Multiscale analysis of HIV-1-induced small T cell syncytia

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HIV-1 dissemination critically depends on migration of infected T cells. Unexpectedly, a fraction of the infected T cells was recently found to exist as small syncytia, containing up to four nuclei. Importantly, these entities differ from larger syncytia which sometimes can be observed in late stages of virus dissemination/pathogenesis. Indeed, and as shown in three independent intravital imaging studies, they are present already at the earliest stages of infection. Our analyses in physiologically relevant in vitro settings further documented that small T cell syncytia can transfer virus to uninfected cells, suggesting that they can contribute to early virus dissemination. With this R01 application, we propose to start exploring whether HIV-1-induced small syncytia can indeed directly contribute to virus spread. We will start our investigations by characterizing motility/migration properties of syncytia and analyzing their role in virus transmission dynamics. Host and viral factors involved in homeostatic maintenance of the syncytial compartment will also be studied. Importantly, we have recruited the support of a leading HIV proteomics lab in order to comprehensively map the expression profiles of syncytia. Should the data resulting from this work support the hypothesis that syncytia contribute significantly to virus dissemination, we will pursue further funding in order to study potential strategies against these entities.