Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model

Hiroki Ikeda, Shinji Nakaoka, Rob J. de Boer, Satoru Morita, Naoko Misawa, Yoshio Koyanagi, Kazuyuki Aihara, Kei Sato, Shingo Iwami

Tetherin is an intrinsic anti-viral factor impairing the release of nascent HIV-1 particles from infected cells. Vpu, an HIV-1 accessory protein, antagonizes the anti-viral action of tetherin. Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo. To quantitatively assess the role of Vpu in viral replication in vivo, we analyzed time courses of experimental data with viral load and target cell levels in the peripheral blood of humanized mice infected with wild-type and vpu-deficient HIV-1. Our recently developed mathematical model describes the acute phase of this infection reasonably, and allowed us to estimate several parameters characterizing HIV-1 infection in mice. Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1. This reveals that Vpu markedly increases the rate of viral replication in vivo. Combining experiments with mathematical modeling, we provide an estimate for the contribution of Vpu to viral replication in humanized mice.