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A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro.

ABSTRACT: Persistence of HIV-1 latent reservoir cells during antiretroviral therapy (ART) is a major obstacle for curing HIV-1. Even though latency-reversing agents (LRAs) are under development to reactivate and eradicate latently infected cells, there are few useful models for evaluating LRA activity in vitro. Here, we establish a long-term cell culture system called the "widely distributed intact provirus elimination" (WIPE) assay. It harbors thousands of different HIV-1-infected cell clones with a wide distribution of HIV-1 provirus similar to that observed in vivo. Mathematical modeling and experimental results from this in vitro infection model demonstrates that the addition of an LRA to ART shows a latency-reversing effect and contributes to the eradication of replication-competent HIV-1. The WIPE assay can be used to optimize therapeutics against HIV-1 latency and investigate mechanistic insights into the clonal selection of heterogeneous HIV-1-infected cells.

SUBMITTER: Matsuda K

PROVIDER: S-EPMC9017183 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents <i>in vitro</i>.

Matsuda Kouki K Islam Saiful S Takada Toru T Tsuchiya Kiyoto K Yang Tan Benjy Jek BJ Hattori Shin-Ichiro SI Katsuya Hiroo H Kitagawa Kosaku K Kim Kwang Su KS Matsuo Misaki M Sugata Kenji K Delino Nicole S NS Gatanaga Hiroyuki H Yoshimura Kazuhisa K Matsushita Shuzo S Mitsuya Hiroaki H Iwami Shingo S Satou Yorifumi Y Maeda Kenji K

Cell reports methods 20211129 8

Persistence of HIV-1 latent reservoir cells during antiretroviral therapy (ART) is a major obstacle for curing HIV-1. Even though latency-reversing agents (LRAs) are under development to reactivate and eradicate latently infected cells, there are few useful models for evaluating LRA activity <i>in vitro</i>. Here, we establish a long-term cell culture system called the "widely distributed intact provirus elimination" (WIPE) assay. It harbors thousands of different HIV-1-infected cell clones with ...[more]

PMID: 35475215

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Project description:Eradicating HIV-1 infection is difficult because of the reservoir of latently infected cells that gets established soon after infection, remains hidden from antiretroviral drugs and host immune responses, and retains the capacity to reignite infection following the cessation of treatment. Drugs called latency-reversing agents (LRAs) are being developed to reactivate latently infected cells and render them susceptible to viral cytopathicity or immune killing. Whereas individual LRAs have failed to induce adequate reactivation, pairs of LRAs have been identified recently that act synergistically and hugely increase reactivation levels compared to individual LRAs. The maximum synergy achievable with LRA pairs is of clinical importance, as it would allow latency-reversal with minimal drug exposure. Here, we employed stochastic simulations of HIV-1 transcription and translation in latently infected cells to estimate this maximum synergy. We incorporated the predominant mechanisms of action of the two most promising classes of LRAs, namely, protein kinase C agonists and histone deacetylase inhibitors, and quantified the activity of individual LRAs in the two classes by mapping our simulations to corresponding in vitro experiments. Without any adjustable parameters, our simulations then quantitatively captured experimental observations of latency-reversal when the LRAs were used in pairs. Performing simulations representing a wide range of drug concentrations, we estimated the maximum synergy achievable with these LRA pairs. Importantly, we found with all the LRA pairs we considered that concentrations yielding the maximum synergy did not yield the maximum latency-reversal. Increasing concentrations to increase latency-reversal compromised synergy, unravelling a trade-off between synergy and efficacy in LRA combinations. The maximum synergy realizable with LRA pairs would thus be restricted by the desired level of latency-reversal, a constrained optimum we elucidated with our simulations. We expect this trade-off to be important in defining optimal LRA combinations that would maximize synergy while ensuring adequate latency-reversal.

Dataset Information

A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro.

Publications

A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents <i>in vitro</i>.

Similar Datasets

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