Quote this article as:
PL Stern (July 2024). Natural history of HPV infection at the cervix. www.HPVWorld.com, 271

This article describes the process of HPV infection at the cervix, the likely natural immunological factors controlling the majority of viral infections and the mechanisms by which natural or vaccine antibodies can block infection.

The life cycle of HPV
Figure 1 summarizes the life cycle of HPV in the cervix, from infection of the cervical epithelium to terminal differentiation of infected cells. Infection of the cervix epithelium typically occurs at the cervical transformation zone, when viral particles can access the basement membrane (BM) exposed following abrasion. Virions first bind to heparin sulphate proteoglycans (HSPG) of the BM, through the capsid protein L1^1,2. This induces a conformational change revealing the amino terminus of the capsid protein L2, which undergoes enzymatic cleavage by extracellular furin as a prerequisite to virus uptake and internalization over several hours by the basal epithelial target cell^1,2. At this point, infection is localized to a few cells surrounding the wound and is not lytic but importantly, it is stealthy and durable^1,2.

The HPV life cycle is completely dependent on the differentiation of the epithelium, does not cause cell death, and there is no systemic viraemia¹. In the infected basal cells (which might include stem cells), the viral genome replicates and establishes about 50 HPV episome copies, which then segregate between the daughter progeny as the cells undergo cell division¹.

The early viral proteins E6 and E7 are key to stimulating the continued proliferation and the conditions for the replication of E1 and E2-driven vegetative viral genome to a very high copy number¹. Terminal differentiation of infected cells in the upper epithelial layers activates the expression of E4 and the capsid proteins L1 and L2, in order to package the very high copy numbers of the viral genome¹. The virions are then released as E4 disintegrates the cytokeratin filaments, and the keratinocyte remnants are sloughed off the epithelial surface¹. Thus, the viral life cycle is completed without directly causing cell death and without systemic viraemia or apparent inflammation to avoid alerting the local immune responses including the APCs (antigen-presenting cells)¹.

Persistent infection with high-risk type HPV is the major risk for developing cervical neoplasia and their viral gene expression has been shown to influence all the hallmarks of cancer^1-4. In particular, this can lead to immune modulation (deviation) and virus persistence^1-4.

Natural immune control of HPV infection
Fortunately, the immune system controls most HPV infections before cancer can develop^1-4. First damage is usually detected by the innate immune response arm leading to the activation of local APCs (Figure 2, step 1)¹.




Subsequently, driven by pro-inflammatory cytokines/chemokines, APCs process viral antigens and migrate to the local lymph nodes (LNs) (Figure 2, step 2)¹.

These activated APCs present MHC-II (major histocompatibility complex-II) processed viral antigens to specific T-cell receptor expressing helper (CD4) T-cells, which facilitate activation of specific cytotoxic (CD8) T-cells targeting early viral antigens presented by MHC-I molecules on infected cells, or help B-cells to produce neutralizing antibodies (nAbs) directed against capsid proteins (Figure 2, step 3)^1,3.

Other components of the innate immune response, including natural killer (NK) cells and the secretion of interferons, can also directly control the HPV infection and recruit more APCs to increase the activation of specific adaptive T-cell immunity (Figure 2, step 4)^1,3,4. This inflammation process attracts the effector CD8 T-cells to the virus-infected cells and it is key to clearing the virus infection (Figure 2, step 5)^1,3,4.

Indeed, HPV-associated cancer involves failure to mount HPV-specific T-cell responses¹. Long-lived plasma cells secrete nAbs that can access the infection site either by transudation from the blood to the mucosal secretions or by serous exudation. Only the viral particles, and not the HPV-infected cells, can be targeted by nAbs, which are thus unable to cure infection but can stop further infections (Figure 2, step 6)^1,3,4.

As virus uptake into epithelial cells takes several hours, there is an opportunity for prevention of infection by vaccine or naturally induced nAbs^1,2,4. Unfortunately, the levels of type-specific antibodies produced in natural infection are often insufficient to protect against subsequent reinfections^1,3. The discovery that the major capsid antigen L1 could self-assemble into empty virus-like particles (VLPs) that are both highly immunogenic and protective led to the licensure of several prophylactic VLP-based HPV vaccines for the prevention of cervical cancer^1,2. Vaccination with HPV capsid antigens can induce different types of type-specific antibodies, most of which can bind to the native virion, but not all will necessarily neutralize the virus by preventing uptake by the target cell¹.

The available data suggest that binding to HSPGs on the BM is an initial step that can be blocked by some L1-VLP-induced nAbs^1,2,5.

DISCLOSURE
The Author declares no conflict of interest to disclose.

References

1. Roden RBS, Stern PL. Opportunities and challenges for human papillomavirus vaccination in cancer. Nat Rev Cancer. 2018 Apr;18(4):240-254. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454884/

2. Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20458-63. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787115/

3. Doorbar J. The human Papillomavirus twilight zone - Latency, immune control and subclinical infection. Tumour Virus Res. 2023 Dec;16:200268. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10774944/

4. Smola S, Trimble C, Stern PL. Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy. Ther Adv Vaccines. 2017 Jun;5(3):69-82. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524244/pdf/10.1177_2051013617717914.pdf

5. Day PM, Thompson CD, Buck CB, et al. Neutralization of human papillomavirus with monoclonal antibodies reveals different mechanisms of inhibition. J Virol. 2007 Aug;81(16):8784-92. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951340/pdf/0552-07.pdf