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Highly efficient CD8+T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8+T cell responses. Our results show that SIV-specific CD8+T cells emerge during primary infection in all animals. The ability of CD8+T cells to suppress SIV is suboptimal in the acute phase but increases progressively in controller macaques before the establishment of sustained low-level viremia. Controller macaques develop optimal memory-like SIV-specific CD8+T cells early after infection. In contrast, a persistently skewed differentiation phenotype characterizes memory SIV-specific CD8+T cells in non-controller macaques. Accordingly, the phenotype of SIV-specific CD8+T cells defined early after infection appears to favor the development of protective immunity in controllers, whereas SIV-specific CD8+T cells in non-controllers fail to gain antiviral potency, feasibly as a consequence of early defects imprinted in the memory pool.

ABSTRACTFavipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitroand in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n= 17) or Mauritian (n= 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.