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Model supported by our ex vivo studies on the effects of genital mucosa-derived cells on HIV infection (Neidleman et al, PLOS Pathogens, 2017). In mucosal tissues lined by single-layered columnar epithelia, such as the endometrium, when barrier function is intact, antiviral factors secreted by the epithelium can limit HIV infection. Breaches in the epithelium caused by physical trauma, ulcerative sexually transmitted diseases, or the effects of progesterone facilitate migration of HIV from the lumen into the stromal compartment. This compartment is replete with fibroblasts that can potently enhance HIV infection of resident CD4+ T cells. Stromal fibroblasts from mucosa lined by stratified squamous epithelia similarly enhance HIV infection.