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Lbachir BenMohamed, Xavier Dervillez, Huma Qureshi, Aziz Chentoufi, Chelsea Nguyen, Oscar Diaz, Anthony Nesburn, Steven Wechsler; The Herpes Simplex Virus-1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8+ T Cells in Trigeminal Ganglia of Latently Infected “humanized” HLA-transgenic rabbits. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2043.
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HSV-1-specific CD8+ T cells that reside in latently infected trigeminal ganglia (TG), appear to control recurrent herpetic disease by aborting or reducing spontaneous viral reactivations. The HSV-1 Latency-Associated Transcript (LAT), the only viral gene that is abundantly transcribed during latency, increases reactivation. In latently infected C57BL/6 mice: 1)HSV-specific (HSV-gB498-505) CD8+ T cells are induced and selectively retained in TG; and 2)more of these CD8+ T-cells expressed markers of exhaustion with LAT(+) compared to LAT(-) virus. However, mice do not mimic spontaneous viral shedding or recurrent disease as occurs in human. Thus, here we examined CD8+ T-cell exhaustion in latently infected “humanized” rabbits.
We used Human Leukocyte Antigen- (HLA-) transgenic rabbits, which: (1) have spontaneous reactivation with clinical features relevant to human disease; and (2) mount “humanized” CD8+ T cell responses specific to HLA-restricted epitopes. HLA-transgenic rabbit were infected with LAT(+) or LAT(-) HSV-1 and the number and function of CD8+ T cells, specific to human gB epitopes was determined in TG at different times.
HLA-transgenic rabbits latently infected with LAT(+) had more HLA-restricted CD8+ T cells than TG from HLA-transgenic rabbits latently infected with LAT(-) viruses. Thus, the previous findings in mice were not an artifact of species. Importantly, to our knowledge we show here for the first time that during LAT(+) virus latency most of the HSV-1 specific TG-resident CD8+ T-cells specific to human epitopes were phenotypically and functionally exhausted, as judged by high expression of PD-1, low proliferation and decreased IFN-γ production. This resulted in LAT(-) TG having more functional HLA-restricted, HSV-gB441-449- and gB561-569-specific CD8+ T cells, compared to LAT(+) TG.
These findings in “humanized” HLA-transgenic rabbits (1) confirm that the HSV-1 LAT promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8+ T cells in latently infected TG. This appears to be a LAT dependent immune evasion mechanism that results in increased reactivation; and (2) Suggest that TG are an immunological battleground where herpes-specific CD8+ T cells are continuously stimulated.
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