Five unique features of HIV-1 transmission through virological synapses.

<p><b>A.</b> Cell–cell adhesion activates virus assembly at the VS. Infected T cells bind to uninfected T cells through an interaction between Env and CD4 (left). This is observed to occur prior to the recruitment of Gag to the site of adhesion (right). <b>B.</b> Regulation of Env-mediated membrane fusion. Cell–cell adhesion involves engagement of Env with CD4 at the surface of the infected and uninfected cell, but does not trigger cell–cell fusion. Host factors and the immature Gag lattice are two mechanisms that may prevent fusion until virus particles have budded from the donor cell and are transferred to the target cell, which has been observed as occurring through an endocytic route. Viral entry after synapse is likely to be activated by viral maturation rather than CD4 binding. <b>C.</b> Neutralization resistance. Cell-free virus is easier to neutralize (has lower IC50) than the same virus when it infects directly from cell to cell. The resistance may be due to regulation of Env conformation that inhibits membrane fusion on the cell surface and promotes Env-dependent viral membrane fusion only after virus particle maturation. <b>D.</b> Multicopy infection and drug resistance. Many viral particles are simultaneously transferred and can infect to high copy number in vitro. This may contribute to a shift in IC50 of some classes of antiretrovirals and can provide an explanation for how selective pressure on HIV-1 acts on cells that have co-inherited multiple sequences rather than individual sequences. <b>E.</b> Viral spread by cell migration and cell–cell interaction. Spatial clustering of genetic HIV-1 variants in human splenic tissue is represented by cells colored in different shades of green. Live imaging studies indicate that infected cells, while slower than their uninfected counterparts, are motile, as represented by elongated cells. Inhibition of T cell migration in humanized mice suggests that infection can be restricted to small tissue subcompartments, and that viral spread in some animal models requires the migration of T cells out of the draining lymph node.