Herpes simplex virus type-2 (HSV-2) infections are lifelong, and a leading cause of genital ulcer disease worldwide. The clinical outcome of genital HSV-2 reactivation varies widely from completely asymptomatic to infrequent and short-lasting recurrences to frequent and severe genital ulcerations: reasons for this variability are not known. Using biopsies of genital skin and mucosa from human volunteers, we have shown that HSV-2 reactivation results in a long-term persistence of local immune responses. CD8 T cells persist at the dermal-epidermal junction (DEJ) contiguous to the sensory nerve endings where virions are released. The unique anatomical distribution suggests that local CDS T cells might play a pivotal role in rapid containment of viral infection in the periphery, thus influencing the clinical and virologic course of HSV-2 disease in humans. In the last grant cycle, we developed a cell-type specific laser capture microdissection (LCM) method to isolate individual CD8 T cells in situ and measure their activity. By using combined approaches of CD8-specific LCM, whole genome transcriptional profiling and TCR repertoire deep sequencing, we can now elucidate associations between tissue resident memory CD8 T cells and genital herpes disease severity in humans. In this project, we will investigate the association between HSV-2 disease severity and the quantity, quality and diversity of tissue resident memory CD8 T cells at the site of previous HSV-2 recurrence in humans.
Our specific aims are: 1) to define whether the anatomic distribution, density, decay kinetics and the antiviral signature genes of tissue resident memory CD8 T cells differ in participants with mild versus severe genital HSV-2 diseases;2) to define whether the T cell receptor (TCR) repertoire dynamics and antigenic specificity of tissue resident memory CD8 T cells are associated with genital herpes disease severity. We will obtain sequential biopsy tissues from patient cohorts with distinct disease outcomes: mild disease, defined as recurrence rate <2 episodes per year and severe disease as recurrence rate >6 episodes per year. This project will define the characteristics of a successful peripheral immune response to HSV-2 that can be harnessed as a potential correlate of immunity during vaccine development.

Public Health Relevance

Genital herpes affects 17% of US population;no cure or vaccine is available. We do not know why some people with this infection have severe disease, and others very mild. We have developed new laboratory methods to study immune cells in samples from people with genital herpes that we will apply to understand the difference between people with mild and severe disease in order to develop an effective vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI030731-24
Application #
8696991
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
$244,115
Indirect Cost
$50,373
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Magaret, Amalia S; Mujugira, Andrew; Hughes, James P et al. (2016) Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples. Clin Infect Dis 62:456-61
Oseso, Linda; Magaret, Amalia S; Jerome, Keith R et al. (2016) Attitudes and Willingness to Assume Risk of Experimental Therapy to Eradicate Genital Herpes Simplex Virus Infection. Sex Transm Dis 43:566-71
Magaret, A; Dong, L; John, M et al. (2016) HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions. Genes Immun 17:412-418
Jing, Lichen; Laing, Kerry J; Dong, Lichun et al. (2016) Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses. J Immunol 196:2205-18
Manguro, Griffins O; Masese, Linnet N; Deya, Ruth W et al. (2016) Genital HSV Shedding among Kenyan Women Initiating Antiretroviral Therapy. PLoS One 11:e0163541
Ramchandani, Meena; Kong, Marlene; Tronstein, Elizabeth et al. (2016) Herpes Simplex Virus Type 1 Shedding in Tears and Nasal and Oral Mucosa of Healthy Adults. Sex Transm Dis 43:756-760
Milman, Neta; Zhu, Jia; Johnston, Christine et al. (2016) In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. J Infect Dis 214:23-31
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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