title: Coregulatory interactions among CD8α dendritic cells, the latency-associated transcript, and programmed death 1 contribute to higher levels of herpes simplex virus 1 latency.
abstract: The latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1), CD8α(+) dendritic cells (DCs), and programmed death 1 (PD-1) have all been implicated in the HSV-1 latency-reactivation cycle. It is not known, however, whether an interaction between LAT and CD8α(+) DCs regulates latency and T-cell exhaustion. To address this question, we used LAT-expressing [LAT(+)] and LAT-negative [LAT(-)] viruses. Depletion of DCs in mice ocularly infected with LAT(+) virus resulted in a reduction in the number of T cells expressing PD-1 in the trigeminal ganglia (TG), whereas depletion of DCs in mice similarly infected with LAT(-) virus did not alter PD-1 expression. CD8α(+) DCs, but not CD4(+) DCs, infected with LAT(+) virus had higher levels of ICP0, ICP4, thymidine kinase (TK), and PD-1 ligand 1 (PD-L1) transcripts than those infected with LAT(-) virus. Coculture of infected bone marrow (BM)-derived DCs from wild-type (WT) mice, but not infected DCs from CD8α(-/-) mice, with WT naive T cells contributed to an increase in PD-1 expression. Transfer of bone marrow from WT mice but not CD8α(-/-) mice to recipient Rag1(-/-) mice increased the number of latent viral genomes in reconstituted mice infected with the LAT(+) virus. Collectively, these data indicated that a reduction in latency correlated with a decline in the levels of CD8α(+) DCs and PD-1 expression. In summary, our results demonstrate an interaction among LAT, PD-1, and CD11c CD8α(+) cells that regulates latency in the TG of HSV-1-infected mice.
  
  
  OBJECTIVE
  Very little is known regarding the interrelationship of LAT, PD-1, and CD8α(+) DCs and how such interactions might contribute to relative numbers of latent viral genomes. We show here that (i) in both in vivo and in vitro studies, deficiency of CD8α(+) DCs significantly reduced T-cell exhaustion in the presence of LAT(+) virus but not LAT(-) virus; (ii) HSV-1 infectivity was significantly lower in LAT(-)-infected DCs than in their LAT(+)-infected counterparts; and (iii) adoptive transfer of bone marrow (BM) from WT but not CD8α(-/-) mice to recipient Rag1(-/-) mice restored latency to the level in WT mice following infection with LAT(+) virus. These studies point to a key role for CD8α(+) DCs in T-cell exhaustion in the presence of LAT, which leads to larger numbers of latent viral genomes. Thus, altering this negative function of CD8α(+) DCs can potentially be used to generate a more effective vaccine against HSV infection.
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Mott
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA.
authors.forename: Sariah J
authors.initials: SJ
authors.lastname: Allen
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA.
authors.forename: Mandana
authors.initials: M
authors.lastname: Zandian
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA ghiasih@cshs.org.
authors.forename: Homayon
authors.initials: H
authors.lastname: Ghiasi
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D006561:Herpes Simplex / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000821:virology; D017735:Virus Latency
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D035683:MicroRNAs; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C477253:latency associated transcript, herpes simplex virus-1