Dr. Christine Johnston completed Infectious Diseases fellowship and an MPH degree in epidemiology at the University of Washington in 2007. This proposal describes a 5 year training program which will allow her to develop an independent academic career in clinical research studying genital herpes simplex virus-2 (HSV-2) infection, and will build on prior experiences studying host-viral interactions and herpesvirus replication at mucosal surfaces. Drs. Anna Wald and Lawrence Corey are internationally renowned leaders in clinical HSV-2 research and are co-mentors for this award. HSV-2 is the most prevalent sexually transmitted infection worldwide and has emerged as a significant risk factor for acquisition and transmission of HIV. HSV-2 transmission most frequently occurs during periods of asymptomatic genital shedding. Our group has recently used intensive sampling (swabbing the genital surfaces 4 times per day) to demonstrate that the majority of genital shedding episodes last less than 12 hours, suggesting a frequent reactivation rate from the ganglia and a brisk peripheral immune response. Preliminary data indicate that subclinical shedding may occur simultaneously at several genital locations and that """"""""short bursts"""""""" of HSV-2 replication occur in the presence of suppressive antiviral therapy. These data suggest that 1) we may have overestimated the degree of suppression provided by antiviral therapy and 2) genital mucosal responses are essential for control of HSV-2 replication. To evaluate """"""""short bursts"""""""" of shedding, a cohort of 50 HSV-2 seropositive persons on suppressive antiviral therapy will obtain genital swabs 4 times per day for 60 days. The rate and duration of HSV-2 shedding episodes will be compared with rates off therapy (Aim 1).
For Aims 2 &3,15 HSV-2 seropositive people not on therapy (Aim 2) and 15 persons on suppressive therapy (Aim 3) will be seen daily over a 30 day period to capture episodes of asymptomatic shedding, using a novel rapid HSV PCR test. Genital biopsies will be performed within hours of HSV-2 detection. Gene expression patterns using microarrays and HSV specific T-cell function will be evaluated. Results will be compared to biopsies obtained from the same participants in the presence of genital lesions. These studies will help us understand HSV-2 pathogenesis and the responses mediating viral clearance, which will inform therapeutic strategies to prevent the epidemic spread of HSV-2 and HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI079394-02
Application #
7644973
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
David, Hagit S
Project Start
2008-07-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$121,326
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Schiffer, Joshua T; Swan, David; Al Sallaq, Ramzi et al. (2013) Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract. Elife 2:e00288
Johnston, Christine; Saracino, Misty; Kuntz, Steve et al. (2012) Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet 379:641-7
Tronstein, Elizabeth; Johnston, Christine; Huang, Meei-Li et al. (2011) Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 305:1441-9
Sandlin, Michael Isiah; Johnston, Christine; Bowe, David et al. (2011) Clinician and patient recognition of anogenital herpes disease in HIV positive men who have sex with men. Sex Transm Dis 38:833-6
Johnston, Christine; Koelle, David M; Wald, Anna (2011) HSV-2: in pursuit of a vaccine. J Clin Invest 121:4600-9
Ross, Kaile; Johnston, Christine; Wald, Anna (2011) Herpes simplex virus type 2 serological testing and psychosocial harm: a systematic review. Sex Transm Infect 87:594-600
Laing, Kerry J; Magaret, Amalia S; Mueller, Dawn E et al. (2010) Diversity in CD8(+) T cell function and epitope breadth among persons with genital herpes. J Clin Immunol 30:703-22
Tata, Sunitha; Johnston, Christine; Huang, Meei-Li et al. (2010) Overlapping reactivations of herpes simplex virus type 2 in the genital and perianal mucosa. J Infect Dis 201:499-504
Johnston, Christine; Orem, Jackson; Okuku, Fred et al. (2009) Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda. PLoS One 4:e4222

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