Herpes simplex virus type 1 (HSV-1) is a medically significant pathogen. 60% of US citizens are infected and rates are higher in developing countries. Serious complications, such as permanent brain damage from encephalitis in adults or neonates, and corneal inflammation leading to blindness and poor long- term outcomes even after corneal transplantation, occur at a low per-person rate. Because infection is so prevalent, the cumulative medical impact of these complications is quite considerable. There is no licensed vaccine for HSV-1. A vaccine for HSV-2, a pathogen with overall 50% amino acid identity, had no clinical activity in a recent phase III trial. This HSV-2 vaccine targeted antibody and CD4 T-cell responses, but not CD8 T-cell responses. The long-term goal of this research is the rational design of preventative and therapeutic vaccines for HSV-1. CD8 T-cells are a critical component of the immune response to HSV-1 and localize to infected skin, cornea, retina, and trigeminal ganglia. By implication from human HSV-2 and murine HSV-1 data, CD8 cells persist at sites of healed skin infection to provide early surveillance for reactivation. Almost nothing is known about their fine specificity in humans. We have developed novel technology what allows us to study the CD8 and CD4 T-cell response to HSV-1 in unprecedented detail, including the study of peripheral blood from person who never have herpetic lesions, that is, person with immunologic success.
Aim 1 uses a sequence of novel methods: efficient cross-presentation, CD137-based sorting, and a library of cloned HSV-1 ORFs, to decode the CD8 response to HSV with high throughput and definition. We will compare immune responses in persons with symptomatic and asymptomatic HSV-1 infection and identify antigens that have both high population prevalence and correlate with asymptomatic infection. HSV-1-specific CD4s localize to infected eyes, TG, and skin in humans, and to infected tissues in mice, and likely provide important direct antiviral and helper functions.
Aim 2 defines with high throughput, using the complete ORFeome, the breadth, specificity, and within-subject true immunodominance hierarchy of HSV-1-specific CD4 responses. The workflow uses CD137-based sorting to and a highly antigenic HSV-1 ORFeome protein set. Dominance assays are combinatorial in two dimensions (responder cell oligoclonality and matrix ORF pooling) and deliver the fine specificity of ~100 individual HSV-1-specific CD4 T-cells per subject to define the CD4 dominance architecture. The overall goal of the Project is to identify HSV-1 ORFs for vaccines that stimulate dominant and prevalent CD8 and CD4 epitopes to persons of diverse HLA type that are correlated with mild infection.

Public Health Relevance

The long term goal of this research is the creation of preventative and therapeutic vaccines to reduce HSV-1 infection and HSV-1-associated disease. HSV-1 causes severe brain and eye infections in adults and devastating infections of newborns. The components of the complex HSV-1 virus that best stimulate arms of the immune response termed CD4 and CD8 T-cells will be uncovered using several novel tools and a cohort of well characterized human volunteer subjects.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Beisel, Christopher E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Traidl, Stephan; Kienlin, Petra; Begemann, Gabriele et al. (2018) Patients with atopic dermatitis and history of eczema herpeticum elicit herpes simplex virus-specific type 2 immune responses. J Allergy Clin Immunol 141:1144-1147.e5
Kleinstein, Sarah E; Shea, Patrick R; Allen, Andrew S et al. (2018) Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). Genes Immun :
Aravantinou, Meropi; Mizenina, Olga; Calenda, Giulia et al. (2017) Experimental Oral Herpes Simplex Virus-1 (HSV-1) Co-infection in Simian Immunodeficiency Virus (SIV)-Infected Rhesus Macaques. Front Microbiol 8:2342
Ott, Mariliis; Jing, Lichen; Lorenzo, Lazaro et al. (2017) T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis. Pediatr Infect Dis J 36:741-744
Bender Ignacio, Rachel A; Ramchandani, Meena S; Laing, Kerry J et al. (2017) T Cell Immunity to Varicella-Zoster Virus in the Setting of Advanced HIV and Multiple Varicella-Zoster Virus Recurrences. Viral Immunol 30:77-80
Koelle, David M; Norberg, Peter; Fitzgibbon, Matthew P et al. (2017) Worldwide circulation of HSV-2?×?HSV-1 recombinant strains. Sci Rep 7:44084
Posavad, C M; Zhao, L; Dong, L et al. (2017) Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract. Mucosal Immunol 10:1259-1269
Johnston, Christine; Magaret, Amalia; Roychoudhury, Pavitra et al. (2017) Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study. PLoS Med 14:e1002475
Hensel, Michael T; Peng, Tao; Cheng, Anqi et al. (2017) Selective Expression of CCR10 and CXCR3 by Circulating Human Herpes Simplex Virus-Specific CD8 T Cells. J Virol 91:
Abana, Chike O; Pilkinton, Mark A; Gaudieri, Silvana et al. (2017) Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects. J Immunol 199:3187-3201

Showing the most recent 10 out of 28 publications