The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8(+) T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8(+) T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT((-)) virus: (1) LAT((+)) virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT((+)) virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-alpha; and (3) DCs infected in vitro with LAT((+)) virus had significantly reduced the ability to stimulate HSV-specific CD8(+) T cells. While a similar number of DCs was found in LAT((+)) and LAT((-)) latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT((+)) virus. Consistent with these findings, HSV-specific cytotoxic CD8(+) T cells in the TG of mice latently-infected with LAT((+)) virus produced less IFN-gamma and TNF-alpha than those from TG of LAT((-))-infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSV-specific CD8(+) T cells in the TG of mice latently infected with LAT((+)) virus.