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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI030731-24
Application #
8696990
Study Section
Special Emphasis Panel (ZAI1-LR-M)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
24
Fiscal Year
2014
Total Cost
$337,055
Indirect Cost
$143,345
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Tjernlund, Annelie; Burgener, Adam; Lindvall, Jessica M et al. (2016) In Situ Staining and Laser Capture Microdissection of Lymph Node Residing SIV Gag-Specific CD8+ T cells--A Tool to Interrogate a Functional Immune Response Ex Vivo. PLoS One 11:e0149907
Nason, Martha C; Patel, Eshan U; Kirkpatrick, Allison R et al. (2016) Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment. Open Forum Infect Dis 3:ofw073
Bender Ignacio, Rachel A; Goldman, Jason D; Magaret, Amalia S et al. (2016) Patterns of human herpesvirus-8 oral shedding among diverse cohorts of human herpesvirus-8 seropositive persons. Infect Agent Cancer 11:7

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