1. The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans
- Author
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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, National Institutes of Health (Estados Unidos), Unión Europea. Comisión Europea. 7 Programa Marco, Red de Investigación Cooperativa en Investigación en Sida (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto de Salud Carlos III, and National Institutes of Health
- Subjects
Biological sciences ,Multidisciplinary ,SDG 3 - Good Health and Well-being ,Immunology ,Natural sciences ,virus diseases ,Toxicology ,Biological sciences research methodologies - Abstract
Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral 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 greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies. This work was supported by an NIH R21 award AI094515 and by the European Commission’s seventh Framework "Combined Highly Active Retroviral Microbicides" (CHAARM) (242135). This work was partially supported by project PI19CIII/00004 and the Spanish AIDS Research Network (RIS) funded by Instituto de Salud Carlos III and co-funded by European Development Fund (ERDF) "A way to build Europe" (project RD16CIII/0002/0001). Sí
- Published
- 2022