HIV- 1 and simian immunodeficiency virus ( SIV), as well as their hosts, face perils at mucosal front lines in early infection. At these sites, ' resting' CD4(+) memory T cells fuel infection ( because they are hosts for virus), depleting CD4(+) memory T cells throughout the lymphoid tissues, particularly in the gut, and eliciting an immunosuppressive regulatory T- cell response that impairs host defence. But HIV- 1 and SIV also risk elimination at the earliest stage of infection, at the mucosal point of entry, if founder populations of infected cells do not expand sufficiently to establish a self- propagating infection. Microbicides and vaccines could increase these viral vulnerabilities at mucosal front lines.