The overarching goal of this Renewal K24 Midcareer Investigator Award in Patient-Oriented Research is to foster training of promising junior investigators in high quality Patient-Oriented Research in clinical virology, with a focus on HSV infections. During the first cycle of K24 funding, the PI achieved her original goals, increased the number of clinical investigators under her supervision, including several with K23 awards, and published 55 manuscripts first-authored by mentees. Additionally, Dr. Wald has expanded her research portfolio, and broadened the scope of her mentoring activities. Ongoing projects include translational, clinical, therapeutic, epidemiologic, and preventative research, as well as clinical trials of drugs and vaccines. Our group has shown that HSV-2 reactivates frequently in the genital tract and that these epithelial infections are rapidly cleared by host immunity. Using biopsies of genital mucosa, we have shown that HSV-2 infection is associated with a dense and persistent infiltrate of immune cells, many bearing HIV entry receptors. The funded projects have these Specific Aims: 1) To determine the frequency of rapidly cleared (<6 hrs) mucosal HSV-2 infections by gender and degree of immunosuppression;2) To define the clearance rate of mucosal HSV reactivation in relation to locally infiltrating HSV-2-specific CD8+ T cells in genital skin at the anatomic site of reactivation. We hypothesize that the clearance of the shedding episode and time to next reactivation will correlate with the density of CD8+ cells at specific anatomic sites. The newly proposed projects include studies of genital HSV-1 and of interactions between HSV-2 and abnormal vaginal microbiota. Recent decade has seen a shift from HSV-2 to HSV-1 as the predominant cause of genital herpes in US. Yet natural history studies of this infection are lacking.
The Specific Aim 3 will address these gaps by: A) determining the frequency of rapidly cleared (<6 hrs) mucosal HSV-1 infections in men and women with newly acquired (<6 months) and established (>2 years) genital HSV-1 infections;2) evaluating the site of HSV infection in persons who transmitted genital HSV-1 infection to their partners. We hypothesize that >50% of sex partners will have HSV-1 shedding from the genital tract, thus indicating the possibility of genital-to-genital HSV-1 transmission. Epidemiologic studies suggest an interaction between HSV and bacterial vaginosis;we will extend these pilot observations into clinical and mechanistic studies.
Specific aim 4 will evaluate the effect of vaginal microbiota on HSV shedding and the effect of HSV suppression on vaginal microbiota. We hypothesize that these 2 conditions will have an adverse effect on each other, and that the effect will be mediated by soluble mediators of inflammation, such as secretory leukocyte protease inhibitor, human neutrophil peptides 1-3 and lactoferrin,. These carefully selected projects provide opportunities for training junior clinical investigators in high-quality Patient-Oriented Research and preparations for an investigative career in clinical virology.

Public Health Relevance

This application supports ongoing training of the next generation of physician investigators in studies in clinical virology, in particular in genital herpes, an infection that affects about 20% of US population. This research aims to investigate the relationship between the virus and the immune response in the genital tract, increase our knowledge about genital infections caused by herpes simplex virus type 1 as well as about interaction between genital herpes and bacterial vaginosis, another common condition of women.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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David, Hagit S
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
Zaniello, Benjamin; Huang, Meei-Li; Cheng, Anqi et al. (2016) Consistent viral DNA quantification after prolonged storage at ambient temperature. J Virol Methods 228:91-4
Neme, Santiago; Wahome, Elizabeth; Mwashigadi, Grace et al. (2015) Prevalence, Incidence, and Clearance of Anogenital Warts in Kenyan Men Reporting High-Risk Sexual Behavior, Including Men Who Have Sex With Men. Open Forum Infect Dis 2:ofv070
Mujugira, Andrew; Huang, Meei-Li; Selke, Stacy et al. (2015) High Rate of β-Globin DNA Detection Validates Self-Sampling in Herpes Simplex Virus Shedding Studies. Sex Transm Dis 42:705-9
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
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
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
Schiffer, Joshua T; Mayer, Bryan T; Fong, Youyi et al. (2014) Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding. J R Soc Interface 11:20140160

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