Modeling viral kinetics predicts a rapid establishment of the cytotoxic immune response targeting distinct infected cell compartments in SIV controller macaques (ANRS SIC study)
V. Madelain 1, C. Passaes 2, A. Millet 3, V. Avettand-Fenoel 3, C. Rouzioux 3, N. Dereuddre-Bosquet 4,5, R. Le Grand 4,5, B. Vaslin 4,5, A. Saez-Cirion 2, J. Guedj 1
1 IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité Paris, France, 2 Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France, 3 Université Paris-Descartes, Sorbonne Paris-Cité, Faculté de Médecine, EA 7327, Paris, France, 4 CEA, DRF/iMETI, Fontenay-aux-Roses, France, 5 Center for Immunology of Viral Infections and Autoimmune Diseases-Inserm U1184 (CEA-Université Paris Sud-INSERM) and IDMIT, Fontenay-aux-Roses, France
Objectives: Our group recently demonstrated that long term control of SIV infection can be obtained in cynomolgus macaques presenting a H6 MHC haplotype or in non-H6 animals infected with a low dose inoculum of SIVmac251 by mucosal route [1]. Here we applied mathematical modeling to viral kinetics in this model to help unraveling the determinants of viral control.
Methods: The kinetics of SIV RNA and SIV DNA was obtained for 18 months in 16 macaques in 3 groups: i) H6 macaques infected with 50 AID50 (n=6) ; ii) non-H6 macaques infected with 5 AID50 (n=4) ; iii) non-H6 macaques infected with 50 AID50 (n=6, controls). SIV RNA and DNA data were jointly fitted with a mechanistic model of viral infection, using nonlinear mixed effect models (SAEM algorithm, implemented in Monolix software).
Results: The rapid viral decline after the peak in controllers could be best reproduced assuming a cytotoxic immune response with a saturable infected cells-dependent growth rate, as previously described in [2]. Interestingly, simulation and Sobol global sensitivity analysis suggested that in our model viral control was mostly driven by an early effective response after peak viremia, and to a lesser extent by the strength of the immune response per se. This result corroborated independently by longitudinal ex-vivo assessment of CD8 T cells cytotoxic activity. Further, SIV-DNA after the peak declined slowly in a biphasic manner, suggesting that SIV-DNA after the peak largely originates from not or low actively productive cells. In fact, best fit to SIV-RNA and SIV-DNA kinetics was obtained assuming 3 compartments of infected cells: highly productive cells with a short half-life decreasing from 5.5 days (early infection) to 0.3 days after peak viremia, and two populations of weakly or nonproductive cells, with half-life of 5.1 and 118 days. Thus one predicts that these compartments respectively account for about 1, 5 and 96% of circulating infected cells, in typical controllers at the setpoint viremia.
Conclusions: In conclusion modeling predicts that an early establishment of an effective CD8 response is key to achieve viral control. Discrepancy between SIV-RNA and SIV-DNA kinetics reveals that more than 90% of SIV-DNA containing cells are not highly producing and not highly targeted by the immune response in these controllers.
References:
[1] Bruel T, Hamimi C, Dereuddre-Bosquet N, Cosma A, Shin SY, Corneau A, et al. J. Virol. 2015;89:3542–56
[2] Conway JM, Perelson AS. Proc. Natl. Acad. Sci. U. S. A. 2015;112:5467–72.
