The human immunodeficiency virus infects T helper immune cells that coordinate immune responses resulting in acquired immune deficiency syndrome (AIDS). We are interested in understanding how virus-induced cell-cell adhesions called virological synapses promote the rapid spread of HIV between T cells. Virological synapses form when an infected T cell binds to an uninfected cell. Using an infectious fluorescent clone of HIV we have conducted live imaging studies of virological synapse formation between T cells and observed that infected T cells form durable adhesions with uninfected T cells. Synapse formation involves the recruitment of viral proteins to the adhesions where a concentrated site of viral assembly called a synaptic button is formed. During this process viral production from the infected cell is associated with transfer of the newly formed virus into the uninfected cell through an endocytic internalization pathway. To understand what role virological synapses may play in vivo, we are examining cell culture models, live microscopy, and humanized mouse models of HIV infection. Our results show that virological synapses are distinct from cell-free virus in their sensitivity to chemical and antibody inhibitors, and may provide a means of immune evasion by sequestering the viral membrane fusion process in an endocytic compartment. We are interested in developing novel microbicide, vaccine, and drug approaches that are designed to inhibit virological synapses.