| High-risk human papillomaviruses (HPV) are linked to several malignancies, including cervical cancer. Since HPV infected women do not always mount protective anti-viral immunity, we explored the interaction of HPV with Langerhans cells (LC), the first antigen-presenting cells (APC) HPV comes into contact with during an infection. We determined that dendritic cells (DC), normally targeted by vaccination procedures, and LC equally internalize HPV virus-like particles (VLP), albeit through different uptake mechanisms. However, in contrast to DC, LC are not activated by HPV VLP.; The HPV proteins E6 and E7 are the only viral proteins expressed in HPV-induced lesions making them attractive targets for anti-HPV immunotherapy. Chimeric HPV VLP (HPV cVLP), which have HPV E7 fused to the L2 capsid protein, are currently being explored as a therapeutic vaccination strategy against cervical cancer. DC cross-present HPV cVLP-derived MHC class I-restricted peptides with costimulation to T cells, whereas HPV VLP uptake by LC leads to cross-presentation without costimulation. If immature LC cross-presenting cVLP-derived peptides on their surface interact with antigen-specific T cells, those T cells would not respond. Efficient HPV cVLP cross-presentation by LC with costimulation can be achieved by the addition of activation stimuli indicating that LC targeted by HPV VLP can be activated and initiate an HPV-specific immune response. Taken together, this indicates that the effectiveness of HPV cVLP as a therapeutic vaccine may be reduced unless another activation stimulus is also administered. In accordance with this, DC and LC incubated with cVLP formulations that activate both DC and LC initiate a potent cVLP-specific response.; Although most women infected with HPV clear their lesions, the long latency period from infection to resolution indicates that HPV evolved immune escape mechanisms. DC incubated with HPV VLP upregulate MAPK and NF-kappaB pathways, which is required for activation marker upregulation. LC incubated with HPV VLP upregulate the PI3K pathway and downregulate MAPK pathways. With the inhibition of PI3K and incubation with HPV cVLP, LC initiate a potent HPV-specific response. PI3K activation in LC defines a novel escape mechanism utilized by HPV and PI3K inhibition may serve as an effective clinical target to enhance anti-HPV immunity. |
