Fig 1.
Biphasic HIV trafficking through dendritic cells to CD4 T cells.
DC-mediated HIV transmission occurs through two mechanisms. First phase or trans-infection is initiated by binding of virus to specific HIV lectin ‘binding receptors’, which rapidly internalises/endocytoses the virus into a nondegradative, virus-containing cave (VCC). Following VCC formation, the virus can undertake two pathways. Firstly, the transmission pathway leads to partial DC maturation, immune and viral degradation evasion, and transport/migration to CD4 T cells. First-phase transmission concludes with the formation of an infectious synapse between the DC and CD4 T cell, where the virus is released from the VCC to the CD4 T cell. The degradation pathways result in the destruction of the virus through the fusion of VCCs with lysosomes. Second phase or cis-infection begins with viral fusion of HIV with the DC membrane, mediated by the binding of virions to the HIV entry receptor, CD4, and its co-receptor CCR5. HIV binding lectin receptors such as Siglec-1, DC-SIGN, and DCIR can also concentrate the virus on the DC surface, leading to CD4/CCR5-mediated HIV infection. Once within the cell, the viral RNA is reverse transcribed to cDNA, which is then transported to the nucleus and integrated into the host cell genome. The virus then hijacks the cells replicatory machinery to produce and release progeny virions. Accompanying de novo virus production, productive infection also enhances T cell–dendritic cell interactions by driving the extension of filopodia that tether to T cells. This facilitates the direct transfer of budding virus to the tethered T cell via a viral synapse, culminating in CD4+ T cell infection and the continued perpetuation of the viral lifecycle. Figures created with Biorender.com.
Fig 2.
Human anogenital APC subsets and tissue compartment localisation.
Skin and Type II mucosa of the distal anogenital tracts are characterised by a stratified squamous epidermis and epithelium, respectively. Both epidermis and stratified squamous epithelium contain LCs and Epi-DCs. Beneath these layers are the dermis (in skin) and lamina propria (in mucosa), which harbour DC1-3 and MDDCs under steady-state conditions. Type I Mucosa is located proximally along the anogenital tracts and is characterised by a superficial columnar epithelium overlying the deeper lamina propria, muscularis mucosa, and submucosa. Within Type I anogenital mucosa, DCs are primarily located in the lamina propria and include DC1-3 and MDDCs under steady-state conditions. The accompanying table summarises the anogenital DC surface markers that most reliably distinguish between anogenital tissues. Figures created with Biorender.com.