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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

Impact of treatment starting time on HIV progression.HIV progression for a 30-day ‘perfect’ treatment starting at three different times after the initial infection: (1) on the 3rd day when the density of all CD4+ T cells is N = 725 cells/μl, (2) when N = 500 cells/μl; (3) when N = 350 cells/μl. The ‘prefect’ treatment here means both cell-to-cell infection and the cell-free infection are completely blocked (i.e. β1 = 0, β2 = 0 and the virus release rate g = 0) for 30 days.
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pcbi.1004179.g005: Impact of treatment starting time on HIV progression.HIV progression for a 30-day ‘perfect’ treatment starting at three different times after the initial infection: (1) on the 3rd day when the density of all CD4+ T cells is N = 725 cells/μl, (2) when N = 500 cells/μl; (3) when N = 350 cells/μl. The ‘prefect’ treatment here means both cell-to-cell infection and the cell-free infection are completely blocked (i.e. β1 = 0, β2 = 0 and the virus release rate g = 0) for 30 days.

Mentions: We therefore further explored the sensitivity of the model to perturbation as a function of treatment starting time (Fig. 5). The “treatment” lasts for 30 days, during which both cell-free and cell-to-cell infection are completely blocked. Once “treatment” is finished, two modes of HIV-1 infection resume. Early treatment in this model (3 days after infection, i.e. post-exposure prophylaxis) leads to no decline in CD4+ T cell density, and no chronic infection phase. The same treatment applied when T cell density reaches the levels (500 CD4+ T cells/μl and 350 CD4+ T cells/μl) at which the World Health Organization recommends ART initiation [45] is followed by a rapid virus rebound after the treatment stops, and the disease progresses according to its normal course. Thus, as HIV-1 progresses it becomes increasingly difficult to control infection in this model.


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)

Impact of treatment starting time on HIV progression.HIV progression for a 30-day ‘perfect’ treatment starting at three different times after the initial infection: (1) on the 3rd day when the density of all CD4+ T cells is N = 725 cells/μl, (2) when N = 500 cells/μl; (3) when N = 350 cells/μl. The ‘prefect’ treatment here means both cell-to-cell infection and the cell-free infection are completely blocked (i.e. β1 = 0, β2 = 0 and the virus release rate g = 0) for 30 days.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383537&req=5

pcbi.1004179.g005: Impact of treatment starting time on HIV progression.HIV progression for a 30-day ‘perfect’ treatment starting at three different times after the initial infection: (1) on the 3rd day when the density of all CD4+ T cells is N = 725 cells/μl, (2) when N = 500 cells/μl; (3) when N = 350 cells/μl. The ‘prefect’ treatment here means both cell-to-cell infection and the cell-free infection are completely blocked (i.e. β1 = 0, β2 = 0 and the virus release rate g = 0) for 30 days.
Mentions: We therefore further explored the sensitivity of the model to perturbation as a function of treatment starting time (Fig. 5). The “treatment” lasts for 30 days, during which both cell-free and cell-to-cell infection are completely blocked. Once “treatment” is finished, two modes of HIV-1 infection resume. Early treatment in this model (3 days after infection, i.e. post-exposure prophylaxis) leads to no decline in CD4+ T cell density, and no chronic infection phase. The same treatment applied when T cell density reaches the levels (500 CD4+ T cells/μl and 350 CD4+ T cells/μl) at which the World Health Organization recommends ART initiation [45] is followed by a rapid virus rebound after the treatment stops, and the disease progresses according to its normal course. Thus, as HIV-1 progresses it becomes increasingly difficult to control infection in this model.

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