1. Viral and Immune System Dynamics of HIV-1, CD4+ T Cells and Macrophages during the Acute, Clinically Latent and Late Phases of HIV Infection
Nargesalsadat Dorratoltaj, Stanca Ciupe, Ryan Nikin-Beers, Stephen Eubank, Pierre Pellegrino, Ian Williams, Persephone Borrow, Kaja Abbas
October 31, 2016
This study is based on the following paper:
Dorratoltaj N, Ciupe S, Nikin-Beers, R, Eubank S, Pellegrino P, Williams I , Borrow P, Abbas K, Viral and Immune System Dynamics of HIV-1, CD4+ T Cells and Macrophages during the Acute, Clinically Latent and Late Phases of HIV Infection (in preparation)

2. HIV study objective
The study objective was to analyze the dynamics of HIV-1, CD4+ T cells and macrophages during the acute, clinically latent and late phases of HIV infection in order to predict their dynamics from acute infection to clinical latency and finally to AIDS in treatment naive HIV-infected individuals.

3. HIV prognosis timeline: Acute, clinically latent & late phases of infection
Source: O’Brien and Hendrickson 2013

4. Clinical significance
Understanding and analysing macrophage dynamics during the phases of acute infection, clinical latency and progression to the AIDS stage in HIV-infected individuals could assist in design of improved and macrophage targeted therapeutic regimens.

5. Conceptual model of HIV viral and immune dynamics

6. Mathematical model
𝑑𝑈 𝑑𝑡 =0.5𝜆+ 0.5𝜆 1+∅𝑉 −𝛽𝑉𝑈−𝑑𝑈 𝑑𝐼 𝑑𝑡 =𝛽𝑉𝑈− 𝑑 𝐼 𝐼 −𝑘𝐼 𝑑𝑀 𝑑𝑡 = 𝜆 𝑀 − 𝛽 𝑀 𝑀𝑉− 𝑑 𝑀 𝑀 𝑑 𝑀 𝐼 𝑑𝑡 = 𝛽 𝑀 𝑀𝑉− 𝑑 𝑀 𝐼 𝑀 𝐼 𝑑𝑉 𝑑𝑡 =𝑁 𝑑 𝐼 𝐼+ 𝑝 𝑀 𝑀 𝐼 10 𝑓(𝑡) −𝑐𝑉

7. Model variables parameters

8. Data source
Acutely infected individuals recruited at the Mortimer Market Centre (London, UK).
Mostly male Caucasians
Viral load and CD4+ T cell counts measured longitudinally
n=39
Study timeline:

9. Parameter estimation CD4+ T cells Viral Load
Minimum Weighted Absolute Percentage Error (WAPE)
𝑊𝐴𝑃𝐸= 𝑡 𝑖 =1 𝑛 | 𝐴 𝐶 𝑡 𝑖 − 𝑃 𝐶 𝑡 𝑖 | 𝐴 𝐶 𝑡 𝑖 𝑡 𝑖 =1 𝑛 | log⁡(𝐴 𝑉 𝑡 𝑖 )− log⁡(𝑃 𝑉 𝑡 𝑖 )| log⁡( 𝐴 𝑉 𝑡 𝑖 )
Model calibration:
Each infected individual
Patient cohort
CD4+ T cells
Viral Load

10. Viral and immune system dynamics of HIV, CD4+ T Cells and Macrophages

11. HIV and CD4+ T cell dynamics in each HIV-infected individual – Reaching AIDS stage

18. Estimated HIV progression timeline to AIDS

19. HIV and CD4+ T cell dynamics in each HIV-infected individual – Not reaching AIDS stage

20. Dynamics of viral load production from CD4+ T cells and macrophages

21. Sensitivity analysis All 14 parameters
Among parameters with significant sensitivity:

22. Discussion
The initial peak in viral load during acute phase of HIV infection is primarily due to viral production from CD4+ T cells.
Macrophages become the dominant producer of HIV during the latent and late phases of HIV infection.

23. Limitations Simplified immune system (No CTL, Dendritic cells)
The model may not be generalizable for other populations.
The macrophage dynamics are not calibrated with patient-level data.

24. Future work
Validation and calibration of HIV viral immune system dynamics model with monocyte/macrophage data.
Analyze the impact of treatment and its interruptions on HIV prognosis timeline to AIDS stage.

25. Clinical implications
Estimation of HIV viral immune dynamics and HIV prognosis timeline to AIDS stage in treatment naive HIV-infected individuals.
Shared medical decision making between clinicians and HIV patients to discuss long term health outcomes of treatment versus no treatment.

26. THANK YOU