Herpes simplex viruses type 1 and 2 (HSV-1, HSV-2) cause genital herpes (GH). GH is medically significant as a co-factor for HlV-1 transmission and progression and results in considerable physical and psychological pain and suffering. Long-term, an effective preventative vaccine w/ill be required to reduce the burden of HSV-1 and HSV-2. Recent trials of adjuvanted subunit vaccines eliciting antibody and CD4 responses but not CDS responses failed to protect against HSV-2 infection or disease. Additionally, an immunotherapeutic vaccine for GH would be a valuable addition to licensed drugs. Recent data from our lab and other groups indicate that HSV-specific CDS T-cells localize and persist at sites of HSV infection suggesting that they prevent peripheral viral replication and thus may modulate primary and recurrent infection.
In Aim 1 we will enroll immunocompetent persons with mild or severe HSV-2 infection phenotypes, as defined by both clinical and HSV shedding criteria, and perform systematic studies of circulating CDS T-cell responses. Our methods provide high definition data concerning abundance, fine specificity and phenotypes of HSV-2- specific cells. Differences in target antigens specific for persons with mild infection may provide vaccine candidates that can elicit protective CDS T-cells. To study localization of CDS T-cells to the genital tract in asymptomatic persons, we will enroll women and in Aim 2 use T-cell receptor (TCR) hypervariable gene sequences as the signature of HSV-2-specific T-cells to study the localization of HSV-2-specific CDS T-cells in the cervix.
These Aim 2 TCR assays will be coordinated with Project 3 which studies skin-resident HSV-2- specific CDS T-cells. Primary genital HSV-1 infection is an emerging problem. In coordination with Project 4, Aim 3 of this Project will measure the dynamics of the T-cell response to primary genital HSV-1 infection. Assays for both CD4 and CDS responses will test if continuous priming of HSV-specific T-cells occurs during the first year following resolution of primary infection. This is important with regards to the possibility of therapeutic vaccination. The kinetics of acquistion of the profound skin homing program of HSV-1-specific CDS T-cells will also be defined.

Public Health Relevance

Understanding of the immune response to herpes simplex types 1 and 2 is an important component of making a vaccine. This Project will determine if a portion of the immune response termed CDS T-cells is correlated with genital herpes severity, and will also study the localization of these immune cells to infected tissues and the development of immunity in persons with new infections. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Posavad, C M; Zhao, L; Mueller, D E et al. (2015) Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract. Mucosal Immunol 8:115-26
Melvin, Ann J; Mohan, Kathleen M; Schiffer, Joshua T et al. (2015) Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr 166:827-33
Perti, Tara; Nyati, Mandisa; Gray, Glenda et al. (2014) Frequent genital HSV-2 shedding among women during labor in Soweto, South Africa. Infect Dis Obstet Gynecol 2014:258291
Dhankani, Varsha; Kutz, J Nathan; Schiffer, Joshua T (2014) Herpes simplex virus-2 genital tract shedding is not predictable over months or years in infected persons. PLoS Comput Biol 10:e1003922
Gantt, Soren; Cattamanchi, Ashok; Krantz, Elizabeth et al. (2014) Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy. J Clin Virol 60:127-32
Johnston, Christine; Zhu, Jia; Jing, Lichen et al. (2014) Virologic and immunologic evidence of multifocal genital herpes simplex virus 2 infection. J Virol 88:4921-31
Slyker, Jennifer; Farquhar, Carey; Atkinson, Claire et al. (2014) Compartmentalized cytomegalovirus replication and transmission in the setting of maternal HIV-1 infection. Clin Infect Dis 58:564-72
Delaney, Shani; Gardella, Carolyn; Saracino, Misty et al. (2014) Seroprevalence of herpes simplex virus type 1 and 2 among pregnant women, 1989-2010. JAMA 312:746-8
Phipps, Warren; Saracino, Misty; Selke, Stacy et al. (2014) Oral HHV-8 replication among women in Mombasa, Kenya. J Med Virol 86:1759-65
Mark, Karen E; Spruance, Spotswood; Kinghorn, George R et al. (2014) Three phase III randomized controlled trials of topical resiquimod 0.01-percent gel to reduce anogenital herpes recurrences. Antimicrob Agents Chemother 58:5016-23

Showing the most recent 10 out of 270 publications