Dataset Information

Probabilistic control of HIV latency and transactivation by the Tat gene circuit.

ABSTRACT: The reservoir of HIV latently infected cells is the major obstacle for eradication of HIV infection. The "shock-and-kill" strategy proposed earlier aims to reduce the reservoir by activating cells out of latency. While the intracellular HIV Tat gene circuit is known to play important roles in controlling latency and its transactivation in HIV-infected cells, the detailed control mechanisms are not well understood. Here we study the mechanism of probabilistic control of the latent and the transactivated cell phenotypes of HIV-infected cells. We reconstructed the probability landscape, which is the probability distribution of the Tat gene circuit states, by directly computing the exact solution of the underlying chemical master equation. Results show that the Tat circuit exhibits a clear bimodal probability landscape (i.e., there are two distinct probability peaks, one associated with the latent cell phenotype and the other with the transactivated cell phenotype). We explore potential modifications to reactions in the Tat gene circuit for more effective transactivation of latent cells (i.e., the shock-and-kill strategy). Our results suggest that enhancing Tat acetylation can dramatically increase Tat and viral production, while increasing the Tat-transactivation response binding affinity can transactivate latent cells more rapidly than other manipulations. Our results further explored the "block and lock" strategy toward a functional cure for HIV. Overall, our study demonstrates a general approach toward discovery of effective therapeutic strategies and druggable targets by examining control mechanisms of cell phenotype switching via exactly computed probability landscapes of reaction networks.

SUBMITTER: Cao Y

PROVIDER: S-EPMC6298123 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Probabilistic control of HIV latency and transactivation by the Tat gene circuit.

Cao Youfang Y Lei Xue X Ribeiro Ruy M RM Perelson Alan S AS Liang Jie J

Proceedings of the National Academy of Sciences of the United States of America 20181119 49

The reservoir of HIV latently infected cells is the major obstacle for eradication of HIV infection. The "shock-and-kill" strategy proposed earlier aims to reduce the reservoir by activating cells out of latency. While the intracellular HIV Tat gene circuit is known to play important roles in controlling latency and its transactivation in HIV-infected cells, the detailed control mechanisms are not well understood. Here we study the mechanism of probabilistic control of the latent and the transac ...[more]

PMID: 30455316

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Project description:The magnitude of transcription factor binding site variation emerging in HIV-1 subtype C (HIV-1C), especially the addition of NF-?B motifs by sequence duplication, makes the examination of transcriptional silence challenging. How can HIV-1 establish and maintain latency despite having a strong long terminal repeat (LTR)? We constructed panels of subgenomic reporter viral vectors with varying copy numbers of NF-?B motifs (0 to 4 copies) and examined the profile of latency establishment in Jurkat cells. Surprisingly, we found that the stronger the viral promoter, the faster the latency establishment. Importantly, at the time of commitment to latency and subsequent points, Tat levels in the cell were not limiting. Using highly sensitive strategies, we demonstrate the presence of Tat in the latent cell, recruited to the latent LTR. Our data allude, for the first time, to Tat establishing a negative feedback loop during the late phases of viral infection, leading to the rapid silencing of the viral promoter.IMPORTANCE Over the past 10 to 15?years, HIV-1 subtype C (HIV-1C) has been evolving rapidly toward gaining stronger transcriptional activity by sequence duplication of major transcription factor binding sites. The duplication of NF-?B motifs is unique and exclusive to HIV-1C, a property not shared with any of the other eight HIV-1 genetic families. What mechanism(s) does HIV-1C employ to establish and maintain transcriptional silence despite the presence of a strong promoter and concomitant strong, positive transcriptional feedback is the primary question that we attempted to address in the present manuscript. The role that Tat plays in latency reversal is well established. Our work with the most common HIV-1 subtype, HIV-1C, offers crucial leads toward Tat possessing a dual role in serving as both a transcriptional activator and repressor at different phases of viral infection of the cell. The leads that we offer through the present work have significant implications for HIV-1 cure research.

Dataset Information

Probabilistic control of HIV latency and transactivation by the Tat gene circuit.

Publications

Probabilistic control of HIV latency and transactivation by the Tat gene circuit.

Similar Datasets

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