Differences in Transcriptional Dynamics Between T-cells and Macrophages as Determined by a Three-State Mathematical Model

Abstract

HIV-1 viral transcription persists in patients despite antiretroviral treatment, potentially due to intermittent HIV-1 LTR activation. While several mathematical models have been explored in the context of LTR-protein interactions, in this work for the first time HIV-1 LTR model featuring repressed, intermediate, and activated LTR states is integrated with generation of long (env) and short (TAR) RNAs and proteins (Tat, Pr55, and p24) in T-cells and macrophages using both cell lines and infected primary cells. This type of extended modeling framework allows us to compare and contrast behavior of these two cell types. We demonstrate that they exhibit unique LTR dynamics, which ultimately results in differences in the magnitude of viral products generated. One of the distinctive features of this work is that it relies on experimental data in reaction rate computations. Two RNA transcription rates from the activated promoter states are fit by comparison of experimental data to model predictions. Fitting to the data also provides estimates for the degradation/exit rates for long and short viral RNA. Our experimentally generated data is in reasonable agreement for the T-cell as well macrophage population and gives strong evidence in support of using the proposed integrated modeling paradigm. Sensitivity analysis performed using Latin hypercube sampling method confirms robustness of the model with respect to small parameter perturbations. Finally, incorporation of a transcription inhibitor (F07#13) into the governing equations demonstrates how the model can be used to assess drug efficacy. Collectively, our model indicates transcriptional differences between latently HIV-1 infected T-cells and macrophages and provides a novel platform to study various transcriptional dynamics leading to latency or activation in numerous cell types and physiological conditions.

Role of saliva use during masturbation in the transmission of Chlamydia trachomatis in men who have sex with men

“…Due to the variations in the frequency of sexual practices in MSM [14], we conducted sensitivity analyses to assess the impact of varying the selected parameters (frequency of solo masturbation and mutual masturbation and proportion of saliva used for solo masturbation and mutual masturbation) on the uncertainty of model calibration and the incidence. Sensitivity analysis was performed using the Latin hypercube sampling method, and we confirmed the model's robustness concerning small parameter perturbations [24]. (Further details are provided in the supplementary Table S3).…”

Extracellular Vesicles from Infected Cells Are Released Prior to Virion Release

“…Previously, we showed that HIV-1 gene expression is characterized by stochastic variability which results in paused polymerase and intermittent transition from latent to active state that allows the synthesis of mostly short non-coding RNAs (i.e., TAR) [ 19 , 20 , 36 , 37 , 38 ]. Paused RNA polymerase II allows synthesis of at least four distinct species of RNA that form a specific set of secondary structures [ 16 , 28 , 39 ].…”

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

“…In addition, high levels of NF-κB and P300 were observed in the nuclei of latent cells cocultured with exosomal vesicles [171]. These vesicles can be targeted with antibodies, antibiotics, drugs, transcription inhibitors, and ARTs to alter the ratio/amount of their individual components and subsequently alter their roles in HIV latency upkeep/reversion [173,174]. For example, ARTs (Indinacir and Emitricitabine), antibiotics (oxytetracycline, tetracycline, methacycline, and demeclocycline), and even interferon treatments showed effects on the proteins in-volved in the endosomal sorting complex required for transport (ESCRT) pathway and caused changes in TAR RNA levels and other contents of these exosomal vesicles [173].…”

“…For example, ARTs (Indinacir and Emitricitabine), antibiotics (oxytetracycline, tetracycline, methacycline, and demeclocycline), and even interferon treatments showed effects on the proteins in-volved in the endosomal sorting complex required for transport (ESCRT) pathway and caused changes in TAR RNA levels and other contents of these exosomal vesicles [173]. In addition, incorporation of a transcriptional inhibitor F07#13 in a mathematical model in various cell types displayed potential to induce changes in HIV latency and LTR dynamics and were different among the cell types used [174]. In a study that used a library of FDAapproved drugs, HIV-1 proviral transcription was activated with febuxostat, eltrombopag, and resveratrol, while mycophenolate inhibited HIV-1 proviral transcription, and these transcriptional modulators exhibited different effects in different cell types (lymphoid versus myeloid lineage) [175].…”