Modeling of the HIV-1 Life Cycle in Productively Infected Cells to Predict Novel Therapeutic Targets
Abstract
:1. Introduction
2. Results
2.1. Mathematical Model
2.1.1. Entry
- binding of virion to CD4 receptors (glycoprotein gp120 binds to CD4 receptors on the T cell surface),
- binding to the co-receptor (CCR5 or CXCR4),
- fusion, i.e., the nucleocapsid is uncoated and the viral RNA is injected into the cell.
2.1.2. Reverse Transcription
- synthesis of minus-strand DNA from viral RNA,
- synthesis of plus-strand DNA,
- double-strand DNA formation.
2.1.3. Integration
2.1.4. Transcription
2.1.5. Translation
2.1.6. Assembly, Budding and Maturation
2.2. Model Parameters
3. Sensitivity Analysis
- maximal achievable level of transcription rate that can be induced by Tat;
- HIV-1 assembly, specifically sensitive to availability and translation rate of Gag molecules;
- full-length RNA transport to membrane and degradation;
- transport of pre-integration complex into nucleus and DNA integration;
- Rev-mediated regulation of splicing rates and export of full-length RNA;
- reverse transcription (rate of reverse transcription, RNA degradation, DNA degradation);
- kinetics of membrane-bound pre-virion complexes and virions;
- binding and fusion of free virions.
4. Discussion
Author Contributions
Funding
Conflicts of Interest
Abbreviations
HIV-1 | Human immunodeficiency virus type 1 |
ART | antiretroviral therapy |
Tat | trans-activator of transcription |
Rev | regulator of expression of virion proteins |
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Parameter | Description | Value | Range, Relev. Refs. |
---|---|---|---|
rate of virion binding to CD4+ T cell membrane | [14,24,25] | ||
d | clearance rate of free mature virions | [23,26] | |
degradation rate of bound virions | |||
[27,28] | |||
rate of virion fusion with the cell | [15,25,29] | ||
reverse transcription rate | [4,9,11] | ||
degradation rate of RNA in cytoplasm | [30] | ||
degradation rate of DNA in cytoplasm | [10,16,31,32] | ||
transport rate of DNA from cytoplasm to nucleus | [4,32] | ||
degradation rate of DNA in nucleus | [16] | ||
integration rate | [4,33,34,35,36] | ||
degradation rate of DNA integrated into chromosome | 0.00002 | [37] | |
cell intrinsic rate of basal transcription | 15 | [4,5] | |
level of transcription induced by Tat transactivation | 1500 | [4,5] | |
threshold for half-maximal boosting of transcription by Tat | 1000 molec. | [4,5], calibrated by [10] | |
threshold for half-maximal boosting on export of and by Rev | 77,000 molec. | , calibrated by [10] | |
inhibitory effect of Rev on the splicing rates implying their 1 / ( 1 − β ) -fold reduction at saturation level of Rev | 0.9 | [4] | |
transport rate of to cell membrane | 2.8 | [38] | |
rate of export from nucleus, | [4,5,6] | ||
rate of export from nucleus | [4,5,6] | ||
rate of splicing for full-length virus RNA | [4,5,6] | ||
rate of splicing for singly spliced virus RNA | [4,5,6] | ||
degradation rate of , | [4,5,6] | ||
degradation rate of protein gp160 | [4] | ||
degradation rate of protein j, | [4,9] | ||
degradation rate of Tat protein | [4,5,6] | ||
degradation rate of Rev protein | [4,5,6] | ||
fraction of coding | |||
, | |||
— | 0.05 | [4] | |
— | 0.95 | [4] | |
— | 0.64 | [18] | |
— | 0.025 | [4] | |
— | 0.2 | [4,5] | |
rate of mRNA to proteins translation | 524 proteins/mRNA/h | [4,5,6,39] | |
degradation rate for the membrane anchored protein Gag-Pol | [40] | ||
degradation rate for the membrane anchored protein Gag | [40] | ||
degradation rate for membrane associated gp160 (Env) | [41] | ||
rate of protein transport to membrane, | [4,38,42] | ||
incorporation rate of molecules into pre-virion complexes | 8 | [19,43] | |
number of viral RNA transcripts in a new virion | 2 | [13,19] | |
number of Gag molecules in a new virion | 5000 | [19,21] | |
number of Gag-Pol molecules in a new virion | 250 | [19,21] | |
number of gp160 molecules in a new virion | 24 | [21,44] | |
degradation rate of assembled pre-virion complex | [43] | ||
budding rate of new virions | [43] | ||
degradation rate for budded immature viral like particle | [26] | ||
(= clearance rate of mature virions) | |||
maturation rate | [8] |
Processes Having Negative Effect on J | p | Processes Having Positive Effect on J | p | ||
---|---|---|---|---|---|
Gag contribution to virion assembly | 1810 | Transcription induced by Tat | 1971 | ||
Degradation of free and mature virions | d | 1721 | Translation of Gag molecules | 1811 | |
Transport of genomic mRNA to membrane | 1697 | Assembly of pre-virion complexes | 1810 | ||
Degradation of RNA during RT | 602 | Transport of proviral DNA to nucleus | 938 | ||
Degradation of assembled complexes | 364 | Inhibitory effect of Rev on splicing rates | 895 | ||
Degradation of DNA during RT | 268 | Reverse transcription | 781 | ||
Splicing of full-length genomic RNA | 262 | Integration of proviral DNA | 712 | ||
Degradation of budded immature particles | 242 | Export of full-length genomic RNA | 415 | ||
Degradation of genomic mRNA | 161 | Budding of immature particles | 412 | ||
Tolerance of mRNA export and | 118 | Maturation of budded particles | 285 | ||
splicing to Rev-mediated regulation | Binding of virions to the cell membrane | 250 | |||
Fusion of virions with the cell | 166 | ||||
Translation of Rev molecules | 118 | ||||
Splicing of singly spliced RNA | 104 |
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Shcherbatova, O.; Grebennikov, D.; Sazonov, I.; Meyerhans, A.; Bocharov, G. Modeling of the HIV-1 Life Cycle in Productively Infected Cells to Predict Novel Therapeutic Targets. Pathogens 2020, 9, 255. https://doi.org/10.3390/pathogens9040255
Shcherbatova O, Grebennikov D, Sazonov I, Meyerhans A, Bocharov G. Modeling of the HIV-1 Life Cycle in Productively Infected Cells to Predict Novel Therapeutic Targets. Pathogens. 2020; 9(4):255. https://doi.org/10.3390/pathogens9040255
Chicago/Turabian StyleShcherbatova, Olga, Dmitry Grebennikov, Igor Sazonov, Andreas Meyerhans, and Gennady Bocharov. 2020. "Modeling of the HIV-1 Life Cycle in Productively Infected Cells to Predict Novel Therapeutic Targets" Pathogens 9, no. 4: 255. https://doi.org/10.3390/pathogens9040255