Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection
This provides insights into HIV-1 pathogenesis for medical researchers and clinicians, suggesting earlier intervention and treatments targeting cell-to-cell spread could delay AIDS progression, though it is incremental as it builds on existing knowledge of HIV spreading mechanisms.
The researchers tackled the problem of understanding how HIV-1's hybrid spreading mechanisms (cell-free and cell-to-cell transmission) affect infection progression by developing a new mathematical model that captures major infection phases and accurately predicts clinical trial results, finding that hybrid spreading is critical for seeding infection and cell-to-cell spread becomes increasingly effective as infection progresses.
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.