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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.


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Progressive CD4+ T cell activation drives progression to AIDS and increased cell-to-cell infection.(A) Progression of HIV-1 infection for different cell activation rates, including (1) normal activation (aNM/N in Equation 1), (2) fixed activation (aNM/N0, where N0 is the initial density of CD4+ T cells), and (3) doubled activation (2 × aNM/N when t > D).(B) Numbers of newly infected cells in a day via cell-to-cell spreading and cell-free spreading, respectively. The inset shows the ratio of susceptible cells to all cells (S/N, left y axis) and the strength of immune response (, right y axis) as a function of time, respectively.
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pcbi.1004179.g004: Progressive CD4+ T cell activation drives progression to AIDS and increased cell-to-cell infection.(A) Progression of HIV-1 infection for different cell activation rates, including (1) normal activation (aNM/N in Equation 1), (2) fixed activation (aNM/N0, where N0 is the initial density of CD4+ T cells), and (3) doubled activation (2 × aNM/N when t > D).(B) Numbers of newly infected cells in a day via cell-to-cell spreading and cell-free spreading, respectively. The inset shows the ratio of susceptible cells to all cells (S/N, left y axis) and the strength of immune response (, right y axis) as a function of time, respectively.

Mentions: In the context of the model, the transition from phase 1 (acute) to phase 2 (stable chronic) is driven by a balance between several processes, including viral spreading through two parallel modes, and the cellular immune response, i.e. killing of infected cells as the cytotoxic CD8+ T cell response becomes active. Paradoxically, in the stable chronic phase, the activation of T cells, which is the hallmark of adaptive immunity and is aimed at protecting the host, in fact contributes to the persistence of HIV-1. The role of CD4+ T cell activation is explored in Fig. 4A. In this model, the rate of T cell activation a(NM/N) increases as the number (N) of T cells falls, which can be considered to represent a type of homeostatic regulation reinforcing immunological activity relevant to the progressive damage of the immune system and its consequences. In the absence of this feedback (i.e. when activation rate is fixed), HIV infection would not progress to AIDS after the onset of the cellular immune response. In contrast, if the activation rate is doubled, then infection progresses significantly faster to AIDS. These results confirm and extend the findings of DeBoer and Perelson [29], which suggested an increasing rate of cellular activation was important in establishment of chronic infection and progression to AIDS. The results are also consistent with evidence that non-pathogenic SIV infection in the natural host species results in viral replication in the absence of chronic immune activation and no AIDS [42]. Fig. 4B depicts the number of CD4+ T cells newly infected via either cell-to-cell spread or cell-free spread as the infection progresses. The model predicts that cell-to-cell transfer becomes increasingly dominant as the total number of CD4+ T cells falls, the proportion of susceptible cells rises (Fig. 4B inset left y axis) and the strength of immune response falls (because of immune exhaustion, see Fig. 4B inset right y axis).


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)

Progressive CD4+ T cell activation drives progression to AIDS and increased cell-to-cell infection.(A) Progression of HIV-1 infection for different cell activation rates, including (1) normal activation (aNM/N in Equation 1), (2) fixed activation (aNM/N0, where N0 is the initial density of CD4+ T cells), and (3) doubled activation (2 × aNM/N when t > D).(B) Numbers of newly infected cells in a day via cell-to-cell spreading and cell-free spreading, respectively. The inset shows the ratio of susceptible cells to all cells (S/N, left y axis) and the strength of immune response (, right y axis) as a function of time, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004179.g004: Progressive CD4+ T cell activation drives progression to AIDS and increased cell-to-cell infection.(A) Progression of HIV-1 infection for different cell activation rates, including (1) normal activation (aNM/N in Equation 1), (2) fixed activation (aNM/N0, where N0 is the initial density of CD4+ T cells), and (3) doubled activation (2 × aNM/N when t > D).(B) Numbers of newly infected cells in a day via cell-to-cell spreading and cell-free spreading, respectively. The inset shows the ratio of susceptible cells to all cells (S/N, left y axis) and the strength of immune response (, right y axis) as a function of time, respectively.
Mentions: In the context of the model, the transition from phase 1 (acute) to phase 2 (stable chronic) is driven by a balance between several processes, including viral spreading through two parallel modes, and the cellular immune response, i.e. killing of infected cells as the cytotoxic CD8+ T cell response becomes active. Paradoxically, in the stable chronic phase, the activation of T cells, which is the hallmark of adaptive immunity and is aimed at protecting the host, in fact contributes to the persistence of HIV-1. The role of CD4+ T cell activation is explored in Fig. 4A. In this model, the rate of T cell activation a(NM/N) increases as the number (N) of T cells falls, which can be considered to represent a type of homeostatic regulation reinforcing immunological activity relevant to the progressive damage of the immune system and its consequences. In the absence of this feedback (i.e. when activation rate is fixed), HIV infection would not progress to AIDS after the onset of the cellular immune response. In contrast, if the activation rate is doubled, then infection progresses significantly faster to AIDS. These results confirm and extend the findings of DeBoer and Perelson [29], which suggested an increasing rate of cellular activation was important in establishment of chronic infection and progression to AIDS. The results are also consistent with evidence that non-pathogenic SIV infection in the natural host species results in viral replication in the absence of chronic immune activation and no AIDS [42]. Fig. 4B depicts the number of CD4+ T cells newly infected via either cell-to-cell spread or cell-free spread as the infection progresses. The model predicts that cell-to-cell transfer becomes increasingly dominant as the total number of CD4+ T cells falls, the proportion of susceptible cells rises (Fig. 4B inset left y axis) and the strength of immune response falls (because of immune exhaustion, see Fig. 4B inset right y axis).

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