Targeting Persistent Human Papillomavirus Infection

Abstract

While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10-20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent prophylactic HPV vaccines, these preventive measures are not effective against pre-existing infection. Additionally, considering that the burden associated with HPV is greatest in regions with limited access to preventative vaccination, the development of effective therapies targeting persistent infection remains imperative. This review discusses not only the mechanisms underlying persistent HPV infection, but also the promise of immunomodulatory therapeutic vaccines and small-molecular inhibitors, which aim to augment the host immune response against the viral infection as well as obstruct critical viral-host interactions.

Keywords: E2 protein; HPV; cervical cancer; episome maintenance; persistent infection; therapeutics; vaccines.

Figure 1

HPV Genome. The HPV genome consists of six early genes (E1, E2, E4, E5, E6, and E7) and two late genes (L1 and L2). Many of the early genes are implicated in viral replication, transcriptional regulation, genome maintenance, along with immune system evasion. E6 and E7 are of particular interest as they are viral oncogenes that bind to and inactivate p53 and pRB, respectively. The URR (upstream regulatory region) consists of various promoter and enhancer elements as well as the viral origin of replication (ori).

Figure 2

Progression of HPV Infection and Associated Disease. HPV typically establishes infection in the basal epithelial layer. A majority of these infections are transient and are cleared by the immune system within a couple of years. However, 10–20% of infections persist latently, leading to disease progression as illustrated by the red arrows. The lesion that develops as a result is also known as a central intraepithelial neoplasia (CIN) and is classified according to its severity. Eventually, low-grade squamous intraepithelial lesions (LSIL) advance to high-grade squamous intraepithelial lesions (HSIL), ultimately leading to invasive carcinoma. Despite tumor regression in response to initial treatment as illustrated by the green arrows, most cases of latent infection prevent complete clearance of the viral infection, and eventually results in lesion reoccurrence.

Figure 3

Activation of the Humoral and Cellular Immune Response by Various Forms of Therapeutic Vaccination. Therapeutic vaccines aim to strengthen and broaden the immune response to HPV by introducing specific antigens to a subset of antigen-presenting cells known as dendritic cells. (A) Recombinant DNA in the form of a plasmid encoding various antigens may be introduced intramuscularly to myocytes where they are transcribed and translated into antigen proteins, which are subsequently engulfed, processed, and presented by dendritic cells to downstream T-cells. The secreted antigens may also interact with B-cells to initiate a humoral immune response; (B) Recombinant DNA can be introduced in the form of a modified viral vector as well (i.e., Influenza A, Modified Vaccinia Ankara, etc.); (C) Additionally, the protein products can be introduced directly to the dendritic cells; in the case of HPV, recombinant protein vaccines usually consist of an E6/E7 fusion protein; (D) Dendritic whole-cell based vaccines are constructed from cultivated monocytes derived from the patients in combination with a particular antigen or peptide. These modified dendritic cells are then introduced to the patient’s immune system and similar humoral and cellular immune responses are incited through the activation of helper T-cells, B-cells, and cytotoxic T-cells.