Specific and Nonspecific Immune Stimulation of MHC-II-Deficient Mice Results in Chronic HSV-1 Infection of the Trigeminal Ganglia Following Ocular Challenge

Abstract

Ocular herpes simplex virus type 1 (HSV-1) infection of MHC-II-deficient mice (AO/Oβ mice) or their parental C57BL/6J wild-type mice resulted in the establishment of typical HSV-1 latent infections in the trigeminal ganglia (TG) of the surviving mice by day 28 postinfection. Latency was characterized by the complete absence of infectious virus in TG extracts, the ability to recover latent virus only following prolonged tissue culture cultivation of explanted TG, and the presence of HSV-1 DNA in TG extracts. When mice were vaccinated prior to ocular HSV-1 challenge, latency appeared unaltered in the C57BL/6J wild-type mice. However, in AO/Oβ mice, clearance of virus from the TG appeared to be seriously impaired, resulting in a chronic productive infection, rather than a latent infection. Infectious virus was readily detected in TG extracts of vaccinated AO/Oβ mice until at least 63 days postinfection. Glycoprotein B mRNA was also readily detected, confirming continued viral transcription. These chronic infections occurred regardless of whether the AO/Oβ mice were vaccinated with HSV-1-specific antigens (i.e., live HSV-1 strain KOS, recombinantly expressed HSV-1 glycoprotein D plus Freund's adjuvant, or a mixture of seven recombinantly expressed HSV-1 glycoproteins plus adjuvant) or non-HSV-1-specific antigens (i.e., tissue culture medium plus 5% fetal bovine serum, the expression vector plus adjuvant, or adjuvant alone). Passive transfer of HSV-1 neutralizing antibody to vaccinated AO/Oβ mice between days 0 and 28 post-ocular challenge did not clear infectious virus from the TG. Passive transfer of anti-HSV-1 antibody or purified naive mouse serum to unvaccinated AO/Oβ mice on days 3 or 6 post-HSV-1 ocular challenge also resulted in chronic, rather than latent, infection of the TG. Passive transfer of naive sera from B-cell-deficient mice or injection of keyhole limpet hemocyanin or purified IgG, but not PBS or dextran, 3 days after HSV-1 challenge also resulted in chronic infection of the TG.