Herpes Simplex Virus (HSV) Infections

Lawrence Corey, MD

HSV Program Project Grant:

Project 1.  Clinical and Mucosal Interactions Between Herpes Simplex Viruses and Human Immunodeficiency Virus (HIV) Infection

There is increasing information on the epidemiological, clinical and molecular synergism between HSV, especially HSV-2, and HIV-1. Among uninfected persons HSV-2 seropositivity increases the acquisition rate of HIV-1. Among HSV-2/HIV coinfected persons HSV-2 reactivation appears to be associated with higher rates of detection and higher titers of mucosal HIV-1. HAART therapy does not appear to reduce HSV reactivation, raising the specter that frequent HSV-2 reactivation may be a factor in driving the continued replication of HIV-1 in HAART treated persons. This proposal is directed at defining whether currently available antivirals for HSV can reduce the acquisition and transmission of HIV-1 and whether anti-HSV therapy reduces in vivo tissue and mucosal HIV-1 replication.

Project 1 consists of 4 specific aims directed at evaluating HSV–HIV interactions:

Specific Aim 1 . Subclinical and clinical HSV-2 reactivation increases mucosal HIV-1 replication. Reducing HSV shedding by daily acyclovir therapy will significantly reduce the prevalence and titer of HIV-1 shedding in rectal and cervicovaginal secretions.

Specific Aim 2 . To demonstrate that reducing HSV-2 shedding with acyclovir will be associated with concomitant reduction in the replication rate of HIV-1 at the cellular level. These studies will be focused on patients with HAART and use newly developed quantitative assays that measure the frequency and quantity of HIV-1 RNA producing cells in tissue and purified populations of mononuclear cells, including activated CD4+ T- cells and monocyte macrophages.

Specific Aim 3 . To determine if HSV-2 infection of the source partner increases HIV transmission to susceptible partners. This is a collaboration with Dr. Susan Allen of the University of Alabama and involves an HIV-1 discordant couples cohort in Zambia.

Specific Aim 4 . To test in a multicenter intervention trial the hypothesis that suppressive acyclovir will reduce the acquisition of HIV-1 among high risk populations across a wide geographic area: the US (Seattle, New York City), Peru, Zimbabwe and Zambia. This proposal requests the central laboratory support for this study which has recently received NIH funding for the clinical trial sites.

Project 2. Prevention of HSV Morbidity in Pregnancy and the Newborn

New data indicate HSV seronegative women have the highest risk of HSV transmission to the neonate and high predictive value of viral shedding at delivery for HSV transmission (R.R. >300) suggesting that of interventions should be directed at: 1) the pregnant woman who acquires genital HSV near term and often transmits HSV, and 2) the HSV-2 seropositive woman who reactivates HSV at the time of delivery, is less likely to transmit, but may have morbidity associated with abdominal delivery.

Project 2 consists of 4 specific aims:

Specific Aim 1 . To evaluate the acceptance and effect of type specific HSV serological assays of pregnant women on sexual behavior at the end of pregnancy.

Specific Aim 2. To evaluate the efficacy of short course acyclovir therapy on preventing HSV shedding at delivery among HSV-2 seropositive women.

Specific Aim 3. To develop a rapid PCR assay to detect genital HSV shedding among women at the time of labor.

Specific Aim 4. To perform a cost effectiveness and utility analysis of various approaches to prevent neonatal herpes. The strategies for evaluation include serological testing, cesarean section, acyclovir treatment, and rapid testing for HSV DNA at the onset of labor.