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
Affiliations
Carolina Herrera
Section of Virology, Faculty of Medicine, St. Mary’s Campus, Imperial College London, UK; Corresponding author
Mackenzie L. Cottrell
University of North Carolina at Chapel Hill, UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA
John Prybylski
University of North Carolina at Chapel Hill, UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA
Angela D.M. Kashuba
University of North Carolina at Chapel Hill, UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA
Ronald S. Veazey
Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
Javier García-Pérez
AIDS Immunopathology Unit. National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
Natalia Olejniczak
Section of Virology, Faculty of Medicine, St. Mary’s Campus, Imperial College London, UK
Clare F. McCoy
School of Pharmacy, Medical Biology Centre, Queen’s University of Belfast, Belfast, UK
Paul Ziprin
Department of Surgery and Cancer, St Mary’s Hospital, Imperial College London, UK
Nicola Richardson-Harman
Alpha StatConsult, LLC, Damascus, MD, USA
José Alcami
AIDS Immunopathology Unit. National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain; HIV Unit, Hospital Clinic-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Karl R. Malcolm
School of Pharmacy, Medical Biology Centre, Queen’s University of Belfast, Belfast, UK
Robin J. Shattock
Section of Virology, Faculty of Medicine, St. Mary’s Campus, Imperial College London, UK
Summary: 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.