HIV-1 establishes a chronic infection that the immune system cannot spontaneously clear. The virus has a remarkable capacity to evade immune responses and generates a high sequence diversity that defies the forces of purifying selection. We and others have found that viral dissemination takes place both in vitro and in vivo through cell-cell contacts, called virological synapses (VS), which mask immune detection of infected cells, and promote viral quasispecies diversity that enable escape. Our data indicate that HIV Env, the central viral protein involved in VS formation and viral entry, assumes distinct conformations on viruses versus on the cell surface. We propose that these conformations can render infected cells as “hypoantigenic” relative to cell-free virus and further suggest that allosteric sensing mechanisms allow Env to detect whether it is cell-associated or virion-associated. The studies address the key problem of how Env is recognized differently on the surface of infected cells and how cell-cell transmission affects viral escape. During VS formation Env works as a cell adhesion receptor between the infected and uninfected cell, prior to its role as viral membrane fusion protein. Through the VS HIV exploits cell biology -- polarized receptor recruitment and viral endocytosis into the target cell -- to enhance cell-to-cell transmission. The T cell VS is critical for viral spread in cell culture and functions in vivo in lymphoid tissues of humanized mice. VS transmission facilitates potent immune evasion. Most broadly neutralizing antibodies (bNabs) are less potent at neutralizing cell-to-cell infection than the same virus in a cell free form. When tested against transmitted founder clones, bNabs incompletely inhibit cell-to-cell infection at maximum concentration, i.e. display reduced efficacy. We propose to define the cellular mechanisms underlying the reduced potency and efficacy of neutralizing antibodies against the VS. We will also test a model for how the multicopy transmission of HIV through VS contributes to maintaining a diverse swarm of mutated sequences, or quasispecies, that can allow HIV to easily escape immune pressures. We hypothesize that cell-to-cell HIV-1 transmission is a pivotal immune evasion and escape strategy that drives viral persistence.