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

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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 languageEnglish
Article number104409
Issue number6
Early online date27 May 2022
Publication statusPublished - 17 Jun 2022


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