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Homayon Ghiasi, Pedram Hamrah, Kevin Mott, Arlene Sharpe, Lbachir BenMohamed, Rafi Ahmed, Steven Wechsler, Carl Ware, Sariah Allen; The Role Of HSV-1 LAT In Enhancement Of Latency And Increase Of CD8+ T Cell Exhaustion In Trigeminal Ganglia Of Infected Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2967.
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© ARVO (1962-2015); The Authors (2016-present)
Herpes simplex virus infection is a classical example of chronic and latent viral infection in both human and experimental animal models. Latency associated transcript (LAT) of HSV-1 plays a major role in HSV-1 recurrences. Whether the presence of LAT will alter viral load and lead to generation of dysfunctional T cell responses in trigeminal ganglia (TG) of infected mice is not known. We have used LAT(+) and LAT(-) viruses to address this issue.
WT (C57BL/6 and BALB/c), PD-1-/- (programmed death 1), PD-L1-/-, PD-L-2-/- (PD-1 ligands), and HVEM-/- (herpes virus entry mediator) mice were infected ocularly with 2 X 105 PFU/eye of WT (LAT-plus) HSV-1 strain McKrae, dLAT2903 (LAT-minus), HSV-gK3 (LAT-minus), or HSV-CD80 (LAT-minus). Individual TG from surviving mice were isolated on day 30 post-infection and used for detection of viral DNA. Isolated TGs were also tested for the presence of viral antigens, and exhaustion markers by FACS, RT-PCR, and immunostaining.
The level of latency was three fold higher in WT mice infected with LAT(+) then LAT(-) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that these TG contain both more CD8+ T cells and more exhausted CD8+ T cells. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1 gB498-505-specific CD8+ T cell pentamer, IL-2, IFN-γ, and TNF-α. The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1 and PD-L1 deficient mice but not PD-L2 deficient mice. Similar to PD-1 and PD-L1 deficient mice, the level of latency in the HVEM-/- mice infected with LAT(+) decreased by three fold and was similar to that of LAT(-) virus. The decrease of latency in HVEM-/- mice was correlated with a significant decline in the level of CD8, PD-1, and Tim-3 transcripts.
Together, these results provide key evidence that both PD-1 and Tim-3 are mediators of CD8+ T cell exhaustion that leads to increased HSV-1 latency. The CD8+ T cell exhaustion is directly due to constant presence of low-level of viral antigens in the TG which require HVEM to negatively impact virus-CD8+ T cell responses and the level of latency.
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