Biochemical mechanism of HIV-1 resistance to rilpivirine

Kamalendra Singh; Bruno Marchand; Devendra K. Rai; Bechan Sharma; Eleftherios Michailidis; Emily M. Ryan; Kayla B. Matzek; Maxwell D. Leslie; Ariel N. Hagedorn; Zhe Li; Pieter R. Norden; Atsuko Hachiya; Michael A. Parniak; Hong Tao Xu; Mark A. Wainberg; Stefan G. Sarafianos

doi:10.1074/jbc.M112.398180

Biochemical mechanism of HIV-1 resistance to rilpivirine

Kamalendra Singh, Bruno Marchand, Devendra K. Rai, Bechan Sharma, Eleftherios Michailidis, Emily M. Ryan, Kayla B. Matzek, Maxwell D. Leslie, Ariel N. Hagedorn, Zhe Li, Pieter R. Norden, Atsuko Hachiya, Michael A. Parniak, Hong Tao Xu, Mark A. Wainberg, Stefan G. Sarafianos

Veterinary Population Medicine

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Abstract

Background: Reverse transcriptase mutations E138K and M184I emerged most frequently in HIV-1 patients who failed rilpivirine/emtricitabine/tenofovir combination therapy. Results: M184I reduces polymerase efficiency, and E138K restores it. E138K also reduces rilpivirine binding affinity mainly by increasing its dissociation rate. Conclusion: E138K abrogates the polymerase defect of M184I and increases rilpivirine dissociation. Significance: Our results provide a biochemical explanation for the selection of E138K/M184I in patients who failed combination therapy.

Original language	English (US)
Pages (from-to)	38110-38123
Number of pages	14
Journal	Journal of Biological Chemistry
Volume	287
Issue number	45
DOIs	https://doi.org/10.1074/jbc.M112.398180
State	Published - Nov 2 2012

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Singh, K., Marchand, B., Rai, D. K., Sharma, B., Michailidis, E., Ryan, E. M., Matzek, K. B., Leslie, M. D., Hagedorn, A. N., Li, Z., Norden, P. R., Hachiya, A., Parniak, M. A., Xu, H. T., Wainberg, M. A., & Sarafianos, S. G. (2012). Biochemical mechanism of HIV-1 resistance to rilpivirine. Journal of Biological Chemistry, 287(45), 38110-38123. https://doi.org/10.1074/jbc.M112.398180

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abstract = "Background: Reverse transcriptase mutations E138K and M184I emerged most frequently in HIV-1 patients who failed rilpivirine/emtricitabine/tenofovir combination therapy. Results: M184I reduces polymerase efficiency, and E138K restores it. E138K also reduces rilpivirine binding affinity mainly by increasing its dissociation rate. Conclusion: E138K abrogates the polymerase defect of M184I and increases rilpivirine dissociation. Significance: Our results provide a biochemical explanation for the selection of E138K/M184I in patients who failed combination therapy.",

author = "Kamalendra Singh and Bruno Marchand and Rai, {Devendra K.} and Bechan Sharma and Eleftherios Michailidis and Ryan, {Emily M.} and Matzek, {Kayla B.} and Leslie, {Maxwell D.} and Hagedorn, {Ariel N.} and Zhe Li and Norden, {Pieter R.} and Atsuko Hachiya and Parniak, {Michael A.} and Xu, {Hong Tao} and Wainberg, {Mark A.} and Sarafianos, {Stefan G.}",

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AU - Singh, Kamalendra

AU - Marchand, Bruno

AU - Rai, Devendra K.

AU - Sharma, Bechan

AU - Michailidis, Eleftherios

AU - Ryan, Emily M.

AU - Matzek, Kayla B.

AU - Leslie, Maxwell D.

AU - Hagedorn, Ariel N.

AU - Li, Zhe

AU - Norden, Pieter R.

AU - Hachiya, Atsuko

AU - Parniak, Michael A.

AU - Xu, Hong Tao

AU - Wainberg, Mark A.

AU - Sarafianos, Stefan G.

PY - 2012/11/2

Y1 - 2012/11/2

N2 - Background: Reverse transcriptase mutations E138K and M184I emerged most frequently in HIV-1 patients who failed rilpivirine/emtricitabine/tenofovir combination therapy. Results: M184I reduces polymerase efficiency, and E138K restores it. E138K also reduces rilpivirine binding affinity mainly by increasing its dissociation rate. Conclusion: E138K abrogates the polymerase defect of M184I and increases rilpivirine dissociation. Significance: Our results provide a biochemical explanation for the selection of E138K/M184I in patients who failed combination therapy.

AB - Background: Reverse transcriptase mutations E138K and M184I emerged most frequently in HIV-1 patients who failed rilpivirine/emtricitabine/tenofovir combination therapy. Results: M184I reduces polymerase efficiency, and E138K restores it. E138K also reduces rilpivirine binding affinity mainly by increasing its dissociation rate. Conclusion: E138K abrogates the polymerase defect of M184I and increases rilpivirine dissociation. Significance: Our results provide a biochemical explanation for the selection of E138K/M184I in patients who failed combination therapy.

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Biochemical mechanism of HIV-1 resistance to rilpivirine

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