Figure 2. Pathways of HIV invasion in the mucosa of the vagina and uterine ectocervix, part A.

The human vagina and ectocervix are covered by non-keratinized squamous epithelium. Shearing during sexual intercourse can lead to physical abrasions of the epithelium, in particular in microanatomical regions where the stromal papillae, enriched with stromal DCs, reach close to the luminal surface of the mucosa. Depicted are two stromal papillae containing arterioles, venules and lymphatic vessels. The stromal papilla on the right signifies the afferent arm shuttling blood cells to the mucosa. Monocytic precursor cells differentiate upon arrival either into macrophages or dendritic cells (DCs), and DCs may differentiate further into subsets. Three stromal DC subsets have been identified in human skin, distinguished by BDCA-1, CD1 and CD14 expression patterns⁶⁵, but their presence and susceptibility to HIV have not been determined in the mucosa. An abrasion of the outer epithelium exposes the stromal papilla tip (left), as well as several epithelial cells located close to or within the basal layer. Infected donor cells and free virions may migrate along such an abrasion, as shown here, and directly contact various target cells in the mucosal epithelium and stroma. Resident mucosal leukocytes such as DCs and T cells tend to cluster in these regions (see Figure 3e), creating susceptible foci for infection. Possible pathways for HIV penetration are depicted on the left side of the illustration and are indicated by letters. Characteristic phenotypic cell receptors and receptors relevant for HIV binding and infection are shown on the top of the figure. a. Trapping of free HIV virions or HIV-infected donor cells in mucus covering the mucosa. b. Attachment of HIV-infected donor cells to the luminal surface of the mucosa and secretion of virions upon contact. c. Penetration of virions into gaps between epithelial cells. d. Capture of penetrating virions by Langerhans cells (LCs) residing within the epithelium, which extend processes toward the vaginal lumen. e. Internalization of virions into endocytic compartments of LCs. f. Fusion of HIV with the surface of intraepithelial CD4⁺ T cells, followed by productive infection. g. Transcytosis of virions through epithelial cells located close to or within the basal layer of the squamous epithelium (Figure 3a–c). h. Productive infection of basal epithelial cells. i. Internalization of virions into endocytic compartments of basal epithelial cells. j. Immigration of infected donor cells along physical abrasions of the epithelium into the mucosal stroma, where they are taken up by lymphatic or venous microvessels and transported to local lymph nodes or the blood circulation. k. Immigration of free virions along microabrasions into the stroma, where they can make direct contact with stromal DCs. l. Productive infection of stromal DCs by HIV. m. Internalization of virions into endocytic compartments of stromal DCs. n. Passage of virus from stromal DCs to CD4⁺ T cells across an infectious synapse (see also Figure 4). o. Massive productive infection of mucosal CD4⁺ T cells activated by contact with antigen-presenting DCs. p. Productive infection of resting mucosal CD4⁺ memory T cells. q. Binding of HIV and possibly productive infection of stromal macrophages. r. Emigration of productively infected CD4⁺ T cells and DCs into the submucosa and the draining lymphatic and venous microvessels. T cells may derive from the epithelium or the stroma. Likewise, emigrating DCs may originate from intraepithelial LCs or stromal DCs. DCs and T cells often form conjugates, and HIV may accumulate between the two cells along an infectious synapse. DCs carry virions in endocytic compartments and some are also productively infected, but it remains unclear at which differentiation stage this occurs.