HPV16 Entry into Epithelial Cells: Running a Gauntlet

Abstract

During initial infection, human papillomaviruses (HPV) take an unusual trafficking pathway through their host cell. It begins with a long period on the cell surface, during which the capsid is primed and a virus entry platform is formed. A specific type of clathrin-independent endocytosis and subsequent retrograde trafficking to the trans-Golgi network follow this. Cellular reorganization processes, which take place during mitosis, enable further virus transport and the establishment of infection while evading intrinsic cellular immune defenses. First, the fragmentation of the Golgi allows the release of membrane-encased virions, which are partially protected from cytoplasmic restriction factors. Second, the nuclear envelope breakdown opens the gate for these virus–vesicles to the cell nucleus. Third, the dis- and re-assembly of the PML nuclear bodies leads to the formation of modified virus-associated PML subnuclear structures, enabling viral transcription and replication. While remnants of the major capsid protein L1 and the viral DNA remain in a transport vesicle, the viral capsid protein L2 plays a crucial role during virus entry, as it adopts a membrane-spanning conformation for interaction with various cellular proteins to establish a successful infection. In this review, we follow the oncogenic HPV type 16 during its long journey into the nucleus, and contrast pro- and antiviral processes.

HPV16 Induces Formation of Virus-p62-PML Hybrid Bodies to Enable Infection

“…HPVs gain access to their host cells via lesions in the epithelium. After initial binding to primary attachment receptors, conformational changes of capsid proteins, and host cell signaling, virus particles are internalized via an unconventional clathrin-independent endocytic pathway [ 8 , 9 , 10 , 11 ]. HPV-containing endosomes undergo maturation to multivesicular endosomes, marked by a low pH, which aids in capsid disassembly and the translocation of L2 across the endosomal membrane whereby the L2 C-terminus faces the cytosol.…”

“…L2 interaction with cytosolic proteins facilitate further virus transport via the retrograde pathway and along the microtubule network. With the onset of mitosis, the breakdown of the nuclear membrane enables the accumulation of viral DNA at promyelocytic leukemia nuclear bodies (PML NBs) [ 8 , 12 , 13 ].…”

“…As additional antiviral defense, HPV16 can be routed to cellular degradation compartments such as autophagosomes or lysosomes [ 8 ]. At the same time, this virus has evolved ways to evade autophagy through activation of the mammalian target of the rapamycin (mTOR) pathway [ 21 ].…”

The impact of human papilloma virus on human reproductive health and the effect on male infertility: An updated review

“…When mitosis begins, the trans‐Golgi network breaks down, allowing virions enclosed in membranes to be released and transported to mitotic chromatin. The released viral DNA may be seen inside the nucleus, and with the subsequent cell cycle, viral protein is translated with the host proteins 35 …”

“…The released viral DNA may be seen inside the nucleus, and with the subsequent cell cycle, viral protein is translated with the host proteins. 35…”