Steps of HIV transmission. A portion of the VS (top left) has been enlarged to illustrate HIV transfer (A) and transmission (B). Two mechanisms would be involved in the transfer of HIV materials from infected to target cells after the VS formation. Both are dependent on Env binding to CD4 but independent of co-receptor engagement. First, a massive budding of viral particles from the infected cell (left) to the synaptic space (middle) and a further virion wrapping in the endosomal vesicles by the target cells (right). Second, membrane patches from infected cells carrying HIV budding machinery could be transferred to uninfected cells by trogocytosis through the formation of tethering tubes, potentially allowing for viral RNA to enter the cytoplasm of target cell (without exposure to the extracellular milieu). Furthermore, membrane tubes may help virions to surf extracellularly towards the uninfected cell. For cell-to-cell transmission events (involving infection of target cells), viral particles require both CD4 and the co-receptor, CXCR4 or CCR5, to fuse with the target cell. This process may occur at the plasma membrane or in endosomal compartments, allowing for HIV RNA release into the cytoplasm and initiation of the infectious cycle, after reverse transcription and nuclear import. In the absence of the co-receptor, transferred HIV particles accumulate in the endosomal compartments.