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Question 3 : How does HPV infects the host?

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Question 3 : How does HPV infects the host?

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1. HPV enters into the normal epithelial cells by abrasion which results to early viral gene expression (E6,E7)

2. These genes induce the proliferation of infected cells by binding to specific protein. (E7 binds to retinoblastoma protein, pRb whereas E6 binds to p53)

3. pRb is a tumor suppressor protein which prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. Binding of E7 to pRb promotes degradation of pRb. P53 has several roles that regulate the cell cycle, induce apoptosis, promote DNA repair and prevent tumor growth. Binding of E6 to p53 will inhibit these functions and could cause unregulated cell proliferation and cancer.

4. Other viral proteins such as E1,E2,E4 and E5 are also begin to express in the infected cells. This causes the conversion of infected cells into LSIL/ASCUS

5. The viral late genes (L1,L2) are expressed and capsid proteins are synthesized to complete genome amplification. HPV now make assembly followed by release.

6. Persistent expression of E6 and E7 causes the integration of viral genome into host cell DNA. LSIL is converted into HSIL and eventually leads to invasive cervical cancer.

LSIL : Low-grade squamous intraepithelial lesion means that the cervical cells show changes that are mildly abnormal.

ASCUS : Atypical squamous cells of undetermined significance

1 https://www.ncbi.nlm.nih.gov/pubmed/8840974
2.https://microbewiki.kenyon.edu/index.php/Human_Papillomavirus_and_Cervical_Cancer

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Link for collabration in blendspace: https://www.tes.com/lessons/_7WCTNhT-8S_hw/collab/lmtgQFfwsKuNcxljpNqnDIeBdGYXtIKY/register

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How does HPV transmit from host to host?

1. HPV can be transmitted from host to host commonly from sexual intercourse and it is also known as the most common infection of all sexually transmitted diseases (STDs).

2. Estimation has been made that two thirds of those who have had sexual contact with HPV-infected persons, will become infected. Infection occurs when the virus from a host to another were transferred via direct genital mucosa contact during sexual intercourse where it enter the cells of the epithelial basal layer.

3. HPV can also be infected orally through oral-genital contact or by mouth-to-mouth contact. HPV genotypes such as HPV1 infect epidermal cells while HPV6, 11, 16 and 18 infect epithelial cells of the oral cavity and other mucosal surfaces.

4. A mother who has been infected with HPV can as well transmit the virus to their infants. This vertical transmission of HPV-DNA presumably may occur when the fetus passes through the infected birth canal or by ascending infection, especially after premature rupture of the amniotic membranes.

5. People who are immunosuppressed are at significantly greater risk of developing HPV infection and are prone to experience a more aggressive course of infection than immunocompetent people as immune system plays an important role in controlling HPV infection.

https://infectagentscancer.biomedcentral.com/articles/10.1186/1750-9378-4-16

https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-6-83

http://mmbr.asm.org/content/68/2/362.long

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905593/

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The term pathogen that came into use in the 1880s is any infectious agent such as virus, bacterium, prion, fungus or any other microorganism that can produce and form diseases. Regarding the topic that we had chosen, which we are more focusing on a type of virus called Human Papillomavirus, it is a type of virus that represent a heterogeneous group of viruses that infect skin and mucosal epithelial tissues. HPV are small double-stranded DNA viruses, which infect stratified epithelium. There are at least 80 different types, which can be divided into those infecting cutaneous surfaces and those infecting mucosal surfaces.

The types have traditionally been differentiated by : sequence divergence - using antibodies to conformational epitopes on the major and minor capsid proteins, that the virions are serologically different. While the viruses often cause benign proliferative lesions or warts, there are a subgroup of viruses which cause premalignant and malignant lesions. Malignant disease occurs most frequently in the genital tract and carcinoma of the cervix is by far the most common cancer.

HPV has its own way of infection. The viruses enter the epithelium through microlesions and infect the basal epithelial cells where they maintain a copy number of 50–100 genomes per cell. Upon cell division, one daughter cell will remain part of the basal epithelium, while the other daughter cell will migrate up to the next level and start to differentiate. At this stage the viral DNA will segregate with the two daughter cells and replicate to maintain the 50–100 copies per cell.

The fact that one daughter cell starts to differentiate is a problem for the virus because it needs the replicative machinery of the cell for viral DNA synthesis and a terminally differentiated cell will contain little or no replicative enzymes. Therefore the virus needs to stimulate G1 to S-phase progression in the face of a cell programmed to terminally differentiate, and so produce the correct environment for DNA replication. However, the virus does require some level of differentiation, since the late promoter, which regulates the mRNA coding for the capsid proteins, is only switched on in partially differentiated cells.

The end result, therefore, is that the virus uncouples G1 to S-phase progression from differentiation, and both processes occur in the same cell. As the infected cells move up through the epithelium and partially differentiate the viral DNA is amplified in the granular layer and late gene transcription and translation occur near the top of the epithelium with viral particle assembly taking place in the cornified layer. Infected cells are sloughed off from the top of the epithelium and may be transmitted directly to individuals. Alternatively, infected cells may remain present in the environment before the virus is transmitted to a new epithelial surface. This latter case is true for viruses which infect cutaneous surfaces. Direct transmission of viruses infecting mucosal surfaces can occur by contact during sexual intercourse.

https://www.sciencedaily.com/terms/pathogen.htm
http://journals.sagepub.com/doi/full/10.1177/154411130301400505
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517699/
http://cdn.intechopen.com/pdfs/26297/InTech-Human_papillomavirus_biology_and_pathogenesis.pdf

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Human Papillomavirus type 16/18 is said to be the most attributable to cervical cancers by 70% of it.
For global burden of HPV,  from 11-12% women without cervical abnormalities  infected with HPV but higher rates in sub-Saharan Africa (24%), Eastern Europe (21%) and Latin America (16%). HPV infection has been identified as a definite human carcinogen for six types of cancer: cervix, penis, vulva, vagina, anus and oropharynx (including the base of the tongue and tonsils).

Of the estimated 12.7 million cancers occurring in 2008, 610,000 could be attributed to the HPV infection.  The less developed region have higher HPV infections compared to more developed regions. For the burden of the disease in family view, they  need for repeated attendances to hospital, social stigma, and parental anxiety about the future of the affected child and unaffected siblings, all appeared to contribute to the burden placed on the family.

In Malaysia, there are estimated 4696 cases or cervical cancers annually and 1372 cases of precancerous lesions. From the article, there are economic burden stated which RM 39.2 million total direct cost and RM 12.4 million indirect costs owing to lost productivity. The solution to this burden is where vaccination was given to who have the potential to have this disease. By vaccination, the cost lost could be prevent. In conclusion, vaccination against HPV will reduce the burden of this disease.

http://www.sciencedirect.com/science/article/pii/S0264410X12010808
http://journals.sagepub.com/doi/full/10.1016/j.otohns.2010.08.005
https://www.ncbi.nlm.nih.gov/pubmed/21338196

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Warts will be appeared when your body are being affected by HPV and there are few type of warts being formed. Sometimes it is a single wart and sometimes it appear in multiple number.

1. Genital warts always appear in women as flat lesion usually in vulva, cervix and vagina. In men it appears in scrotum or around anus and can cause itch.

2. Common warts appear as rough and raised bump and simply unsightly but it can leas to bleeding.

3. Plantar warts are hard and grainy growth that usually appear on the heel or balls of feet.

4. Flat warts is slightly raised lesions darker than your skin, children tend to get them on the face, men on the beard and women on the leg.

Other than that, precancerous lesion can also occur which lead to cancer but it need to be tested by PAP test to detect the disease.

http://www.mayoclinic.org/diseases-conditions/hpv-infection/symptoms-causes/dxc-20199064

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139291/

http://www.sciencedirect.com/science/article/pii/S1386653204003622

http://www.webmd.com/sexual-conditions/hpv-genital-warts/hpv-symptoms-tests#1

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quest 7 & 8 Immune response to HPV infection

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quest 7 & 8 Immune response to HPV infection

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Effective immunity consists of a cell mediated response to the early proteins, principally E2 and E6, necessary for lesion regression accompanied or followed by sero-conversion and antibody to the major capsid protein L1.

Innate Immune Response, Immune Evasion Mechanisms, and Humoral Immune Response

HPV infects keratinocytes of the basal layer of the cervical epithelium. Keratinocytes here express several types of Toll Like Receptors (TLRs), including endosomal TLRs involved in combating viral infections. Activation of TLR-9 in keratinocytes results in production of TNF-α, IL-8, CCL2, CCL20, CXCL9 and type 1 IFN. However, HPV is able to modify cytokine production, as in the figure below.

Receptors of NK cells, including NKp30 and NKp46 receptors, which recognize and kill virus-infected and transformed cells, 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.

Sero conversion in natural genital infection results in detectable serum neutralising antibody to the major capsid protein L1 but this response is slow with an average time to sero-conversion after the first detection of HPV16 DNA of 8-9 months, antibody concentrations are low and only 50-70% of women with incident HPV infection sero convert. However, anti L1 antibody persists in many women for at least 10 years and these low levels of antibody are protective against disease

http://www.mdpi.com/1999-4915/5/11/2624/htm
http://cvi.asm.org/content/8/2/209.short
https://infectagentscancer.biomedcentral.com/articles/10.1186/1750-9378-5-19

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http://onlinelibrary.wiley.com/doi/10.1111/adj.12020/pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441494/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149670/

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Podophyllotoxin (Condyline™) solution is a patient applied treatment for external genital warts, recommended for men only as it is too difficult for women to self-apply. For men, it is easy to use and safe if instructions are followed. Contraindicated in pregnancy.

Imiquimod (Aldara™) cream is a patient applied treatment for external genital and perianal warts. It is easy to use and safe if instructions are followed. If other treatments are unsuitable, Aldara is available by fully subsidised prescription from your doctor through Special Authority application. Not recommended in pregnancy.

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http://www.rxlist.com/gardasil-drug.htm

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http://www.hopkinsmedicine.org/healthlibrary/conditions/adult/gynecological_health/cervical_cancer_85,p00549/

HPV is a sexually transmitted disease. There are currently two vaccines that prevent the strains of HPV responsible for most cases of cervical cancer:

The HPV quadrivalent (Types 6, 11, 16, 18) vaccine protects against four types of the HPV virus: the two types of viruses that cause most cervical cancers and the two that cause 90 percent of genital warts. It also protects against other cancers caused by HPV, such as cancers and precancerous conditions of the vagina, vulva and anus.

The HPV bivalent vaccine protects against the two types of the HPV virus that cause most cervical cancers. It also protects against anal cancers.

These vaccines can only be used to prevent certain types of HPV infection before a person is infected. They cannot be used to treat an existing HPV infection. Both vaccines are administered as a series of three injections over a six-month period. To be most effective, one of the vaccines should be given before a person becomes sexually active.

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Epidemiology and Natural History of Human Papillomavirus Infections in the Female Genital Tract

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Epidemiology and Natural History of Human Papillomavirus Infections in the Female Genital Tract

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1581465/

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HPV can cause genital warts or abnormal cell changes in the cervix and other genital area which can cause cancer.

Some of the best medications for the treatment of HPV include:

1. Gardasil is one of the top drugs for the HPV virus. It is a non-infectious quadrivalent recombinant vaccine, with highly purified virus-like particles, in combination with an aluminum-containing vaccine adjuvant.

2. Imiquimod (Aldara) is a prescription medication that acts as an immune response modifier. Imiquimod is a patient-applied cream used to treat certain diseases of the skin as well as HPV.

3. Podofilox(Condylox) is a drug used to treat the HPV virus. It is a non-alkaloid toxic lignan extracted from the roots and rhizomes of the podophyllum species. It is a topical gel used for the treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by the human papillomavirus (HPV).

SPECIAL:

4. Trichloroacetic acid is an analogue of acetic acid in which three hydrogen atoms of the methyl group have all been replaced by chlorine atoms. Solutions containing trichloroacetic acid as an ingredient are used for the treatment of genital warts, caused by some type of HPV.

5. A new study has found that the human papillomavirus (HPV) vaccine protects against the sexually transmitted virus that causes cervical cancer.  It also helps prevent genital warts and low-grade cervical growths.

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quest 8 Links to Scientific Articles Related to Diagnosis of HPV (IKMAL, UM)

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quest 8 Links to Scientific Articles Related to Diagnosis of HPV (IKMAL, UM)

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-https://www.ncbi.nlm.nih.gov/pubmed/26003284
-http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006168
-http://www.sciencedirect.com/science/article/pii/S0166093414003991
-http://www.sciencedirect.com/science/article/pii/S0890850814000462
-http://www.tandfonline.com/doi/full/10.1080/14737159.2017.1293525