Level of Herpes Simplex Virus Type 1 Latency Correlates with Severity of Corneal Scarring and Exhaustion of CD8⁺T Cells in Trigeminal Ganglia of Latently Infected Mice

Abstract

A hallmark of infection with herpes simplex virus type 1 (HSV-1) is the establishment of latency in ganglia of the infected individual. During the life of the latently infected individual, the virus can occasionally reactivate, travel back to the eye, and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) is the scarring induced by HSV-1 following reactivation from latency. In this study, we evaluated the relationship between the amount of CS and the level of the HSV-1 latency-associated transcript (LAT) in trigeminal ganglia (TG) of latently infected mice. Our results suggested that the amount of CS was not related to the amount of virus replication following primary ocular HSV-1 infection, since replication in the eyes was similar in mice that did not develop CS, mice that developed CS in just one eye, and mice that developed CS in both eyes. In contrast, mice with no CS had significantly less LAT, and thus presumably less latency, in their TG than mice that had CS in both eyes. Higher CS also correlated with higher levels of mRNAs for PD-1, CD4, CD8, F4/80, interleukin-4, gamma interferon, granzyme A, and granzyme B in both cornea and TG. These results suggest that (i) the immunopathology induced by HSV-1 infection does not correlate with primary virus replication in the eye; (ii) increased CS appears to correlate with increased latency in the TG, although the possible cause-and-effect relationship is not known; and (iii) increased latency in mouse TG correlates with higher levels of PD-1 mRNA, suggesting exhaustion of CD8 ؉ T cells.

Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

“…In a previous study, we correlated higher levels of CS with increased expression of CD8 and PD-1 in the TG of HSV-1-infected mice (38). We have also previously observed a higher level of virus replication and a reduction in viral clearance in the TG of gKimmunized mice (2,20).…”

“…Previously, we and others have shown that reduced functionality of CD8 ϩ T cells is associated with the expression of the exhaustion marker PD-1 (15,38). CD8 ϩ T cell exhaustion has been observed in a multitude of chronic infections, such as cytomegalovirus (CMV), HSV-1, Friend virus, simian immunodeficiency virus (SIV), hepatitis C virus (HCV), hepatitis B virus (HBV), and Mycobacterium tuberculosis (27,28,33,42,44,46,53).…”

“…This peptide increased levels of viral neurovirulence and virus-induced CS in ocularly infected mice. Moreover, in HSVinfected "humanized" HLA-A*0201 transgenic mice, the gK peptide induced strong cytotoxic responses (38). Recently, we have shown that the level of HSV-1 latency correlates with severity of CS and exhaustion of CD8 ϩ T cells in the trigeminal ganglia (TG) of latently infected mice (38).…”

“…Moreover, in HSVinfected "humanized" HLA-A*0201 transgenic mice, the gK peptide induced strong cytotoxic responses (38). Recently, we have shown that the level of HSV-1 latency correlates with severity of CS and exhaustion of CD8 ϩ T cells in the trigeminal ganglia (TG) of latently infected mice (38). As described above, gK immunization (2,(17)(18)(19)(20), gK recombinant viruses expressing two extra copies of gK (41), or a gK peptide (39) exacerbates eye disease in different strains of mice.…”

Virus Diagnostics and Antiviral Therapy in Acute Retinal Necrosis (ARN)

“…HSV-1 was shown to induce a local, CD8+ T cell-mediated, non-lytical inflammation in human trigeminal ganglia (Mott et al, 2009;Theil et al, 2003). These CD8+ T cells seem to block HSV reactivation via release of granzyme B which selectively degrades one of the regulatory proteins of HSV-1 and inhibits reactivation already in the very early phase (Khanna et al, 2004;Knickelbein et al, 2008).…”