Sunday, March 4, 2012

From the Bed to the Streets: A Look Into The Human Papillomavirus


Click image for source
 I often come across beautiful animated renditions of various viral pathogens, with their symmetrical shape, rounded features, and overall elegance of design, I almost always forget the power of such small substances. The Human Papillomavirus (HPV, seen above) is an example of a virus most of us would probably not suspect to cause such wide spread harm. Unlike the common flu, or even HIV, HPV often slips under people’s health conscious radar. Even though it falls under the category of sexually transmitted infection (STI), there are many aspects about its virology, transmission, and prevention that makes it a unique contribution to the world of STI’s. As I dig deeper into data surrounding HPV, the more impressed I become at the level of destruction achieved by something so small and relatively simple.        

Falling in the family Papillomaviridae, HPV is a nonenveloped, double-stranded DNA virus. Isolates of HPV are classified as "types," each designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8 kilo-base circular genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2 (depicted in the picture above by star-shaped structures budding from the surface). Purified L1 protein will self-assemble to form virus-like particles (VLPs) which are used in vaccines to trigger antibody production in the recipient.

In addition to the structural genes, the genome encodes several early genes (E1, E2, E4, E5, E6, and E7) that enable viral transcription and replication, allowing interaction with the host genome. E6 and E7 proteins are the primary contributors of cancer; they manipulate cell cycle regulators, induce chromosomal abnormalities, and block apoptosis. HPV obviously comes equipped with the tools necessary to complete the job of proper infection; all it needs is a site of entry into a host so one can witness its drastic health effects.
   
HPV enters the body through micro-abrasions that expose areas of the basement membrane. This disturbed epithelial barrier is typical during sexual intercourse or after minor skin abrasions. Interestingly, the use of condoms does not fully protect against infection, as the virus can be spread through contact by other genital areas not covered. It can also be spread through oral sex. 

Once inside, the infection is limited to the stratified epithelium, as this is the only tissue within which it can replicate. Being isolated to this area allows it to be shielded from much of the body’s immune response. HPV lesions are thought to arise from the proliferation of infected basal keratinocyte (the predominate cell type in the epidermis). The circular, double stranded DNA is transported into the nucleus of these cells and by using host replication machinery; HPV establishes itself at a copy number between 10-200 viral genomes per cell. It takes about 12-24 hours for the virus to even initiate transcription, however; after this period it can proliferate uncontrollably.

Once an HPV viron invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before it can be clinically detected. I am sure by now the reader is asking, "Sure the biology behind the virus is interesting, but why should I care?" To answer this question, we can take a look at the various detrimental health effects associated with infection.

HPV is a lovely package of afflictions that comes complete with genital warts and a myriad of cancers that can affect numerous areas of the body. While genital warts only represent 1% of the active population, cancers such as, penile, throat, colorectal, and tonsil represent 10,000 cases each year in the U. S. The effect on women is even more severe. HPV is actually the number one cause of cervical cancer, killing 4000 women each year. Just knowing these quick facts allows one to realize how dangerous HPV actually is and it only gets worse when you consider its prevalence in the population.

It is the most common STI in the U.S. According to the Center for Disease Control and Prevention (CDC), 45% of college aged woman are currently infected. There are currently 20 million people infected in the U.S. with 6 million new infections annually. Most HPV infections are asymptomatic or simply unrecognized with 90% of people able to clear infection within two years. Put in another way, about half of sexually active people will contract HPV some point in their lives.

According to the CDC there are around 120 different types. Around 30-40 of those are actually associated with sexual transmission. Of these there are what are considered to be high-risk and low risk types. High-risk includes cancer causing types and low-risk includes wart causing types (see below). Interestingly, a viral type cannot cause both; it is either wart or cancer causing. Given all of this information, it is imperative to have a means of prevention in order to thwart possible infection.

Click on image for source: Low-risk genital warts
Click on image for source: High-risk cervical cancer


Of two vaccines that are currently on the market today, the most popular is the quadrivalent vaccine, Gardasil, which contains HPV types 11, 6, 18, and 16. These represent four of the most common types, with 16 and 18 representing 70% of cervical cancers, 11 and 6 representing 90% of genital warts. The other vaccine, Cervarix, is a bivalent vaccine containing types 16 and 18 only. Currently, either vaccine can be administered to women ages 9-26 with an efficacy close to 100%. As of the October of 2011, the Gardasil vaccine has also been approved for men between 9-26 years of age. For either gender, administration of the vaccine before the onset of sexual maturity is optimal. Introducing the vaccine into a young immune system gives the body the ability to produce sufficient levels of antibodies against these four main types. This protection of course, comes at a price. 

Click on image for source
Both of the vaccines are administered in a 3 dose series over a 6 month period with each does costing $120. The total $360 does not give you fool proof protection. Remember, this vaccine only covers the four main types and significant time needs to pass before your body produces sufficient levels of antibodies to fight any sort of exposure. Women who have received an HPV vaccine should continue routine cervical cancer screening as 30% of cervical cancers are caused by HPV types other than 16 or 18. For anyone interested in getting the vaccine, it is important to know that it does not eliminate the need to have regular cervical screens and will not help cure a current infection.  

More recently, the use of the HPV vaccine has been under political debate. Following its introduction in 2006, Gardasil has been proposed as a possible mandatory vaccine. In 2007 Texas Governor Rick Perry aimed to pass an executive order that would mandate the vaccination for all young girls in Texas. The bill was met with much opposition and, even though it did not pass, the idea of an HPV vaccine mandate still lingers.

The Advisory Committee on Immunization Practices(ACIP) put forth their recommendation for the use of an HPV vaccine by taking into account much of the information discussed in this article. ACIP models have suggested that vaccination of an entire cohort of females aged 12 years could reduce the lifetime risk for cervical cancer by 20%-66%, depending on the efficacy of the vaccine and the duration of vaccine protection. One study assumed 100% vaccine coverage, 90% vaccine efficacy against HPV 16/18, and lifetime duration of protection. Under these assumptions, an estimated 58% reduction was achieved in the lifetime risk for cervical cancer for the vaccinated cohort.

In a summary of their findings, ACIP suggests routine vaccination of females aged 11-12 years based on several considerations, including studies suggesting that quadrivalent HPV vaccine among adolescents will be safe and effective, high antibody counts achieved after vaccination at age 11-12 years, and the high probability of HPV acquisition within several years of sexual debut.

Regardless of the vaccine debate, there is no argument that HPV presents a mounting threat to the sexually active population in the United States. The virus, so beautifully depicted by animated images and models, remains sinister in its behavior. Stealthy existence in the host, ease of transmission, and fine-tuned virology make it an expert pathogen. Reading articles like this and doing basic research on the internet is a useful way for people to protect themselves, providing a basis from which to cultivate an appreciation and fear of the possible detrimental health effects associated with infection. Getting vaccinated is a proactive way to shield oneself from the growing HPV problem that is sweeping the nation. Hopefully, as HPV’s reputation as a killer spreads and more people begin to protect themselves, it will prevent many needless deaths.       

1 comment:

  1. The two blogs concerning HPV complement each other well. While Kevin McNaught's blog provides a big picture view of how the HPV issue fits into the history and framework of vaccinations, Srdjan Kamenko's blog provides a detailed blow-by-blow description of the the virus, how it is transmitted and what it does. The prevalence of the HPV viruses are truly surprising and their ability to be "silent" or remain undetected for so long make them particularly scary.

    The one figure that I have not seen cited that seems particularly important is the relative proportion of the different virus types within the infected population. In the Javitt et al. (2008) article, the authors state "Many women will never be exposed to the cancer-causing strains of HPV; indeed the prevalence of these strains in the U.S. is quite low." If this is the case, while the percent of the population infected by HPVs may be quite high, if the percent of cancer-causing HPVs within this infected population is low, then the high infection rate, in general, may not be that meaningful. It is hard to assess the true threat and how "scary" these viruses are without these critical figures.

    ReplyDelete