In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide.
Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-02-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2824823?pdf=render |
| _version_ | 1818855522655272960 |
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| author | Lisa C Rohan Bernard J Moncla Ratiya Pamela Kunjara Na Ayudhya Marilyn Cost Yunda Huang Fang Gai Nicole Billitto J D Lynam Kara Pryke Phillip Graebing Nicole Hopkins James F Rooney David Friend Charlene S Dezzutti |
| author_facet | Lisa C Rohan Bernard J Moncla Ratiya Pamela Kunjara Na Ayudhya Marilyn Cost Yunda Huang Fang Gai Nicole Billitto J D Lynam Kara Pryke Phillip Graebing Nicole Hopkins James F Rooney David Friend Charlene S Dezzutti |
| author_sort | Lisa C Rohan |
| collection | DOAJ |
| description | Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy.Formulation assessment of tenofovir gel included osmolality, viscosity, in vitro release, and permeability testing. Safety was evaluated by measuring the effect on the viability of vaginal flora, PBMCs, epithelial cells, and ectocervical and colorectal explant tissues. For efficacy testing, PBMCs were cultured with tenofovir or vehicle control gels and HIV-1 representing subtypes A, B, and C. Additionally, polarized ectocervical and colorectal explant cultures were treated apically with either gel. Tenofovir was added basolaterally to simulate systemic application. All tissues were challenged with HIV-1 applied apically. Infection was assessed by measuring p24 by ELISA on collected supernatants and immunohistochemistry for ectocervical explants. Formulation testing showed the tenofovir and vehicle control gels were >10 times isosmolar. Permeability through ectocervical tissue was variable but in all cases the receptor compartment drug concentration reached levels that inhibit HIV-1 infection in vitro. The gels were non-toxic toward vaginal flora, PBMCs, or epithelial cells. A transient reduction in epithelial monolayer integrity and epithelial fracture for ectocervical and colorectal explants was noted and likely due to the hyperosmolar nature of the formulation. Tenofovir gel prevented HIV-1 infection of PBMCs regardless of HIV-1 subtype. Topical and systemic tenofovir were effective at preventing HIV-1 infection of explant cultures.These studies provide a mechanism for pre-clinical prediction of safety and efficacy of formulated microbicides. Tenofovir was effective against HIV-1 infection in our algorithm. These data support the use of tenofovir for pre-exposure prophylaxis. |
| first_indexed | 2024-12-19T08:09:57Z |
| format | Article |
| id | doaj.art-50f202cf80554ce48f7cec9fec903b9e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T08:09:57Z |
| publishDate | 2010-02-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-50f202cf80554ce48f7cec9fec903b9e2022-12-21T20:29:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-02-0152e931010.1371/journal.pone.0009310In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide.Lisa C RohanBernard J MonclaRatiya Pamela Kunjara Na AyudhyaMarilyn CostYunda HuangFang GaiNicole BillittoJ D LynamKara PrykePhillip GraebingNicole HopkinsJames F RooneyDavid FriendCharlene S DezzuttiTenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy.Formulation assessment of tenofovir gel included osmolality, viscosity, in vitro release, and permeability testing. Safety was evaluated by measuring the effect on the viability of vaginal flora, PBMCs, epithelial cells, and ectocervical and colorectal explant tissues. For efficacy testing, PBMCs were cultured with tenofovir or vehicle control gels and HIV-1 representing subtypes A, B, and C. Additionally, polarized ectocervical and colorectal explant cultures were treated apically with either gel. Tenofovir was added basolaterally to simulate systemic application. All tissues were challenged with HIV-1 applied apically. Infection was assessed by measuring p24 by ELISA on collected supernatants and immunohistochemistry for ectocervical explants. Formulation testing showed the tenofovir and vehicle control gels were >10 times isosmolar. Permeability through ectocervical tissue was variable but in all cases the receptor compartment drug concentration reached levels that inhibit HIV-1 infection in vitro. The gels were non-toxic toward vaginal flora, PBMCs, or epithelial cells. A transient reduction in epithelial monolayer integrity and epithelial fracture for ectocervical and colorectal explants was noted and likely due to the hyperosmolar nature of the formulation. Tenofovir gel prevented HIV-1 infection of PBMCs regardless of HIV-1 subtype. Topical and systemic tenofovir were effective at preventing HIV-1 infection of explant cultures.These studies provide a mechanism for pre-clinical prediction of safety and efficacy of formulated microbicides. Tenofovir was effective against HIV-1 infection in our algorithm. These data support the use of tenofovir for pre-exposure prophylaxis.http://europepmc.org/articles/PMC2824823?pdf=render |
| spellingShingle | Lisa C Rohan Bernard J Moncla Ratiya Pamela Kunjara Na Ayudhya Marilyn Cost Yunda Huang Fang Gai Nicole Billitto J D Lynam Kara Pryke Phillip Graebing Nicole Hopkins James F Rooney David Friend Charlene S Dezzutti In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS ONE |
| title | In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. |
| title_full | In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. |
| title_fullStr | In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. |
| title_full_unstemmed | In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. |
| title_short | In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. |
| title_sort | in vitro and ex vivo testing of tenofovir shows it is effective as an hiv 1 microbicide |
| url | http://europepmc.org/articles/PMC2824823?pdf=render |
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