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

Abstract

BackgroundTetherin 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.ResultsTo 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.ConclusionsCombining experiments with mathematical modeling, we provide an estimate for the contribution of Vpu to viral replication in humanized mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0252-2) contains supplementary material, which is available to authorized users.

Experimental Adaptive Evolution of Simian Immunodeficiency Virus SIVcpz to Pandemic Human Immunodeficiency Virus Type 1 by Using a Humanized Mouse Model

“…These observations suggest that HIV-1M is more optimally adapted to infect humans than the other viruses. Importantly, only HIV-1M Vpu potently antagonizes the antiviral action of human tetherin (29), and our experimental-mathematical analyses have recently shown that HIV-1M Vpu markedly increases the rate of viral replication in vivo (47). All together, these findings strongly suggest that the Vpu-tetherin interaction may be a critical step for increasing viral fitness in vivo.…”

“…5B and C). We have previously demonstrated that HIV-1M Vpu augments viral dissemination in our humanized-mouse model (39,47). To directly evaluate the effect of the antitetherin ability of Vpu on viral propagation in vivo, we prepared an SIVcpzPtt MB897 derivative that incorporates the transmembrane domain of HIV-1M (strain NL4-3) Vpu and is designated MB897 NLvpuTM, in accordance with a previous report (28).…”

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