Topology from the Bottom Up

evolved to promote and integrate virus production with VS formation. In addition to initiating signal transduc-tion in the infected cell, adhesion molecule engagement at the VS ostensibly activates the uninfected target cell. Activation would ensure expression of virus receptors by the uninfected cell and promote virus replication once the virus has entered its new target. The identity of the HTLV-I receptor has eluded investigators for two decades, but recent work with a soluble version of the HTLV-I Env glycoprotein promises to remedy this situation. These new studies show that a cell surface protein that binds to the soluble form of the HTLV-I Env glycoprotein was rapidly expressed by naïve T cells activated by im-munological or pharmacological means (6, 7). The possibility that the HTLV-I receptor is expressed by the uninfected T cell and segregates to the cell-cell interface during the later stages of VS formation is attractive. If this did not take place later during VS formation, then association of the HTLV-I receptor with the viral Env expressed by the infected T cell would lead to premature cell fusion. Although HTLV-I appears to be especially dependent on cell-to-cell transmission, this may be the rule rather than the exception. Recent reports indicate that other viruses including HIV-1 and the Ebola virus, which efficiently infect cells by a cell-free route in vitro, may rely on cell-to-cell transmission in vivo (8). During the early stages of infection, both viruses preferentially infect macrophages, which then migrate to different sites in the body and transfer concentrated packages of virus in a cell-to-cell fashion. In addition, infectivity of these two viruses is enhanced when they are presented on the surface of dendritic cells via interactions of their viral envelope proteins with the C-type lectin DC-SIGN expressed by dendritic cells (9). Experiments by Emerman's group underscore the importance of contact between T cells and den-dritic cells for the rapid and efficient propagation of HIV-1 when the lifespan of the infected cell is very brief (10). This mode of virus transmission sustains high virus loads in the face of an antiviral immune response. HTLV-I has evolved intricate and integrated systems to establish persistent infection of T cells. Virus transmission through the VS may be a cornerstone of this process. In addition to addressing long-standing issues related to cell-to-cell versus cell-free transmission of HTLV-I, the work of Igakura et al. poses many new questions and provides an attractive framework …