Mucosal transmission and single variant systemic dissemination. There are multiple barriers to infection and, most likely, multiple mechanisms by which the virus overcomes these barriers. Barriers include mucus, pH, intact epithelium, target cell availability, innate cells, and inhibitory chemokines/cytokines. After successfully traversing the mucosal epithelium, cell-free virus interacts with CD4 and coreceptor to initiate primary infection of susceptible target cells, either with or without previous transport and facilitated transfer of virions by Langerhans cells or DCs. During the next 2-5 days, the virus replicates and is amplified locally, initially fueled by preexisting targets but paradoxically expands rapidly with the recruitment of activated target cells chemotactically recruited to the site to quench the budding infection. For cervicovaginal transmission, this local expansion of virus and infected cells appears to be a prerequisite for dissemination to local lymph nodes and then systemically. Although the exact proportion of virions “lost” at each barrier is unknown, presumably, virions can be successful at crossing the epithelial barrier only to be ineffective at finding target cells (red and green virions) or unable to expand locally (orange infected cell) at a sufficiently large reproductive ratio before target cell recruitment and dissemination as to be unable to establish a systemic, disseminated productive infection.