title: Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection.
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.
authors.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.
authors.forename: Changwang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Computer Science, University College London, London, United Kingdom.
authors.forename: Shi
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Groppelli
authors.affiliation: Centre for Sexual Health & HIV Research, Mortimer Market Centre, London, United Kingdom.
authors.forename: Pierre
authors.initials: P
authors.lastname: Pellegrino
authors.affiliation: Centre for Sexual Health & HIV Research, Mortimer Market Centre, London, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Williams
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Chain
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Jolly
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019295:Computational Biology; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D008297:Male; D018448:Models, Immunological
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