Phenotypic and Functional Signatures of Herpes Simplex Virus–Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes

Abstract

HSV type 1 (HSV-1)-specific CD8 T cells protect from herpes infection and disease. However, the nature of protective CD8 T cells in HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (with no history of clinical herpes disease) remains to be determined. In this study, we compared the phenotype and function of HSV-specific CD8 T cells from HLA-A*02:01-positive ASYMP and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that although SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8 T cells, the "naturally" protected ASYMP individuals have a significantly higher proportion of multifunctional HSV-specific effector memory CD8 T cells (CD73CD45RACCR7CD8 effector memory RA (T) and CD73CD45RACCR7CD8 effector memory (T) as compared with SYMP individuals. Similar to humans, HSV-1-infected ASYMP B6 mice had frequent multifunctional HSV-specific CD73CD8 T cells in the cornea, as compared with SYMP mice. Moreover, in contrast to wild type B6, CD73 deficient mice infected ocularly with HSV-1 developed more recurrent corneal herpetic infection and disease. This was associated with less functional CD8 T cells in the cornea and trigeminal ganglia, the sites of acute and latent infection. The phenotypic and functional characteristics of HSV-specific circulating and in situ CD73CD8 T cells, demonstrated in both ASYMP humans and mice, suggest a positive role for effector memory CD8 T cells expressing the CD73 costimulatory molecule in the protection against ocular herpes infection and disease. These findings are important for the development of safe and effective T cell-based herpes immunotherapy.

NLRP3, NLRP12, and IFI16 Inflammasomes Induction and Caspase-1 Activation Triggered by Virulent HSV-1 Strains Are Associated With Severe Corneal Inflammatory Herpetic Disease

“…Early during viral infections, canonical, and non-canonical inflammasomes detect virulent and less-virulent virus pathogens orchestrating the innate and adaptive immunity to clear the infection and cure the disease [reviewed in Sutterwala et al (31) and Elliott and Sutterwala (32)]. Activation of inflammasomes by viral factors triggers maturation of proinflammatory cytokines and chemokines that function to recruit immune cells, such as neutrophils, dendritic cells, inflammatory monocytes and CD4 + T cells, to the site of viral infection (8, 9). This optimal activation of inflammasomes is highly beneficial to the well-being of the host as it helps the innate and adaptive immune system in clearing the infection and/or curing the ensuing disease (5–7).…”

“…Moreover, we are also determining whether these inflammasome pathways will be associated with the severity of eye disease and the neuroinvasiveness, comparing wild type B6 mice to NLRP3, NLRP6, NLRP12, AIM2, and IFI16 inflammasomes deficient mice (KO mice). Over the last few years, we have focused on determining how factors in the host's immune system, particularly T cells, affect SYMP and ASYMP individuals with herpes infections (9, 88, 89). Besides potential differences in the immune system between SYMP and ASYMP individuals, it is likely that clinical isolates from SYMP but not from ASYMP have a specific genotypic profile with potential genes (or factors) of virulence.…”

Antiviral CD19+CD27+ Memory B Cells Are Associated with Protection from Recurrent Asymptomatic Ocular Herpes Infection

“…Current anti-viral drug therapies (e.g., Acyclovir and derivatives) do not eliminate the virus and reduce recurrent herpetic disease by only ~45% (5,6). The challenge in developing an effective herpes treatment or vaccine is to determine the immune correlates of protection (7)(8)(9)(10)(11)(12)(13). Profiling humoral immunity in asymptomatic (ASYMP) and symptomatic (SYMP) HSV-1 infected individuals will further help in the 1) understanding if SYMP individuals have dampened humoral immune response in natural infection, 2) knowing immune correlates of protection that will help to understand vaccine efficacy, and 3) standardizing methods to explore vaccine efficacy.…”

Therapeutic Mucosal Vaccination of Herpes Simplex Virus 2-Infected Guinea Pigs with Ribonucleotide Reductase 2 (RR2) Protein Boosts Antiviral Neutralizing Antibodies and Local Tissue-Resident CD4 + and CD8 + T RM Cells Associated with Protection against Recurrent Genital Herpes

“…Currently, the medical opinion is that an effective antiviral therapeutic vaccine would constitute the best approach to protect from recurrent genital herpetic disease (2,4). It is becoming increasingly clear that the acquired immune responses that develop following first exposure to the virus are not sufficient for protection against recurrent genital herpes in symptomatic women (12)(13)(14). This implies that a successful therapeutic vaccine must be able to boost an immune response that is stronger and/or different than the acquired immunity induced by the virus itself (15).…”