Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding

Abstract

Herpes simplex virus (HSV)-2 is periodically shed in the human genital tract, most often asymptomatically, and most sexual transmissions occur during asymptomatic shedding. It would be helpful to identify a genital viral load threshold necessary for transmission, as clinical interventions that maintain viral quantity below this level would be of high utility. However, because viral expansion, decay and re-expansion kinetics are extremely rapid during shedding episodes, it is impossible to directly measure genital viral load at the time of sexual activity. We developed a mathematical model based on reproducing shedding patterns in transmitting partners, and median number of sex acts prior to transmission in discordant couples, to estimate infectivity of single viral particles in the negative partner's genital tract. We then inferred probability estimates for transmission at different levels of genital tract viral load in the transmitting partner. We predict that transmission is unlikely at viral loads less than 10 4 HSV DNA copies. Moreover, most transmissions occur during prolonged episodes with high viral copy numbers. Many shedding episodes that result in transmission do not reach the threshold of clinical detection, because the ulcer remains very small, highlighting one reason why HSV-2 spreads so effectively within populations.

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

“…Over the course of 30 consecutive samplings of 498 immunocompetent HSV-2-seropositive individuals, virus DNA was detected without genital lesions *10 % of the time (Tronstein et al, 2011). Mathematical modelling of HSV-2 shedding data (frequency, duration, burden) has led to the interesting hypothesis that latent HSV-2 reactivation is nearly constant with the continued release of lowtitre virus from neuronal termini (Schiffer et al, 2009(Schiffer et al, , 2014. If confirmed, our view of latency as a quiescent state of virus dormancy must be re-evaluated and perhaps animation of the virus DNA is an ongoing process.…”

A Dual-Modality Herpes Simplex Virus 2 Vaccine for Preventing Genital Herpes by Using Glycoprotein C and D Subunit Antigens To Induce Potent Antibody Responses and Adenovirus Vectors Containing Capsid and Tegument Proteins as T Cell Immunogens

“…The presence of vaginal HSV-2 DNA shedding in the absence of genital disease in guinea pigs is similar to observations in humans; however, HSV-2 DNA shedding is less well understood for guinea pigs, since there is no transmission model to correlate shedding with infectivity (70,72,73). Using mathematical modeling, a threshold for transmitting infection in humans was proposed to be 10 4 HSV-2 DNA copies (74). DNA shedding correlates well with virus culture results from genital swab samples; however, even at 10 6 HSV-2 DNA copies, only 50% of virus cultures are positive (75).…”

Antiviral Activity of a Single-Domain Antibody Immunotoxin Binding to Glycoprotein D of Herpes Simplex Virus 2

“…As a result, a potential use of this immunotoxin is in the context of an HSV-2-discordant couple hoping to prevent transmission to the uninfected partner. Because shedding episodes are frequent and subclinical shedding accounts for 80% of shedding, it is unrealistic to rely on avoidance of sexual contact during times of shedding as a means to prevent transmission (55). While oral antiviral drugs such as valacyclovir decrease viral shedding, they do not completely eliminate viral shedding or prevent transmission (49).…”

“…Immunotoxins targeting KSHV through binding of surface glycoproteins were tested in combination with nucleoside analog antivirals and demonstrated greater efficacy with combination treatment than with immunotoxin treatment alone (36,37). R33ExoA treatment in combination with oral antiviral drugs could potentially maintain the amount of virus shed below the level estimated to be needed for transmission (55). In a newly acquired HSV-2 infection, R33ExoA could also be used to limit the number of latently infected neurons, thereby reducing future shedding and occurrence of ulcers following reactivation.…”