Acyclovir Sensitivity of Sequential Herpes Simplex Virus Type 2 Isolates from the Genital Mucosa of Immunocompetent Women

Gupta, Rachna; Hill, Edward C.; McClernon, Dan; Davis, Gray; Selke, Stacy; Corey, Lawrence; Wald, Anna

doi:10.1086/432766

Cited by 32 publications

(17 citation statements)

References 28 publications

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“…However, because definitive CC 50 values have not been identified, the TI values for all compounds represent a lower limit, and the TIs for the ␣-hydroxytropolones relative to ACV have not yet been precisely determined. A broad range of EC 50 s for ACV-sensitive HSV-2 clinical isolates has been reported (63), even within a single individual over time (64), which likely contributes to the 9-fold difference in apparent EC 50 s that we observed for ACV against an HSV-1 versus an HSV-2 clinical isolate. A small amount of cytotoxicity (measured as a loss of mitochondrial function in MTT assays) caused by two compounds, compounds 111 and 120, may be due to inhibition of human RNase H1 because RNase H contributes to mitochondrial DNA replication and pre-rRNA processing (65)(66)(67).…”

Section: Discussionmentioning

confidence: 57%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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cHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ␤-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ␣-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ␣-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC 50 ) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC 50 ] of 50 to >100 M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ␣-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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Section: Discussionmentioning

confidence: 57%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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“…In general, in this population, drug resistance was not associated with an adverse clinical outcome, due to immune competence. Cases of HSV resistance reported in immunocompetent patients were associated with diagnosis of recurrent genital herpes (81,109,125,126,153,219), keratitis (156,188), disseminated HSV infection (66), and encephalitis (197). Recently, a report documented a relatively high (6.4%) prevalence of ACV-resistant HSV-1 isolates in immunocompetent patients with herpes keratitis, and some of these cases were clinically refractory to ACV therapy (77).…”

Section: Prevalence Of Drug-resistant Hsvmentioning

confidence: 99%

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Piret

Boivin

2011

Antimicrob Agents Chemother

460

406

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“…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.…”

mentioning

confidence: 99%

Rapid Viral Expansion and Short Drug Half-Life Explain the Incomplete Effectiveness of Current Herpes Simplex Virus 2-Directed Antiviral Agents

Schiffer

Swan

Corey

et al. 2013

Antimicrob Agents Chemother

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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...

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Acyclovir Sensitivity of Sequential Herpes Simplex Virus Type 2 Isolates from the Genital Mucosa of Immunocompetent Women

Abstract: Among immunocompetent women, the finding of acyclovir-resistant HSV-2 isolates likely represents transient mucosal variants and does not predict treatment failure.

Cited by 32 publications

References 28 publications

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Rapid Viral Expansion and Short Drug Half-Life Explain the Incomplete Effectiveness of Current Herpes Simplex Virus 2-Directed Antiviral Agents

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