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Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection.

Zhang C, Zhou S, Groppelli E, Pellegrino P, Williams I, Borrow P, Chain BM, Jolly C - PLoS Comput. Biol. (2015)

Bottom Line: HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts.Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS.This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, University College London, London, United Kingdom; Security Science Doctoral Research Training Centre, University College London, London, United Kingdom; School of Computer Science, National University of Defense Technology, Changsha, China.

ABSTRACT
HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Two modes of HIV-1 infection.The density of CD4+ T cells as a function of time for different values of cell-to-cell infection rate β1 and cell-free infection rate β2: (1) both use their default value, (2) β1 uses its default value and β2 = 0, (3) β1 = 0 and β2 uses its default value, (4) β1 is twice its default value and β2 = 0, (5) β1 = 0 and β2 is twice its default value.
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pcbi.1004179.g003: Two modes of HIV-1 infection.The density of CD4+ T cells as a function of time for different values of cell-to-cell infection rate β1 and cell-free infection rate β2: (1) both use their default value, (2) β1 uses its default value and β2 = 0, (3) β1 = 0 and β2 uses its default value, (4) β1 is twice its default value and β2 = 0, (5) β1 = 0 and β2 is twice its default value.

Mentions: Having confirmed that the model gives realistic estimations and predictions of real clinical data, we investigated the behaviour of the model in more detail. The role of the two spreading routes was further examined by systematic variation of the cell-to-cell infection rate, β1, and the cell-free infection rate, β2. The predicted outcome of infection are shown in Fig. 3. When either route is abolished, infection is blocked completely; T cell level returns to normal and virus is cleared after the cellular immune response kicks in. If cell-to-cell spread is removed from the model (β1 = 0) even a doubling in cell-free infection rate does not result in infection progression. In contrast, a doubling of cell-to-cell infection rate increases the set-point of viral load, and greatly speeds up the progression of infection even in the absence of cell-free infectivity. Thus the model suggests cell-to-cell spread may be an important force in allowing virus to establish infection in lymphoid tissue [38].


Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection.

Zhang C, Zhou S, Groppelli E, Pellegrino P, Williams I, Borrow P, Chain BM, Jolly C - PLoS Comput. Biol. (2015)

Two modes of HIV-1 infection.The density of CD4+ T cells as a function of time for different values of cell-to-cell infection rate β1 and cell-free infection rate β2: (1) both use their default value, (2) β1 uses its default value and β2 = 0, (3) β1 = 0 and β2 uses its default value, (4) β1 is twice its default value and β2 = 0, (5) β1 = 0 and β2 is twice its default value.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383537&req=5

pcbi.1004179.g003: Two modes of HIV-1 infection.The density of CD4+ T cells as a function of time for different values of cell-to-cell infection rate β1 and cell-free infection rate β2: (1) both use their default value, (2) β1 uses its default value and β2 = 0, (3) β1 = 0 and β2 uses its default value, (4) β1 is twice its default value and β2 = 0, (5) β1 = 0 and β2 is twice its default value.
Mentions: Having confirmed that the model gives realistic estimations and predictions of real clinical data, we investigated the behaviour of the model in more detail. The role of the two spreading routes was further examined by systematic variation of the cell-to-cell infection rate, β1, and the cell-free infection rate, β2. The predicted outcome of infection are shown in Fig. 3. When either route is abolished, infection is blocked completely; T cell level returns to normal and virus is cleared after the cellular immune response kicks in. If cell-to-cell spread is removed from the model (β1 = 0) even a doubling in cell-free infection rate does not result in infection progression. In contrast, a doubling of cell-to-cell infection rate increases the set-point of viral load, and greatly speeds up the progression of infection even in the absence of cell-free infectivity. Thus the model suggests cell-to-cell spread may be an important force in allowing virus to establish infection in lymphoid tissue [38].

Bottom Line: HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts.Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS.This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, University College London, London, United Kingdom; Security Science Doctoral Research Training Centre, University College London, London, United Kingdom; School of Computer Science, National University of Defense Technology, Changsha, China.

ABSTRACT
HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus