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Interaction of human papillomaviruses with the host immune system: A well evolved relationship

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Interaction of human papillomaviruses with the host immune system: A well evolved relationship

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1. Cellular responses

Antigen specific effector T cell responses clear infection by release of proinflammatory cytokines and chemokines which reinforce innate effector mechanisms and by release of cytotoxic and pro-apoptotic macromolecules to kill virus infected cells. Effector responses induced by immunisation are relatively short lived, though they can be recalled more rapidly upon rechallenge with antigen, and therefore immunotherapy to induce antigen specific cellular responses is designed for immediate therapy of persistent viral infection or of cancer. Papillomavirus infected epithelial cells present non structural proteins to the host immune system in the context of MHC Class I. Class I restricted effector T cell responses can be generated in animal models and in humans by immunisation with E7 protein with appropriate adjuvants, or with recombinant vectors encoding this protein, reviewed in (Frazer, 2004). In animal models, transplantable tumours expressing E7 can be cured by E7 specific immunotherapies, and cure is dependent on induction of E7 specific cytotoxic T cells (Feltkamp et al., 1993). E6 and E7 specific immunotherapeutics in humans also induce antigen specific cellular immune responses (Kenter et al., 2008), though evidence for efficacy of the induced immune responses against papillomavirus associated disease is limited.

- Local administration of proinflammatory stimuli inducing innate immune responses, including the alpha interferons (Frazer and McMillan, 1997) and the toll like receptor 7 agonist, imiquimod (Wagstaff and Perry, 2007), has moderate efficiency as therapy for genital warts.

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The host innate immune response becomes the first line of defense against the HPV infection during the early stages of the infection. Dendritic (DC), Langerhans (LC), natural killer (NK), natural killer T (NKT) cells and keratinocytes, among others, are important cells involved in promoting a good adaptive immune response against HPV infection. Most of these cell types can promote a cytokine-mediated pro-inflammatory process, which links the innate with the adaptive immune response. Moreover, NK cells are able to directly eliminate HPV infected cells.

1.       Keratinocytes at the Initiation of HPV Infections

HPV infects keratinocytes of the basal layer of the cervical epithelium and possibly stem cells. The keratinocytes are part of the innate immune defense system and known as immune sentinels. They can function as non-professional antigen presenting cells and are able to induce the expression of TH1 and TH2 type cytokines and cytotoxic responses in CD4+ and CD8+ memory T cells, respectively. Keratinocytes in female genital tracts express several Toll-like receptors (TLRs), located either on the cell surface (TLR-1, TLR-2, TLR-4, TLR-5 and TLR-6) or in the endosomes (TLR-3 and TLR-9). The TLRs are a family of immunological receptors that recognize pathogen-associated molecular patterns (PAMPs), their activation initiates signaling pathways that result in innate and adaptive immune responses. Endosomal TLRs play an important role in combating viral infections and in the recognition of viral nucleic acids. The activation of the receptors promotes the production of cytokines and creates a powerful pro-inflammatory environment.

2.       Down-Regulation of Toll-Like Receptors by HPV and the Use of TLR Agonists to Improve Immunity

The key TLR in relation to double-stranded DNA virus infection is TLR-9. TLR-9 synthetic agonists used to suppress E7-expressing tumors in animals. Other TLR agonists shown non-canonical action against DNA virus infections also induce immune response against HPV infection. The agonists include 3M-002 (TLR-8 agonist) and resiquimod (TLR-8 and 7 agonist), which together with virus-like-particle VLP-L1-L2 or VLP-L1-L2-E7 (Table 1), are able to activate Langerhans cells, to induce the overexpression of chemokines and pro-inflammatory TH1 cytokines (MIP, IL-6, TNF-α, IL-12 and IL-8), to stimulate LC migration related to CCL21, and to induce a specific CD8+ T-cell response.

3.       The Pro-Inflammatory Response: Deregulation of the Link between the Innate and the Acquired Immune Responses

The induction of a pro-inflammatory response can be used as a tool to break the tolerance induced by HPV. Demonstration has been conducted using models of E7-transgenic as well as non-transgenic mice to observe the effectiveness of this approach when receiving an E7 transgenic skin graft were unable to respond to the E7 antigen. In these mice, stimulation with live or inactivated Listeria monocytogenes or endotoxin was sufficient to promote an E7-specific, CD8+ T cell immune response leading to the rejection of E7-grafts. Therefore, the successful initiation of pro-inflammatory signaling is important for developing new treatments to induce an effective immune response and disrupt the anti-inflammatory barrier triggered by HPV infections.

4.       Natural Killer Cells: An Important Barrier against Cells Expressing HPV Antigens

NK cells represent an important barrier and a key component of the innate immune system. These cells have the capacity to recognize and kill virus-infected and transformed cells through two mechanisms: granule-dependent cytotoxicity; and the apoptosis pathway in the target cells. NK cell activity is tightly regulated through a balance between inhibitory and activating receptors. However, deregulation of these receptors is common in cancer and HPV infections. NKp30 and NKp46 receptors are found at low levels in NK cells from patients with cervical cancer and precursor lesions, which is correlated with low cytotoxic activity of NK cells. Another important receptor in NK cells that is related to cytotoxicity is NKG2D. This receptor is involved in cell lysis through the interaction with the major histocompatibility complex class I-related chain A (MICA) proteins. Both NKG2D and MICA are modulated in the presence of HPV-infection.

5.       The Promising Role of NKT Cells in Controlling HPV Infection

Invariant or type 1 natural killer T cells (iNKT) are a group of T lymphocytes defined as CD1d1-restricted T cells that express a semi-invariant αβ T cell antigen receptor (TCR) and surface antigens typically associated with natural killer cells such as CD161 in humans. NKT cells have long been implicated in tumor immunity. In a murine model of adoptive immunotherapy using an established tumor expressing E7 from HPV16 (TC-1), NKT cells were necessary to inhibit early but not late tumor growth.

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Cell-mediated immune responses play crucial roles in controlling HPV-associated neoplasms. T cells recognize MHC class I and class II epitopes of HPV proteins.  It is identified that a major murine T helper (Th) cell epitope on HPV-16 E7 protein. This Th epitope was recognized due to its association with all five MHC Class II I-A and I-E alleles that was found to provide help for the production of antibody to several B-cells epitopes, including B-cell epitope of HPV-18 E7 protein. Cytotoxic T cell also has been identified on HPV-16 E6 and E7 through H-2Kb and H-2Db MHC class I peptide binding.

Other immune cells that participate in cell-mediated immunity is natural killer (NK) cells and macrophages. NK cells are present in most HPV-associated lesions and CIN. However, HPV-positive cervical cancer cells and HPV-immortalized human cervical epithelial cells, which possess properties similar to cervical dysplasia, are resistant to NK cells. Other than that, macrophages are also important cellular mediators of anti-tumor immunity. Banks et al. stated that NIH-3T3 cells transfected with HPV-16 E7 oncogene exhibit cytolytic susceptibility to murine-activated macrophages. Thus, the activated macrophages may selectively recognize and destroy HPV-16 associated neoplastic cells. Other relevant local host immune responses also play important roles in defense against HPV infections. This includes changes in the number of antigen-presenting cells (APCs), changes in the secretion of cytokines and changes in the expression of MHC molecules.

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Cell-Mediated Immune Response to Human Papillomavirus Infection

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Cell-Mediated Immune Response to Human Papillomavirus Infection

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HPV exhibits an extensive range of strategies for evading the host immune-surveillance.

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Nowdays, human papillomavirus (HPV) infection well known as the main cause of the cervical cancer. Genital HPV infection is the most common that attack adult women around 18-28 years of age. It is shown that majority of this infection occurred due to the sexual transmitted where particularyly had a multiple sex partners. In conclusion, genital HPV infection is the common among sexually active populations and causes both benign and malignant neoplasms of the genital tract. Current research has focused on the determinants of the oncogenic HPV types, the assesment of the prophylactic and therapeutic vaccines and the development of screening that help to decline this HPV infection.

The epithelial lining of the anogenital tract is the target for infection by a group of mucosotropic viruses, the human papillomaviruses (HPVs).

• Subclinical and clinical genital warts, also known as condylomata acuminata, and virtually all squamous cell cancers of the anogenital tract are caused by specific HPV types.

• HPVs are DNA viruses with a genome size of about 8000 base-pairs.

• There are more than 100 HPV types defined on the basis of DNA homology, of which more than 40 infect the anogenital tract.

• Genital HPV types are typically divided into groups according to their presumed oncogenic potential.21,22

• HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 are considered to be of oncogenic risk.

• The remaining genital types — types 6, 11, 42, 43 and 44 — are considered of low or no oncogenic risk

First treament is by having a PAP smear screening. There have been no controlled of the screening efficacy of PAP test. The evidence for its efficacy comes from 3 sources :

l Epidemiologic examinations, showing that the danger of intrusive cervical tumor is 2– 10 times more noteworthy among ladies who have not been screened and that the hazard increments with time since the last typical spread or with bring down recurrence of screening.

l Surveillance measurements from various areas, demonstrating that cervical growth frequency and mortality have diminished pointedly following the presentation of screening in Scandinavian nations, Canada and in the United States, with decreases in occurrence and mortality being relative to the scope of the screening programs.

l  Multiple national and worldwide agreement boards

In women with obtrusive malignancy, extra tests are required to set up the phase of the sickness. Treatment depends principally on the degree of the injury, however it additionally relies upon components, for example, the patient's age, her want to save richness and the nearness of other therapeutic conditions.46 Virtually all patients with organize IA infection are cured with either basic hysterectomy or, if fruitfulness conservation is wanted, by conization if edges are free of ailment. For women with organize IB disease without association of the lymph nodes , guess is best after radical hysterectomy. Late randomized stage III trials including ladies with arrange IB or stage II illness and metastatic pelvic hub contribution showed huge survival benefits for the joined utilization of cisplatin chemotherapy and radiation at the season of essential surgery, with a lessening in danger of death of 30%– 50%.47– 49 More progressed clinical stages are related with moderately bring down survival rates, even after radiation or chemotherapy, or both.

Current and Future Research

Vaccination against HPV may have greatest value in developing countries, where 80% of the global burden of cervical cancer occurs each year and where Pap screening programs have been largely ineffective. Two main types of vaccine are currently being developed: prophylactic vaccines to prevent HPV infection and consequently the various HPV-associated diseases, and therapeutic vaccines to induce regression of precancerous lesions or remission of advanced cervical cancer.

Summary of guidelines from the National Workshop on Screening for Cancer of the Cervix37 ratified by the Cervical Cancer Prevention Network in 1998

• Pap screening is to begin at age 18 or at initiation of sexual activity and to continue annually.

• After 2 negative consecutive results, 1 year apart, Pap screening is to proceed every 3 years to age 69.

This frequency of screening should be used in areas where a population-based information system exists for identifying the clientele and allowing rapid case notification and recall. In the absence of such a system it is advisable to repeat Pap smears annually.

• If mild dysplasia (cytologic equivalent of cervical intraepithelial neoplasia [CIN] grade 1, or low-grade squamous intraepithelial lesion [SIL]) is found, the smear is to be repeated every 6 months for 2 years. • If the lesion persists or progresses to moderate or severe dysplasia (CIN grades 2 and 3, respectively, or high-grade SIL) the patient must be referred for colposcopy.

• Refer for immediate colposcopy all initial cases of moderate dysplasia or worse lesions.

• Cytologic evidence of HPV infection in the smear per se should not guide management.

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HPVs (human papillomaviruses) and other papillomaviruses have an exceptional component of contamination that has likely developed to confine disease to the basal cells of stratified epithelium, the main tissue in which they imitate. Late investigations in a mouse cervicovaginal challenge demonstrate show that, shockingly, the infection cannot tie to keratinocytes at first in vivo. Or maybe it should first tie by means of its L1 significant capsid protein to heparan sulfate proteoglycans (HSPGs) on sections of the cellar layer (BM) uncovered after epithelial injury and experience a conformational change that uncovered the N-end of L2 minor capsid protein to furin cleavage. L2 proteolysis uncovered a formerly impeded surface of L1 that ties a so far undetermined cell surface receptor on keratinocytes that have moved over the BM to close the injury. Papillomaviruses are the main infections that are known to start their irresistible procedure at an extracellular site. As opposed to the in vivo circumstance, the virions can tie specifically to numerous refined cell lines through cell surface HSPGs and afterward experience a comparative conformational change and L2 cleavage. Exchange to the auxiliary receptor prompts disguise, uncoating in late endosomes, escape from the endosome by a L2-subordinate instrument, and possible trafficking of a L2– genome complex to particular subnuclear areas assigned ND10 bodies, where viral quality translation is started. The irresistible procedure is amazingly moderate and nonconcurrent both in vivo and in refined cells, taking 12– 24 h for start of interpretation. The broadened introduction of counter acting agent killing determinants while the virions dwell on the BM and cell surfaces may, partially, represent the noteworthy viability of immunizations in view of killing antibodies to L1 infection like particles or the area of L2 uncovered after furin cleavage.

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HPV Infection- Immunological Aspects and Their Utility in Future Therapy

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HPV Infection- Immunological Aspects and Their Utility in Future Therapy

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HPV- Immune response to infection and vaccination

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HPV- Immune response to infection and vaccination

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Effect of HPV infection on the immune system

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Effect of HPV infection on the immune system

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Immunology, Pathogenic, Main topic, Genetic

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Genes involve in HPV infection

During infection, products of viral E6 and E7 oncoproteins are important for the process of transformation and immortalization

These proteins are regulated by E2 gene product which represses the transcription of E6 and E7 genes

E2 ORF has been identified as the preferential site of HPV integration(frequently disrupted)

Lack of control of E2 over E6 and E7 gene transcription, consequences of integration process, contribute to progression and development of carcinogenic lesions

Detection of integrated forms of HPV

Southern blot analysis

Two-dimensional gel electrophoresis

Amplification by PCR

Qualitative real-time PCR (based on assumption that non-integrated form contains the same number of copies of both E2 and E6. Upon integration, disruption of E2 gene causes reduction in number, thus integration is detected by measuring the E2/E6 ratio)