Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation
- Vaccine and Infectious Disease Division, University of Washington, United States
- Department of Medicine, University of Washington, United States
- Clinical Research Division, Fred Hutchinson Cancer Research Center, United States
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, United States
- Department of Pathology, University of Washington, United States
Figures
Figure 1
Study design and mathematical modeling.
(A) Twenty-two pig-tailed macaques were infected with SHIV and suppressed with ART. Next, 17/22 underwent hematopoietic stem and progenitor cell (HSPC) transplantation following myeloablative …
Figure 2 with 1 supplement
Post-transplantation, pre-ATI CD4+ and CD8+ T cell dynamics.
(A) Empirical data for peripheral CD4+ CCR5+ (top row), CD4+CCR5- (middle row), and CD8+ T cell counts (bottom row) for control (blue), wild-type (red), and ΔCCR5 (green) transplantation groups. …
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Figure 2—source code 1
R code for plots and tests in Figure 2.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig2-code1-v1.zip
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Figure 2—source data 1
Complete data set of blood T cell counts for Figures 2 and 3.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig2-data1-v1.zip
Figure 2—figure supplement 1
CD4+ and CD8+ T cell levels pre-ATI in control group (n = 5) at times relative to post-transplantation in WT and ΔCCR5 transplant groups.
Range of blood (A) CD4+ and (B) CD8+ T cell counts using all data points for the period before ATI in control animals (p-value calculated with a paired t-test for averaged measurements from a time …
Figure 3 with 4 supplements
Mathematical model of T cell reconstitution after hematopoietic stem and progenitor cell (HSPC) transplantation.
(A) Schematics of the model. Each circle represents a cell compartment: T represents the HSPCs from the transplant; P, the progenitor cells in bone marrow (BM) and thymus; S and N, CD4+CCR5+ and CD4+…
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Figure 3—source code 1
Best model file for T cell reconstitution in Monolix format.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-code1-v1.zip
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Figure 3—source code 2
R code for plots in Figure 3.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-code2-v1.zip
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Figure 3—source data 1
Values of the fraction of protected cells in transplant product , dose or number of hematopoietic stem and progenitor cell (HSPCs) in transplant product and time of transplantation of each animal for model fitting and projections.
We assumed animal weight of 5 Kg.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-data1-v1.docx
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Figure 3—source data 2
Competing models for fitting T cell reconstitution with respective AIC values.
Best fit in bold-red (lowest AIC). The AIC values presented for each statistical assumption is the lowest of 10 runs of the SAEM algorithm with different randomly selected initial guesses.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-data2-v1.docx
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Figure 3—source data 3
Population parameter estimates for the best fits of the model in Equation 2 in the main text (lowest AIC in Figure 3—source data 2) to the T cell reconstitution dynamics.
RSE: relative standard error. Empty fields represent a standard deviation of random effects, , fixed to zero. Values of for and shown here are in log10 cell counts/μL assuming a blood volume of of 3 × 105 μL (calculated assuming blood:weight ratio of 60 mL/kg and body weight of 5 kg). Red values represent an RSE greater than 100% implying that the number of data points may not be enough to estimate the respective parameter.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-data3-v1.docx
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Figure 3—source data 4
Individual parameter estimates for the best fits of the model in Equation 2 in the main text (lowest AIC in Figure 3—source data 2) to the T cell reconstitution dynamics.
Values obtained for and shown here are in log10 cell counts/μL assuming a blood volume of of 3 × 105 μL (calculated assuming blood:weight ratio of 60 mL/kg and body weight of 5 kg). Initial values for the control group where obtained assuming steady state.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-data4-v1.docx
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Figure 3—source data 5
Population parameter estimates for the best fits used in the R code for Figure 3.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig3-data5-v1.zip
Figure 3—figure supplement 1
Individual fits of the best model to the blood T cell observations pre-ATI in control group from a time relative to post-transplantation in transplant groups.
Empirical data for peripheral T cell subset counts (blue data points) and best fits of the model (black lines) in Equation 2 in the main text to all blood T cell subsets before/after ATI for the …
Figure 3—figure supplement 2
Individual fits of the best model to the blood T cell observations post-transplantation, pre-ATI for the wild-type-transplant group.
Empirical data for peripheral T cell subset counts and plasma viral load (red data points) and best fits of the model (black lines) in Equation 2 in the main text to all blood T cell subsets before …
Figure 3—figure supplement 3
Individual fits of the best model to the blood T cell observations post-transplantation, pre-ATI for the ΔCCR5-transplant group.
Empirical data for peripheral T cell subset counts and plasma viral load (green data points) and best fits of the model (black lines) in Equation 2 in the main text to all blood T cell subsets …
Figure 3—figure supplement 4
Predictions of the best model for the contributors to cell expansion in CD8+ TEM cells in animals from the transplant groups.
Solid line represents the total number of cells that proliferate over time . Dashed lines indicate the number of exogenous cells differentiated from Tnaive and TCM () over time using the maximum …
Figure 4 with 1 supplement
Plasma viral load and CD4+ T cell kinetics after ATI.
(A) Empirical data for viral load (top row) and peripheral T cell counts (middle and bottom rows) for control (blue), wild-type (red) and ΔCCR5 (green) transplantation groups. Each data point shape …
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Figure 4—source code 1
R code for plots and test in Figure 4.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig4-code1-v1.zip
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Figure 4—source data 1
Complete data set of blood T cell counts and viral load for Figures 4 and 5.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig4-data1-v1.zip
Figure 4—figure supplement 1
Blood CD4+CCR5+ and CD4+CCR5- T cell kinetics post-ATI.
(A) Distribution of the CD4+CCR5+ T-cell nadir post-ATI normalized relative to the CD4+CCR5+ concentration at ATI. (B) Distribution of the CD4+CCR5- T-cell nadir post-ATI normalized relative to the …
Figure 5 with 3 supplements
Mathematical model of virus and T cell dynamics following ATI.
(A) Model: Susceptible cells, S, are infected by the virus, V, at rate β. Ip represents the fraction τ of the infected cells that produce virus, and, Iu, the other fraction that becomes …
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Figure 5—source code 1
Best model file for T cell and virus dynamics from acute infection after ATI in Monolix format.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-code1-v1.zip
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Figure 5—source code 2
R code for plots in Figure 5B.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-code2-v1.zip
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Figure 5—source code 3
R code for plots and tests in Figure 5C–D.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-code3-v1.zip
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Figure 5—source data 1
Competing models for fitting T cell and viral dynamics (Equations 2-3 in main text) using the best model in Figure 3—source data 2 and fixing parameter values as in Figure 3—source data 3, with AIC values.
Best fit in bold-red (lowest AIC).
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-data1-v1.docx
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Figure 5—source data 2
Population parameter estimates for the fits of the model with lowest AIC in Figure 5—source data 1 to the T cell and virus dynamics.
RSE: relative standard error. Empty fields represent cases when the standard deviation of random effects, , was fixed to zero. Values of for , and shown here are transformed assuming a blood volume of 3 × 105 μL (calculated assuming blood:weight ratio of 60 mL/kg and body weight of 5 kg). Red values represent an RSE greater than 100% implying that the number of data points may not be enough to estimate the respective parameter.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-data2-v1.docx
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Figure 5—source data 3
Individual parameter estimates for the fits of the model in Equations 2-3 in main text (lowest AIC in Figure 5—source data 1) to the T cell and virus dynamics.
Values of for , and shown here are transformed assuming a blood volume of 3 × 105 μL (calculated assuming blood:weight ratio of 60 mL/kg and body weight of 5 kg). Shown are individual estimates for animals that continued study after ATI.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-data3-v1.docx
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Figure 5—source data 4
Individual parameter estimates obtained from Monolix for the best fits used in the R code for Figure 5.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig5-data4-v1.zip
Figure 5—figure supplement 1
Individual fits of the best model to the blood T cell and viral load observations before/after ATI for control group.
Empirical data for peripheral T cell subset counts and plasma viral load (blue data points) and best fits of the model in Equations 2 and 3 to all blood T cell subsets before/after ATI for the …
Figure 5—figure supplement 2
Individual fits of the best model to the blood T cell and viral load observations before/after ATI for the wild-type-transplant group.
Empirical data for peripheral T cell subset counts and plasma viral load (red data points) and best fits of the model in Equations 2 and 3 to all viral load observations and blood T cell subsets …
Figure 5—figure supplement 3
Individual fits of the best model to the blood T cell and viral load observations before/after ATI for the ΔCCR5-transplant group.
Empirical data for peripheral T cell subset counts and plasma viral load (green data points) and best fits of the model in Equations 2 and 3 to all viral load observations and blood T cell subsets …
Figure 6 with 2 supplements
Model predictions of factors governing post-rebound viral control after CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplant.
(A) Predictions for plasma viral loads post-ATI using the optimized mathematical model. Here, and is the composite determinant of viral control. Parameter estimates for animal A11219 (Figure …
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Figure 6—source code 1
R code for plots in Figure 6A–B.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig6-code1-v1.zip
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Figure 6—source code 2
R code for plots in Figure 6C–D.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig6-code2-v1.zip
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Figure 6—source data 1
Results from all simulations varying fp, D, and Pr.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig6-data1-v1.zip
Figure 6—figure supplement 1
Model predictions for post-rebound viral control after CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation based on .
Model predictions of the effective reproductive ratio that lead to post-ATI viral control or not. was computed using varying values of : fraction of HSPCs in transplant, : total amount of …
Figure 6—figure supplement 2
Model predictions of the fraction of protected hematopoietic stem and progenitor cell (HSPCs) in the transplant (y-axis) and the fraction of transplanted HSPCs with respect to the total infused plus remaining post-TBI HSPCs (x-axis) required for spontaneous viral control.
Blue color represents the parameter space with post-ATI viral control or . Yellow-to-red colors represent the parameter space with no control or . Data points (green and red shapes) represent …
Figure 7
Model predictions of time to post-ATI viral control given varying times for the start of ATI.
(A-B) Examples of projected (A) viral load and (B) total, modified and unmodified CD4+ CCR5- (solid) and ΔCCR5 CD4+ T cells (dashed) from the model for animal A11219 when , HSPCs and HSPCs, …
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Figure 7—source data 1
Results from all simulations varying time to ATI.
- https://cdn.elifesciences.org/articles/57646/elife-57646-fig7-data1-v1.zip
