Human Papillomavirus: The Implications on Health and Viral Pathogenesis
Having HPV is like having a clingy ex—hard to get rid of and always popping up at the worst times.
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YOU CAN READ THE FULL BLOG HERE: Human Papillomavirus (HPV): Disease Manifestations and Pathogenesis of the Virus
What is HPV and Why is it a concern?
The Human papillomavirus is a double-stranded DNA virus from the Papillomaviridae family, most commonly known for their oncogenic properties, specifically in the anogenital area.
Most people infected with HPV experience subclinical infections, showing no signs whatsoever. In some instances, these infections are cleared by the body's innate immune response. However, certain strains of HPV can become active, causing benign, hyperproliferative lesions on the epithelium, commonly referred to as warts, papillomas, or condylomata, depending on the location of the infection.
It can be spread via sexual contact between individuals, including oral, vaginal or anal. However, it can also be spread through skin-to-skin contact.
Some History Lessons
4th Century B.C
Hippokrates first mentioned an infection in the 4th century B.C. He postulated that if the infection is not taken care of, the growth will increase in size and possibly become cancerous.
Year 1949
Using the electron microscope, Strauss et al examined extracts of wart tissue.
Year 1963
Crawford and Crawford described the physical properties of the HPV DNA.
In the 1970s
The first breakthrough in HPV infections came about in the 1970s when Professor Harald zur Hausen, also known as The Father of HPV Virology, postulated the role of HPV in cervical cancer. It is now widely believed that HPV has a role in carcinogenesis mostly in the anogenital area.
Viral Pathogenesis
HPV interacts with epithelial cells through integrin α6 receptors, abundant in basal and stem cells, allowing infection of primitive basal cells by low-copy viruses. E1 and E2 proteins initiate DNA replication, forming a complex that recruits additional molecules, leading to E1 double-trimer intermediates and double-hexameric E1 helicases that unwind DNA. During plasmid maintenance, viral gene expression is minimal, tightly regulating oncogenes like E6 and E7. In infected cells, gene expression increases during cellular proliferation, with viral DNA replication reaching 1,000 copies per cell, enhancing expression of L1 and L2 capsid proteins for virus assembly. These features help HPV evade immune recognition, crucial for its pathogenesis, characterized by nonlytic immunity and the absence of viremia and inflammation. Understanding HPV's life cycle is vital for developing strategies to combat its infections and associated diseases.
Immune Response
High-risk HPV strains, including HPV16, HPV18, and others, pose significant health risks. During infection, antigen-presenting cells (APCs) encounter HPV proteins. Specialized APCs like Langerhans Cells (LCs) present these proteins in the epidermis, failing to elicit an immune response against HPV16 L1. In the adaptive immune response crucial for lesion regression, skin monocyte-macrophages and dendritic cells (DCs) recognize HPV antigens, triggering effector immune responses. They release pro-inflammatory cytokines like IL-1, IL-6, TNF-α, and IL-12, promoting local inflammation that serves as an immune response trigger. Understanding these immune mechanisms is vital for developing strategies to combat HPV infections effectively, particularly those caused by high-risk strains. By elucidating how HPV evades immune detection and understanding the role of APCs and cytokines, researchers aim to enhance vaccine efficacy and therapeutic interventions, ultimately reducing the burden of HPV-related diseases like cervical cancer
Cell Evasion
HPV has multiple mechanisms to down regulate the immune system which may lead to cancer later on.
Expression of viral antigens at a very low level.
Production of virions in the outermost layer of the epithelial cells which does not lyse the cells that would otherwise trigger an immune response.
HPV can alter gene expression of host cells by DNA methylation which down-regulates important mediators of immune responses such as chemokines, adhesion molecules, and Toll-like receptors (TLRs).
Through protein-protein interaction, HPV can disrupt the function of host proteins.
The interferon pathway in HPV-infected keratinocytes is disrupted when E5, E6, and E7 proteins bind to interferon response factors (IRFs), which serve as transcription factors for interferon-induced genes.
HPV18 plays an important role in the dysregulation of the expression of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING), which is crucial in defense mechanism against DNA viruses.
Immunoproteasome subunits PSMB8 and PSMB9 involve in antigen processing show a decrease in expression levels in infected HPV16 cells.
The E5 oncoprotein of HPV decreases the cell-surface presence of major histocompatibility complex class I (MHC-I) by causing its retention in the Golgi complex.
Signs and Symptoms
HPV 6 and 11 commonly cause anogenital warts and respiratory papillomatosis, affecting children and young adults.
Cutaneous warts (verrucae) are another manifestation of HPV infection.
Condyloma acuminata, warts in the anogenital region or on the tongue and lips, can occur.
Integration of viral oncoproteins E5, E6, and E7 into the human genome can lead to HPV-related malignant lesions.
Carcinomas of the cervix, anogenital area, and head and neck are often caused by high-risk genotypes like HPV 16 and 18.
High-risk HPV can induce low-grade squamous intraepithelial lesions (L-SIL) such as CIN 1, which may progress to high-grade lesions (H-SIL).
Squamous intraepithelial lesions (SIL) are precancerous growths resulting from HPV infection.
Penile cancer may result from downexpression of hsa-miR-218 and miRNA-246a and overexpression of EFGR, all influenced by HPV infection.
Currently, there is no cure for HPV infections and its clinical manifestations.
Non-cancerous warts and pre-cancerous lesions can be surgically removed or treated by ablation. The earlier the diagnosis, the better chance of effective treatment.