϫ/Ϫ mice infected with LAT(ϩ) virus was similar to that in WT mice, and adoptive T cell transfer did not alter LAT RNA levels in LT␣ Ϫ/Ϫ infected mice. Increased latency in the absence of LT␣ correlated with upregulation of HVEM, LIGHT, CD160, and BTLA transcripts as well as with an increase in markers of T cell exhaustion. The results of our study suggest that LT␣ has antipathogenic and anti-inflammatory functions and may act to protect the host from infection. IMPORTANCE Recently, we evaluated the effects of HVEM and its ligands (LIGHT, CD160, and BTLA) on HSV-1 infectivity. However, the effect of LT␣, another member of the TNF superfamily, on HSV-1 latency and eye disease is not known. Here, we demonstrate increased latency and corneal scarring in LT␣ Ϫ/Ϫ infected mice, independent of the presence of LAT. In addition, infected mice were highly susceptible to HSV-1 infection, and survival was partially but not significantly restored by adoptive T cell transfer. These results suggest that the absence of LT␣ affects HSV-1 infectivity differently than the absence of HVEM, LIGHT, CD160, and BTLA.

Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM −/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D

“…We also demonstrated that efficient levels of latency, but not reactivation, depended on BTLA, CD160, and LIGHT (40). On the other hand, expression of LT␣ did not affect latency levels (41). To determine whether rescue of latency and reactivation in HVEM hWT , HVEM hY23A , or HVEM mY23A transgenic mice is due to differential effects on known HVEM binding partners in HVEM Ϫ/Ϫ and transgenic mice, expression of BTLA, CD160, and LIGHT was measured in the TG of mice latently infected with HSV-1 by qRT-PCR as described above.…”

“…Interestingly, we have also demonstrated that BTLA, LIGHT, and CD160 play roles in efficient establishment of latency but not in reactivation (40). LT␣, on the other hand, does not affect the establishment of latency (41). Currently, the mechanism of HVEM function in the latency and reactivation cycle is unclear.…”

Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 Glycoprotein K Binding Partner, Reduces Virus InfectivityIn Vivo

“…Each swab was placed in 1 ml of tissue culture medium and stored at -80°C until processing. The amount of virus in the medium was determined by a standard plaque assay using RS cells as we described previously (41,73).…”

Role of TH17 Responses in Increasing Herpetic Keratitis in the Eyes of Mice Infected with HSV-1

“…Quantitative real-time RT-PCR (qRT-PCR) was performed using QuantStudio 5 System (Applied Biosystems, Foster City, CA, USA) in 384-well plates as we described previously. 118,119…”