HIV-1 dissemination critically depends on migration of infected T cells. Unexpectedly, a minor fraction of the infected T cells exist as small syncytia, containing up to four nuclei. Importantly, these entities are not precursors for larger, macrophage- or dendritic cell-based syncytia which can be observed in late stages of virus dissemination/pathogenesis. Rather, 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 directly contribute to virus dissemination. With this R21 application, we propose to start exploring whether HIV-1-induced small syncytia can also indirectly contribute to virus spread. We hypothesize that they do that because the surface expression of immunoregulatory host factors differs from that in infected mononucleated cells. Such an altered surface profile would trigger different, at least partially stronger innate immune responses and this, in turn, could support virus spread as, for example, localized inflammation can aid in recruiting potential target cells to sites of virus replication. Should the data resulting from this exploratory work support our hypothesis, we will pursue further funding in order to study the mechanistic basis for the altered host response against syncytia.