Genital herpes simplex virus (HSV) infections affect an estimated 25 million Americans, and result in substantial physical and psychological morbidity. In addition, genital disease may pose an increased risk for the acquisition of HIV. The greatest burden of genital disease is due to reactivation of latent virus in sensory neurons. Little is understood about the unique virus-neuron interactions that permit the establishment of latent infection and the modulation of subsequent reactivation events. We have shown that guinea pigs, like humans, develop self-limited primary genital herpes, establish latency, and experience spontaneous and induced recurrences. Both HSV-1 and HSV-2 produce primary genital infection and establish latency, however, the vast majority of recurrent genital disease in both humans and guinea pigs is due to HSV-2. This suggests that HSV-2 may have special functions which facilitate reactivation from dorsal root sensory neurons. Recent evidence indicates that the HSV-2 LAT transcription unit is an important determinant of the pattern of recurrent genital herpes. Studies have shown that capsaicin, a drug with selective effects on sensory neurons, reduces the severity of primary genital herpes without altering viral replication, possibly by interfering with intraneuronal viral transport. Additionally, capsaicin treatment alters recurrent disease, suggesting it may interfere with latency. Indirect evidence suggests that two other important neuro-regulatory substances, nitric oxide and nerve growth factor may play roles in HSV-neuronal interactions. We will explore virus-neuron interactions in the uniquely suited guinea pig model of genital infection.
The specific aims are to: (1) Examine the role of the LAT transcription unit in defining type- specific genital recurrence phenotype; (2) Characterize primary, latent and recurrent genital infection caused by a HSV-2 LAT/lacZ mutant; (3) Examine the effects of capsaicin on latent infections; (4) Explore the role of nitric oxide in latency; (5) Determine if latent infection is predominantly localized to sensory neurons that express high affinity nerve growth factor receptors. These complementary studies will increase our understanding of the pathogenesis of latent and recurrent HSV genital infections and yield new information regarding HSV-neuron interactions. This information may facilitate the development of novel strategies for the control of HSV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI022667-09A1
Application #
2061936
Study Section
Virology Study Section (VR)
Project Start
1985-09-01
Project End
2000-07-31
Budget Start
1995-09-30
Budget End
1996-07-31
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Bourne, N; Bernstein, D I; Stanberry, L R (1999) Civamide (cis-capsaicin) for treatment of primary or recurrent experimental genital herpes. Antimicrob Agents Chemother 43:2685-8
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Da Costa, X J; Bourne, N; Stanberry, L R et al. (1997) Construction and characterization of a replication-defective herpes simplex virus 2 ICP8 mutant strain and its use in immunization studies in a guinea pig model of genital disease. Virology 232:1-12
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Bourne, N; Stanberry, L R; Bernstein, D I et al. (1996) DNA immunization against experimental genital herpes simplex virus infection. J Infect Dis 173:800-7

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