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

ABSTRACT: 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.

SUBMITTER: Ikeda H

PROVIDER: S-EPMC4834825 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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

Ikeda Hiroki H Nakaoka Shinji S de Boer Rob J RJ Morita Satoru S Misawa Naoko N Koyanagi Yoshio Y Aihara Kazuyuki K Sato Kei K Iwami Shingo S

Retrovirology 20160418

<h4>Background</h4>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.<h4>Results</h ...[more]

PMID: 27086687

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Project description:Although current combinatorial antiretroviral therapy (cART) is therapeutically effective in the majority of HIV patients, interruption of therapy can cause a rapid rebound in viremia, demonstrating the existence of a stable reservoir of latently infected cells. HIV latency is therefore considered a primary barrier to HIV eradication. Identifying, quantifying, and purging the HIV reservoir is crucial to effectively curing patients and relieving them from the lifelong requirement for therapy. Latently infected transformed cell models have been used to investigate HIV latency; however, these models cannot accurately represent the quiescent cellular environment of primary latently infected cells in vivo For this reason, in vivo humanized murine models have been developed for screening antiviral agents, identifying latently infected T cells, and establishing treatment approaches for HIV research. Such models include humanized bone marrow/liver/thymus mice and SCID-hu-thy/liv mice, which are repopulated with human immune cells and implanted human tissues through laborious surgical manipulation. However, no one has utilized the human hematopoietic stem cell-engrafted NOD/SCID/IL2r?null (NSG) model (hu-NSG) for this purpose. Therefore, in the present study, we used the HIV-infected hu-NSG mouse to recapitulate the key aspects of HIV infection and pathogenesis in vivo Moreover, we evaluated the ability of HIV-infected human cells isolated from HIV-infected hu-NSG mice on suppressive cART to act as a latent HIV reservoir. Our results demonstrate that the hu-NSG model is an effective surgery-free in vivo system in which to efficiently evaluate HIV replication, antiretroviral therapy, latency and persistence, and eradication interventions.IMPORTANCE HIV can establish a stably integrated, nonproductive state of infection at the level of individual cells, known as HIV latency, which is considered a primary barrier to curing HIV. A complete understanding of the establishment and role of HIV latency in vivo would greatly enhance attempts to develop novel HIV purging strategies. An ideal animal model for this purpose should be easy to work with, should have a shortened disease course so that efficacy testing can be completed in a reasonable time, and should have immune correlates that are easily translatable to humans. We therefore describe a novel application of the hematopoietic stem cell-transplanted humanized NSG model for dynamically testing antiretroviral treatment, supporting HIV infection, establishing HIV latency in vivo The hu-NSG model could be a facile alternative to humanized bone marrow/liver/thymus or SCID-hu-thy/liv mice in which laborious surgical manipulation and time-consuming human cell reconstitution is required.

Dataset Information

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

Publications

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

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