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Topical Tenofovir, a Microbicide Effective against HIV, Inhibits Herpes Simplex Virus-2 Replication
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Cell & Host Microbe Oct 4 2011

Graciela Andrei1, Andrea Lisco2, Christophe Vanpouille2, Andrea Introini2, Emanuela Balestra3, Joost van den Oord4, Tomas Cihlar5, Carlo-Federico Perno3, Robert Snoeck1, Leonid Margolis2, , , Jan Balzarini1, ,

1 Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

2 Program of Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA

3 Department of Experimental Medicine and Biochemical Science, University of Roma Tor Vergata, 00143 Rome, Italy

4 Department of Morphology and Molecular Pathology, K.U. Leuven, B-3000 Leuven, Belgium

5 Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA

Received 25 March 2011; revised 23 June 2011; Accepted 25 August 2011. Published: October 19, 2011. Available online 19 October 2011.


The HIV reverse-transcriptase inhibitor, tenofovir, was recently formulated into a vaginal gel for use as a microbicide. In human trials, a 1% tenofovir gel inhibited HIV sexual transmission by 39% and, surprisingly, herpes simplex virus-2 (HSV-2) transmission by 51%. We demonstrate that the concentration achieved intravaginally with a 1% tenofovir topical gel has direct antiherpetic activity. Tenofovir inhibits the replication of HSV clinical isolates in human embryonic fibroblasts, keratinocytes, and organotypic epithelial 3D rafts, decreases HSV replication in human lymphoid and cervicovaginal tissues ex vivo, and delays HSV-induced lesions and death in topically treated HSV-infected mice. The active tenofovir metabolite inhibits HSV DNA-polymerase and HIV reverse-transcriptase. To exert dual antiviral effects, tenofovir requires topical administration to achieve a drug concentration higher than systemic levels achieved by oral treatment. These findings indicate that a single topical treatment, like tenofovir, can inhibit the transmission of HIV and its copathogens.


→ Tenofovir, an anti-HIV drug, inhibits HSV in human cervical tissue ex vivo → Tenofovir inhibits HSV in human epithelial rafts and delays death of HSV-infected mice → The active tenofovir metabolite directly inhibits the HSV DNA polymerase → Topical tenofovir administration is required for its dual anti-HIV/HSV effects


Unprotected heterosexual intercourse remains a major transmission mode of HIV-1. In the absence of a protective vaccine, an efficient topical vaginal microbicide would be critical to the prevention of male-to-female HIV-1 transmission and to curbing the worldwide AIDS epidemic ( [Balzarini and Van Damme, 2007] and [Klasse et al., 2008] ). HIV-1 infection is commonly associated with other sexual infections, such as HSV, that facilitate the risk of HIV acquisition and worsen the clinical course of HIV disease ( [Blower and Ma, 2004] , [Corey, 2007] and [Buvé, 2010] ). Therefore, it would be beneficial if a future microbicide was efficient not only against HIV-1, but also against other sexually transmitted infections.

Unfortunately, until recently, all microbicide formulations that successfully passed preclinical testing failed to demonstrate efficiency in the early stages of clinical development ( [Van Damme et al., 2002] , [Van Damme et al., 2008] and [Abdool Karim, 2010] ), and some of them apparently promoted HIV-1 infection ( [Van Damme et al., 2002] and [Van Damme et al., 2008] ).

Instead of testing new compounds as potential microbicides, tenofovir, an efficient nucleotide HIV reverse-transcriptase (RT) inhibitor (Balzarini et al., 1993) widely used in HIV therapy, was recently formulated as a 1% gel and tested in a double-blind placebo-controlled study in 889 women (CAPRISA 004 [Abdool Karim et al., 2010]). Tenofovir convincingly diminished HIV-1 transmission (by 39%). Surprisingly, in the CAPRISA 004 trial, a significant 51% reduction of the risk of acquiring HSV-2, a common HIV-1 copathogen that facilitates HIV transmission, was also observed (Cates, 2010). This effect of tenofovir gel on HSV was rather unanticipated because this highly potent antiretroviral and antihepadnaviral drug has been previously shown to exhibit minimal, if any, anti-HSV activity (Balzarini et al., 1993). Therefore, one might have envisioned a complicated and indirect mechanism to explain this phenomenon. It turned out not to be the case.

In the present study, we report on the resolution of this apparent contradiction. We provide compelling evidence that, at the concentrations achieved intravaginally by the topical administration of a 1% gel, tenofovir exhibits direct antiherpetic activity. These data and the therapeutic principles emerging from our study are important for the development of new drug formulations and administration protocols to design and/or optimize future microbicide trials.


Tenofovir is a common anti-HIV drug that, in the currently approved dose (300 mg tablet), suppresses HIV-1 replication in vivo and in vitro but is not reported to markedly affect herpes viruses (Balzarini et al., 1993). Recently, however, it was reported that, in the microbicide CAPRISA 004 trial, topical vaginal administration of tenofovir significantly diminished the acquisition not only of HIV-1, but also of HSV-2. We hypothesized that the discrepancy between the earlier reported lack of significant antiherpetic activity and the CAPRISA 004 data is explained by the striking differences in drug concentrations between systemic and topical applications of tenofovir.

We demonstrated that the antiretroviral drug tenofovir is indeed endowed with a direct antiherpetic activity in a variety of experimental models at drug concentrations that are lower than the median concentration achieved in cervicovaginal fluid following the administration of 1% tenofovir gel and that were nontoxic for the exposed cells (Rohan et al., 2010 and data of this study). Indeed, tenofovir levels in the cervicovaginal fluid were reported as 18.6 mg/, measured over a 24 hr time period (AUC24hr) after topical administration, and levels were still at ~100 μg/ml at 24 hr after drug exposure (Schwartz et al., Abstract LBPEC03, 5th IAS, Cape Town, South Africa, 19-22 July 2009). Rather, it was shown by Dumond et al. (2007) that the steady-state genital concentration of tenofovir was ~100 ng/ml (24 hr), and peak concentrations of tenofovir reached ~500 ng/ml (6 hr) after administration of tenofovir by oral route.

Several recent publications report lower concentrations of tenofovir in the female genital tract upon in vivo application, with some concentrations equal to or even slightly higher than the EC50 that we determined in vitro and ex vivo. In this respect, our findings might explain why HSV-2 transmission prevention by tenofovir was not absolute but, rather, reached 51% (Abdool Karim, 2010), although the extrapolation of active drug concentrations ex vivo to the situation in vivo has its limitation.

We observed tenofovir activity against both laboratory and clinical HSV-1 and HSV-2 isolates (wild-type and drug-resistant thymidine kinase-deficient virus strains) in: (1) HEL cell fibroblasts, (2) primary macrophages and keratinocytes, (3) organotypic epithelial raft cultures, (4) human lymphoid and cervicovaginal tissues ex vivo, and (5) HSV-1- and HSV-2-infected mice. The most pronounced antiherpetic activity of tenofovir was observed in macrophages. Although HSV targets in tissues are still poorly understood and it is not known whether macrophages are important HSV targets in vivo, it seems that both HIV-1 and HSV-2 can infect macrophages. HIV-1 has been recovered frequently from genital herpes lesions in coinfected individuals (Schacker et al., 1998). Cells of the M/M lineage reside in genital mucosal tissues and are thought to be reservoirs of HIV-1 in the genital tract ( [Lehner et al., 1991] and [Spira et al., 1996] ). Moreover, there is evidence that HSV infection can also stimulate macrophages in vitro and induce HIV-1 replication in these cells (Moriuchi et al., 2000). The observed marked inhibitory activity of tenofovir against HSV-2 in M/M cultures is likely due to the low endogenous dNTP pools (Perno et al., 1996) and/or to low HSV-2 replication in this cell type. Low endogenous dNTP pools give tenofovir a competitive advantage to interact with the herpetic DNA polymerase activity. Furthermore, we deciphered that the molecular mechanism of the tenofovir antiherpetic activity: tenofovir diphosphate, to which tenofovir converted in various human cell types, efficiently inhibits HSV DNA polymerase. Concentrations of this compound in the cells were in the range of concentrations that inhibited HSV DNA polymerase in a cell-free system.

Thus, our findings provide a direct explanation for the dual anti-HIV/HSV activity reported by the CAPRISA 004 microbicide trial ( [Abdool Karim et al., 2010] and [Cates, 2010] ). Indeed, in our experiments, tenofovir suppressed HSV activity at concentrations of approximately ~ 10-200 μg/ml, which are in the range of the drug concentrations reached in cervicovaginal fluid upon application of 1% tenofovir gel (Schwartz et al., Abstract LBPEC03, 5th IAS, Cape Town, South Africa, 19-22 July 2009). Such tenofovir concentrations were not found to be toxic in our cell models, in agreement with previous findings that a 1% tenofovir gel does not affect either PBMCs or epithelial cells (Rohan et al., 2010). Neither was any toxicity observed in the CAPRISA 004 trial.

Shortly after the publication of the CAPRISA 004 results, oral Truvada, a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine, was reported to provide a 44% reduction in the incidence of HIV in case of pre-exposure chemoprophylaxis in men who have sex with men (Grant et al., 2010). In contrast to topical application, steady-state tenofovir concentrations in the genital tract following oral administration (300 mg/day) have been shown to be ~ 100 ng/ml (Dumond et al., 2007). Although tenofovir concentrations generated during oral drug administration may be sufficient for an effective systemic inhibition of HIV infection, they are substantially lower than those necessary to inhibit the replication of herpesviruses. Accordingly, prevention of HSV-2 acquisition was not reported in this trial. Also, no epidemiological evidence has emerged of concomitantly decreased incidence of HSV-2 infection in HIV-infected individuals treated with systemic (oral) tenofovir DF. In fact, it was very recently reported that oral tenofovir administered as part of combination antiretroviral therapy had no suppressive effect on HSV shedding in HIV/HSV-coinfected asymptomatic adults (Tan et al., 2011). Also, another recent report showed that daily oral tenofovir DF (in coformulation with FTC) did not reduce HSV-2 acquisition among high-risk men who have sex with men, likely because TDF concentrations in the rectal or penile tissues insufficiently decrease acquisition of HSV-2 infection (Lama et al., Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, USA, 27 February-2 March 2011, # 1002).

Surprisingly, in contrast to the partial prevention of HIV acquisition upon topical intravaginal administration of a 1% tenofovir gel (Abdool Karim et al., 2010) and upon oral drug administration in men who have sex with men (Grant et al., 2010), the FEM-PrEP HIV prevention study with oral Truvada has been stopped due to inability to determine effectiveness ( No significant differences on the number of new HIV infections were observed between placebo- and drug-treated individuals. Although the reasons for this apparent discrepancy have not been revealed yet, it should be clear that the oral administration of tenofovir does not affect the rate of HSV-2 sexual transmission (Tan et al., 2011), in contrast with the topical drug administration. This conclusion will be further tested in the ongoing VOICE clinical trial, which has both topical and systemic application arms.

Although we have consistently demonstrated the antiherpetic activity of tenofovir in different systems, its potency is predictably lower than that of specific antiherpetic drugs like acyclovir. Indeed, tenofovir was designed to suppress HIV-1, not herpesviruses. However, when the drug was tested upon oral administration, the high concentrations achieved with topical application were not considered. With the CAPRISA 004 trial, it became clear that these concentrations have now become clinically relevant and have been shown to suppress not only HIV-1, but also HSV. Here, we showed that tenofovir affects HSV directly, rather than through a complex, indirect mechanism. Together, these findings argue that “marginal” antiviral activities of a variety of existing drugs should be revisited in light of possibly missed antiviral activities in topical applications as new microbicides with dual or multiple antiviral properties. In this respect, it would be important to consider acyclovir prodrugs as potential microbicidal candidates. Indeed, acyclovir, which traditionally has been regarded only as a potent antiherpesvirus inhibitor, has recently been shown to have dual antiviral properties: in lymphoid and cervicovaginal tissues coinfected with herpesviruses, it efficiently inhibits HIV-1 as well (Lisco et al., 2008).

Thus, in this respect, like tenofovir, acyclovir prodrugs can become potential dual-targeted microbicides. Importantly, it has been shown that prodrugs of phosphorylated acyclovir that bypass the requirement of the presence of herpesvirus for drug activation (phosphorylation) release the activated form of acyclovir intracellularly and are endowed with both antiherpetic and anti-HIV activity ( [Derudas et al., 2009] and [Vanpouille et al., 2010] ). However, findings on the antiviral activities of various compounds in ex vivo models (and even in ex vivo human tissues that closely reflect human tissues in vivo) have their limitations and should be verified in clinical trials.

In conclusion, our data provide a plausible explanation for the unexpected antiherpetic activity of 1% tenofovir gel observed among treated African women participating in the CAPRISA 004 trial. Furthermore, our results provide specific considerations for designing new microbicides with a dual antiviral effect and indicate that topical creams, rather than oral administration of anti-HIV compounds, particularly tenofovir and its derivatives, may be efficient in preventing transmission of HIV-1 and its copathogens.


Tenofovir Inhibits HSV-1 and HSV-2 Replication in Various Cell Cultures

Tenofovir inhibited cytopathicity of the laboratory strains of HSV-1 and HSV-2 in human embryonic lung (HEL) fibroblasts and in primary human keratinocytes (PHKs) with EC50 values of 103-193 μg/ml (Table 1). In HEL fibroblasts, tenofovir consistently inhibited the cytopathic effects of a variety of wild-type HSV-1, thymidine kinase-deficient (TK-) HSV-1, wild-type HSV-2, and HSV-2 TK- clinical isolates with mean EC50 values of 123 μg/ml (range of 101-160 μg/ml), ≥ 139 μg/ml (100 to ≥ 159 μg/ml), 154 μg/ml (125-176 μg/ml), and 133 μg/ml (85-179 μg/ml), respectively. The antiherpesvirus activity of tenofovir was revealed at a concentration range that is markedly higher than those established for antiherpetic drugs, such as acyclovir and its closely related acyclic nucleoside phosphonate congeners, adefovir and cidofovir (Table 1).

There was no marked difference in the suppression of HSV-1 and HSV-2 replication by tenofovir and the reference antiherpesvirus agents. Importantly, there were no signs of tenofovir cytotoxicity, as assessed from HEL cell morphology, even at the highest drug concentrations used (500 μg/ml). The effects of tenofovir on HSV-2 yield in HEL cells were also determined at 24, 48, and 72 hr postinfection to confirm the data obtained using the cytopathic effect (CPE) reduction assay. The dose-response curves of tenofovir for two clinical HSV-2 isolates (RV-124 and NS) at two different multiplicities of infection (moi) were determined using the plaque-forming unit (PFU) reduction assay and are depicted in Figure 1. Tenofovir inhibited the replication of both viruses with EC99 values (i.e., the drug concentration that decreases the virus titers by two orders of magnitude) in the range of 214-390 μg/ml, whereas no changes in cell number were noted at any drug concentration.

The effect of tenofovir was also evaluated against HSV-2 in primary monocyte/macrophage (M/M) cell cultures using two different methods, CPE reduction and PFU reduction assays. Tenofovir dosage of 500 or 100 μg/ml completely suppressed HSV-2 replication in M/M. HSV-2 production dropped from 3.7 x 105 TCID50/ml (~95% cytopathicity) in the culture supernatants of untreated cells by more than one log10 in 20 μg/ml and an approximate half log10 in 5 μg/ml tenofovir-treated cultures. At 1 μg/ml or 0.2 μg/ml drug concentrations, no significant protective effect of tenofovir was observed (2.4-3.0 x 105 TCID50/ml; 66%-81% cytopathicity) (Table 2 and Figure S1 available online). As expected, the structurally related reference compound adefovir, which was included as a control in the assay, proved to be more potent in its anti-HSV-2 activity in the M/M cell cultures (full CPE suppression at 5 μg/ml) than tenofovir (Table 2).

Tenofovir Suppresses Viral Replication in Organotypic Epithelial Raft Cultures

Because differentiated keratinocytes are the main target cells for productive infection of HSV in vivo, we evaluated the antiviral activity of tenofovir in organotypic raft cultures of keratinocytes. The organotypic epithelial raft cultures were infected after 10 days of differentiation and treated with tenofovir. After 5 days of drug treatment, histological examination of the noninfected raft cultures revealed completely differentiated epithelium with characteristic layers, whereas HSV-infected rafts revealed a pronounced viral infection that had spread all along the epithelium (Figure 2). At a concentration of 200 μg/ml, tenofovir caused a 2.6 (HSV-1) and a 5.4 (HSV-2) log10 reduction in virus production and complete protection of virus-induced cytopathicity (Figure 3). A 0.81 (HSV-1) and a 1.75 (HSV-2) log10 reduction was recorded at a concentration of 50 μg/ml of tenofovir. At 20 and 5 μg/ml, tenofovir was partially protective, with areas of a normal epithelium and areas of destructed rafts. At a concentration of 2 μg/ml, tenofovir was inactive against HSV-2 (Figure 3). The higher activity of tenofovir against HSV-2, but not HSV-1, can be due to the different levels of replication between these two viruses: in the untreated control cultures, the HSV-2 titers were lower (~1.5 x 106 PFU/raft) than the HSV-1 titers (~9 x 106 PFU/raft).

Tenofovir Suppresses HSV-2 in Singly Infected and in HIV-1-Coinfected Human Lymphoid and Cervicovaginal Tissue Ex Vivo

The effect of tenofovir on the replication of HSV-1F, HSV-2G, and HSV-2MS was investigated in infected human tonsillar tissues ex vivo (Figure 4). Upon inoculation in human tonsillar tissues ex vivo, HSV-1F, HSV-2G, or HSV-2MS replicated efficiently, as shown by accumulation of viral DNA in culture medium. The median accumulation throughout the 9 days of culture was 7.8 log10 DNA copies/ml (interquartile range [IQR] 7.1-8.1, n = 5); 7.25 log10 DNA copies/ml (IQR 7.2-7.9, n = 6); and 6.4 log10 DNA copies/ml (IQR 6.1-7.5, n = 3) for HSV-1F, HSV-2G, and HSV-2MS, respectively.

Tenofovir suppressed replication of HSV-1F, HSV-2G, and HSV-2MS in a dose-dependent manner (Figure 4). On the basis of the real-time PCR data presented above, we calculated the EC50 for HSV suppression of tenofovir as 7 μg/ml (95% confidence interval [CI] 10-44) for HSV-1F; 14 μg/ml (CI 10-163) for HSV-2G (Figure 4A); and 19 μg/ml (CI 27-127) for HSV-2MS. The EC50 calculated by this technique is in agreement with that obtained with the PFU reduction assay (Thi et al., 2006). Accordingly, tenofovir at a concentration of 66 μg/ml reduced HSV-1F, HSV-2G, and HSV-2MS replication by 99% ± 0.1%, 87% ± 12%, and 91.7% ± 3.2%, respectively, compared to infected donor-matched untreated tissue (p < 0.01). At the 66 μg/ml tenofovir concentration, the suppression of HSV-1F, HSV-2G, and HSV-2MS replication was not associated with measurable tonsillar depletion of either total T cells (CD3+), total B cells (CD19+), or subsets of naive and memory T cells compared to donor-matched untreated tissues (n = 3, p > 0.4), in which the loss of these cells between days 1 and 12 in culture was negligible (Grivel et al., 2000). In tonsillar tissues coinfected with HSV-2G and HIV-1LAI, 66 μg/ml tenofovir (maintained throughout the entire culture period) inhibited replication of both viruses: in the untreated control tissues, HSV-2G DNA release into culture medium was 7.3 log10 DNA copies/ml (IQR 6.8-7.4), whereas in donor-matched tissues treated with 66 μg/ml tenofovir HSV-2G, replication was suppressed by 96% ± 1% (n = 6; p < 0.01). In these tissues, HIV-1LAI was inhibited completely (Figure 4B). The antiherpetic effect of tenofovir is not a general property of the nucleoside reverse-transcriptase inhibitors (NRTIs) as we found no effect of lamivudine (3TC) on HSV-2G replication (data not shown). Finally, we found no effect of tenofovir (at 66 μg/ml) on the release of 15 cytokines (IL-1α, IL-6, IL-8, IL-15, IL-16, CCL3/MIP-1α, CCL4/MIP-1ß, CCL20/MIP-3α, CCL5/RANTES, CXCL12/SDF-1ß, CCL2/MCP-1, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP-10, and GM-CSF) into the culture medium (p > 0.15). Tenofovir at a concentration of 150 μg/ml also inhibited HSV-2G replication in cervicovaginal tissue ex vivo from 6.6 log10 DNA copies/ml (IQR 5.3-8.2) to 5.5 log10 DNA copies/ml (IQR 4.8-5.7, n = 5) (Figures 4C and 4D), reflecting 78% ± 9% reduction when the reductions of viral replication in each experiment were averaged (p < 0.01).

Activity of Tenofovir in HSV-Infected Mice

The anti-HSV-1- and HSV-2 activities of tenofovir were evaluated in virus-infected athymic nude mice (lumbosacral scarification model). The drug was administered to HSV-1- and HSV-2-infected mice at a concentration of 1% in DMSO for 5 days, starting at the day of infection. Mice treated with placebo (DMSO) developed lesions in the lumbosacral area, leading to paralysis of the hind legs and, finally, death. Treatment with tenofovir (1%) resulted in a statistically significant delay of morbidity and prolonged the survival of the mice infected with HSV (Figure 5A). Tenofovir was somewhat more active against HSV-1 than HSV-2, for unknown reasons. Also, when formulated in a 1% gel (as used in the CAPRISA 004 microbicide trial), tenofovir significantly (p < 0.01) delayed the appearance of herpesvirus-related lesions and subsequent death of the animals compared to placebo (same gel formulation without drug) (Figure 5B). Adefovir performed markedly better against HSV-1 than HSV-2 in the 1% gel-treated mice, but was virtually not superior to tenofovir against HSV-2 (Figure 5B).

Tenofovir Is Converted to Its Antivirally Active Metabolite in Relevant Cell Cultures

In lymphocytic CEM, epithelial TZM-Bl, and fibroblast HEL cultures, [2,8-3H]tenofovir (0.60 μg/ml, applied for 24 hr starting from 72 hr postinitiation of the cultures) was converted into tenofovir-diphosphate. Concentrations of this metabolite reached 5.4 ± 0.6, 5.2 ± 2.2, and 19 ± 17 ng/109 cells in lymphocytic cells, epithelial cells, and fibroblasts, respectively. We also demonstrated that, at increasing tenofovir concentrations (i.e., 0.6, 6, 60, or 600 μg/ml), concomitantly higher tenofovir diphosphate concentrations were formed (5.18 ± 2.2, 103 ± 15.2, 1,026 ± 103, and 10,400 ± 800 ng/109 TZM-Bl cells, respectively). Thus, epithelial cells exposed to 600 μg/ml tenofovir concentrations produced as much as 10.4 ± 0.8 ng of tenofovir diphosphate/106 cells (this corresponds to an ~3 μg/ml if we consider a cell volume to be 4 pl (Alberts et al., 1994)) without any sign of toxicity, as measured upon microscopic inspection. Also, MTT dye viability testing of epithelial cell cultures that were exposed to up to 1,000 μg/ml tenofovir did not show measurable toxicity (data not shown). Such a linear relationship between external tenofovir concentrations and intracellular tenofovir diphosphate concentrations has been observed earlier (Balzarini et al., 1991). This characteristic of tenofovir allows sufficiently high HSV-2-suppressive levels of tenofovir diphosphate metabolite upon application of 1% tenofovir (10 mg/ml) gel. Thus, tenofovir is efficiently converted to its antivirally active metabolite in multiple different cell types that represent relevant target cells for either HIV or HSV infection in vivo.

The Active Metabolite of Tenofovir Efficiently Inhibits Both HSV DNA Polymerase and HIV Reverse-Transcriptase

The active tenofovir metabolite, tenofovir diphosphate, has been evaluated for its inhibitory activity against the HIV-1 reverse-transcriptase and HSV DNA polymerase using activated calf thymus DNA as the primer/template and [2,8-3H] 2'-deoxyadenosine triphosphate (dATP) as the competing substrate. Tenofovir diphosphate efficiently inhibited HIV-1 RT with an IC50 of 1.3 μg/ml in the presence of dATP (3.2 μM) as the competing deoxynucleotide triphosphate (dNTP). Tenofovir diphosphate also inhibited herpesvirus DNA polymerase-catalyzed polymerization at IC50s of 0.38 ± 0.03 μg/ml, 7.1 ± 5 μg/ml, 8.5 ± 3.8 μg/ml, and 25 ± 1.8 μg/ml in the presence of competing dATP (3.2 μM), dGTP (2.8 μM), dTTP (1 μM), or dCTP (2.5 μM), respectively.

Thus, the antiherpetic activity of tenofovir in cell cultures, organotypic epithelial raft cultures, human lymphoid and cervicovaginal ex vivo tissues, and virus-infected mice can be fully explained by the inhibition of the viral DNA polymerase by its active metabolite, tenofovir diphosphate.

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