Control of herpes simplex virus type 1 latency in human trigeminal ganglia

Held, Kathrin (2012): Control of herpes simplex virus type 1 latency in human trigeminal ganglia. Dissertation, LMU München: Fakultät für Biologie

Abstract

Herpes simplex virus type 1 (HSV-1) is a double-stranded DNA virus that infects humans and, after a primary lytic infection, establishes lifelong latency in the sensory neurons of the trigeminal ganglia (TG). HSV 1 latency is accompanied by a chronic immune cell infiltration of the TG, the infiltrate being mainly composed of CD8+ T cells. These T cells are believed to control viral latency, but cellular and viral factors like viral microRNAs are also considered to play a crucial role in the establishment and maintenance of viral latency. In the present work, it was investigated whether the tissue-infiltrating T cells are clonally expanded, which would indicate that these T cells are activated by antigen. By applying complementarity determining region 3 (CDR3) spectratyping and immunohistochemistry, several clonal expansions were identified in the TG-resident T cells. In addition, several T cells were present that seemed to be unspecific bystander T cells. Strikingly, some expanded T cell clones were present in the right and left TG of the same individual. This strongly suggests that similar antigens are present in both TG and that the infiltration of immune cells to the TG is driven by antigen. The morphology of the TG was investigated by immunohistochemistry and in situ hybridiza¬tion. Analysis of the distribution of T cells throughout the TG provided puzzling results: unexpectedly, most neurons surrounded by T cells did not harbour the only known prominent transcript during latency, the latency associated transcript (LAT). Whether these neurons do actually harbour latent virus was addressed by a combination of LAT in situ hybridisation, T cell immunohistochemistry, and single cell analysis of laser microdissected sensory neurons by PCR. This analysis revealed that only LAT+ neurons were harbouring HSV 1 DNA and viral microRNAs. Also, mRNA for a viral gene product was only detected in LAT+ neurons. All analysed LAT– neurons were devoid of viral microRNAs and DNA of HSV 1. DNA of HSV 2 or varicella-zoster virus (VZV) was not detected in any of the excised neurons. Alto¬gether this indicates that in the vast majority of infected human neurons, HSV 1 latency is not directly controlled by T cells, but rather by cellular or viral factors like the miRNAs. Our data suggest that CD8+ T cells only come into action if these mechanisms are overrun.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. April 2012
• 1. Bericht­erstatter:in: Straka, Hans