The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans

Carolina Herrera; Mackenzie L.  Cottrell; John  Prybylski; Angela D.M. Kashuba; Ronald S.  Veazey; Javier  García-Pérez; Natalia  Olejniczak; Clare F. McCoy; Paul  Ziprin; Nicola  Richardson-Harman; José  Alcami; Karl R. Malcolm; Robin J Shattock

doi:10.1016/j.isci.2022.104409

The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans

Carolina Herrera, Mackenzie L. Cottrell, John Prybylski, Angela D.M. Kashuba, Ronald S. Veazey, Javier García-Pérez, Natalia Olejniczak, Clare F. McCoy, Paul Ziprin, Nicola Richardson-Harman, José Alcami, Karl R. Malcolm, Robin J Shattock

School of Pharmacy

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Abstract

Non-human primate (NHP) models of infection and pharmacokinetics are widely used as part of preclinical assessment of antiretrovirals for HIV treatment and prevention. However, the utility of these models is questionable given differences in antiretroviral (ARV) pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and challenge of mucosal tissue explants to help compare and define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations for tenofovir (TFV) and maraviroc were predictive of antiviral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (P = 0.042). In humans this relationship was inverted with lower levels in colorectal tissue (P = 0.027). TFV-resistance caused a greater loss of viral fitness for HIV-1 than SIV. Thus, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

Original language	English
Article number	104409
Journal	iScience
Volume	25
Issue number	6
Early online date	27 May 2022
DOIs	https://doi.org/10.1016/j.isci.2022.104409
Publication status	Published - 17 Jun 2022

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The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Herrera, C., Cottrell, M. L., Prybylski, J., Kashuba, A. D. M., Veazey, R. S., García-Pérez, J., Olejniczak, N., McCoy, C. F., Ziprin, P., Richardson-Harman, N., Alcami, J., Malcolm, K. R., & Shattock, R. J. (2022). The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans. iScience, 25(6), Article 104409. https://doi.org/10.1016/j.isci.2022.104409

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abstract = "Non-human primate (NHP) models of infection and pharmacokinetics are widely used as part of preclinical assessment of antiretrovirals for HIV treatment and prevention. However, the utility of these models is questionable given differences in antiretroviral (ARV) pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and challenge of mucosal tissue explants to help compare and define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations for tenofovir (TFV) and maraviroc were predictive of antiviral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (P = 0.042). In humans this relationship was inverted with lower levels in colorectal tissue (P = 0.027). TFV-resistance caused a greater loss of viral fitness for HIV-1 than SIV. Thus, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.",

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AU - Herrera, Carolina

AU - Cottrell, Mackenzie L.

AU - Prybylski, John

AU - Kashuba, Angela D.M.

AU - Veazey, Ronald S.

AU - García-Pérez, Javier

AU - Olejniczak, Natalia

AU - McCoy, Clare F.

AU - Ziprin, Paul

AU - Richardson-Harman, Nicola

AU - Alcami, José

AU - Malcolm, Karl R.

AU - Shattock, Robin J

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N2 - Non-human primate (NHP) models of infection and pharmacokinetics are widely used as part of preclinical assessment of antiretrovirals for HIV treatment and prevention. However, the utility of these models is questionable given differences in antiretroviral (ARV) pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and challenge of mucosal tissue explants to help compare and define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations for tenofovir (TFV) and maraviroc were predictive of antiviral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (P = 0.042). In humans this relationship was inverted with lower levels in colorectal tissue (P = 0.027). TFV-resistance caused a greater loss of viral fitness for HIV-1 than SIV. Thus, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

AB - Non-human primate (NHP) models of infection and pharmacokinetics are widely used as part of preclinical assessment of antiretrovirals for HIV treatment and prevention. However, the utility of these models is questionable given differences in antiretroviral (ARV) pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and challenge of mucosal tissue explants to help compare and define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations for tenofovir (TFV) and maraviroc were predictive of antiviral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (P = 0.042). In humans this relationship was inverted with lower levels in colorectal tissue (P = 0.027). TFV-resistance caused a greater loss of viral fitness for HIV-1 than SIV. Thus, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

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DO - 10.1016/j.isci.2022.104409

M3 - Article

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The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans

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