Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium.DOI: http://dx.doi.org/10.7554/eLife.00288.001

Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly.

eThe nucleoside analogues acyclovir (ACV) and famciclovir (FCV) reduce the frequency and severity of herpes simplex virus 2 (HSV-2) genital shedding, yet despite their high potency in vitro and a lack of induced drug resistance, frequent episodes of breakthrough mucosal shedding occur. We tested a published stochastic, spatial mathematical model of HSV-2 replication and spread, in concert with pharmacokinetic and pharmacodynamic equations, against virologic data from clinical trials of twice-daily acyclovir and famciclovir suppression. The model reproduced the key features of clinical trial data, including genital shedding episode rate, expansion and decay dynamics, and heterogeneous peak viral production and duration. In simulations, these agents shortened episode duration by limiting the extent of viral production by 1 to 2 log units and limiting the formation of secondary ulcers by ϳ50%. However, drug concentrations were noninhibitory during 42% of the dosing cycle. Even if drug concentrations were high at episode initiation, prolonged episodes often ensued due to drug decay over ensuing hours and subsequent rebound of rapidly replicating HSV-2. The local CD8؉ T-cell density was more predictive of episode viral production (R 2 ‫؍‬ 0.42) and duration (R 2 ‫؍‬ 0.21) than the drug concentration at episode onset (R 2 ‫؍‬ 0.14 and 0.05, respectively), though the model projected that an agent with an equivalent potency but a two times longer half-life would decrease shedding by 80% compared to that of standard twice-daily regimens. Therefore, long half-life is a key characteristic of any agent that might fully suppress HSV-2 reactivations.T he agents currently licensed for treatment of herpes simplex virus 2 (HSV-2) infection, acyclovir (ACV), famciclovir (FCV), and valacyclovir (VCV), decrease genital tract viral shedding and lesion rates (1-3), yet they do not eliminate shedding, even when given three times daily at maximal doses (4). The reason that shedding episodes lasting several days still occur in most treated patients is unknown. Drug resistance does not explain breakthrough shedding and is usually clinically relevant only in immunocompromised hosts (5). Other possibilities include inadequate penetration of drug into tissue or breakthrough replication due to subtherapeutic concentrations. Recent evidence highlights that certain antiretroviral agents bind cooperatively with viral target enzymes (6, 7). A lack of cooperative binding is another possible mechanism for diminished antiviral potency.We recently published a stochastic spatial model of HSV-2 pathogenesis (8) that provides hypotheses for the shedding patterns observed in persons off therapy. In simulations of this model off treatment, viral spread occurs in several stages: neurons release HSV-2 in a slow drip throughout the genital tract. Mucosal replication is initiated when epithelial cells are infected (9). Rapid cellto-cell spread of HSV ensues within a single ulcer, and the extent of infection inversely correlates with the local density of resi...

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.