The initial announcement of the latest outbreak of Ebola was on 25 March, in Guinea – part of West Africa, where the virus has never been known in the population, meaning that they would have been totally unprepared for such an epidemic to occur. As of 14 April, a total of 202 clinical cases of Ebola virus disease (EVD) – which includes confirmed and suspected cases – have been reported in Guinea, Liberia, Mali and Sierra Leone, including 128 deaths. Researchers have also determined that it is genetically similar to Ebola Zaire, but it is a brand new strain. This is significant because it shows that this Ebola epidemic has arisen separately from the previous epidemics in Central Africa. The Ministry of Health of Guinea has announced that with the decrease in the number of new cases, this latest epidemic of EBV is coming to an end; however, the fact that the latest wave of cases involved people in Conakry, Guinea’s capital with an airport, is slightly worrying.
Ebola is a fairly lethal virus, which is actually part of the reason why it hasn’t turned into a pandemic yet; it kills its hosts too quickly – up to 90% of the infected will be dead in a couple of weeks after manifesting symptoms – for them to pass on the virus very far. The other reason is because it is spread via contact with an infected victim’s fluids, unlike the flu, which can spread via air. And that is the next fear – that the virus will mutate such that it can be transmitted through the air, which was suspected to have happened with another species of Ebolavirus known as Reston virus, of the book The Hot Zone fame. On the bright side, it seems that the more people the Ebola virus infects, and the more it adapts to humans, the less lethal it gets.
News broke recently where more than 600 people on a cruise ship fell ill with gastrointestinal symptoms such as vomiting and diarrhea. Unfortunately, the only unusual thing about this is that such a large percentage of the passengers became sick – from 2008 to 2013, there were 83 cruise ships that the CDC reported as having gastrointestinal illness outbreaks. Cruise ships from other countries also reported similar outbreaks.
Going by the symptoms presented, the pathogen in question is most likely to be norovirus (Norwalk virus). This virus is able to spread from person-to-person, and by contact with surfaces contaminated by the virus, such as door handles, elevator buttons, and cutlery. Norovirus spreads even faster in where large groups of people are kept close together in enclosed spaces such as cruise ships and schools. The best way to counteract the spread of norovirus is to sanitize high contact surfaces and minimize item exchange between people as much as possible with chlorine and chlorine-based cleaners; alcohol-based cleaners have less of an effect on noroviruses because they do not have a lipid envelope which could be disrupted by alcohol. People should avoid touching their faces, particularly around the mouth, nose or eyes, and wash their hands prior to eating.
Most sanitizing wipes, unfortunately, are not chlorine-based; nevertheless, they act as a reminder to myself to wash my hands; I also use them to wipe my cutlery and door handles, and throw them away once used. Call me a germaphobe, but I do like to stay healthy as much as I can, and I really don’t fancy spending my days on a cruise ship vomiting or running to the toilet to vacate my bowels every hour.
(Although there were about 20,000 U.S. cruises from 2008 to 2013, not all of the outbreaks occurring may have been reported; only cruises of 3-21 days length, with more than 100 passengers and more than 3% of the passengers ill, coming from an international port to a U.S. port, are required to be reported by the CDC. As the average number of passengers on a cruise ship tends to hover around 100, this means that about half of the 20,000 cruises are not reported upon; if we take into account the other conditions mentioned, it is likely that the number of cruises within the purview of the outbreak updates by the CDC falls even further.)
Severe acute respiratory syndrome (SARS), as its name suggests, is a respiratory illness which largely targets the upper respiratory tract, with its defining symptom being a fever with a temperature of 38°C (100.4°F) or higher. Other symptoms include flu-like symptoms such as chills, muscle aches, headaches, fatigue and sore throat. As the illness progresses, patients may then develop a dry cough and/or shortness of breath, followed by pneumonia, respiratory failure, and acute respiratory distress, potentially leading to death. The incubation period of the virus is about 2-13 days, with a mean of 5 days.
SARS is caused by the virus SARS-coronavirus (SARS-CoV). This virus was responsible for the SARS epidemic of November 2002 to July 2003. At the end of epidemic, there were a total of 8273 cases, and 775 deaths. The case fatality rate – that is, the number of deaths as a ratio of the number of cases – has been stated as being somewhere between 9.6%-11%, depending on the definition of case fatality rate used. Although the case fatality rate was somewhat high (the case fatality rate for the recent 2009 influenza pandemic was about 0.03%), the number of deaths was likely mitigated by the fact that many of the people infected by SARS-CoV had access to very good supportive/palliative healthcare, helping their immune systems to fight off the virus.
SARS-CoV is a coronavirus, so named for the protein spikes that surround this spherical virus, which looks like a corona. Although SARS-CoV was initially suspected to have originated in masked palm civets – which were commonly sold in markets in China, where some of the first cases of SARS was reported – it was finally traced back via phylogenetics to the Chinese horseshoe bat. Both the human and civet cat SARS-CoV were found to have descended from bat coronaviruses.
Although there are no cures or vaccines currently available for SARS-CoV, there is a vaccine in development by MassBiologics, cooperating with researchers at NIH and the CDC. The 2002-2003 epidemic was successfully controlled by quarantining those infected, and suspected to be infected by the virus, and is a viable alternative solution in countries where such measures can be effectively implemented. The determination of the incubation period of the virus was a vital part of this counter-measure, as it enabled health officials to determine how long had to elapse before people who had come into contact with SARS patients could be declared free from SARS.
A similar coronavirus surfaced in Saudi Arabia in April 2012. Known as Middle East respiratory syndrome coronavirus (MERS-CoV), there have been 94 confirmed cases, 16 probable cases and 47 dead, with a case fatality rate of approximately 50%, as of August 2013. Like SARS, this is a viral respiratory illness; its symptoms include fever, cough and shortness of breath, which may be followed by kidney failure and respiratory distress, potentially leading to death. People who have weaker immune systems are more likely to die from Middle East respiratory syndrome (MERS). Thus far, all cases have been linked to the Middle Eastern area.
MERS-CoV can be transmitted from person to person if there has been close contact without protective equipment e.g. gloves and masks, but in general, it appears that there has not been a sustained spread of MERS in people. There are three main epidemiological patterns to the transmission of MERS-CoV – 1) sporadic cases, probably after coming into contact with an animal carrying MERS-CoV. 2) Family clusters and 3) healthcare workers are similar, as they are both sets of people who would have come into close contact with an infected person while the person is contagious. The incubation period of MERS-CoV seems to be from 2-14 days; thus, isolation protocols similar to those as carried out in the SARS 2002-2003 epidemic can be applied to people who are suspected to be infected with MERS-CoV. There is also no known cure or vaccine for MERS-CoV. The only treatment available is supportive/palliative care, ensuring that the patient manages to live while their immune system fights off the virus.
Not much is known about MERS-CoV; it seems to be a genetic match to a coronavirus found in Egyptian tomb bats, but recently there has been a report that camels may be the actual animal reservoir for this strain of coronavirus. It also appears that a large amount of virus is actually needed to cause an infection, as only about 20% of our respiratory epithelial cells – that is to say, about 20% of our lungs and airways – are carrying the protein receptor DPP4, which allows MERS-CoV to enter, and hence infect, them.
On an slightly more unsettling note, it seems that there has been at least one case of asymptomatic MERS – that is to say, a person was infected, and then produced anti-MERS-CoV antibodies, without ever showing signs of MERS. If asymptomatic MERS can be confirmed, and people with asymptomatic MERS can transmit the virus to other people, this could potentially explain the sporadic cases of MERS that seem to pop up out of nowhere. Of course, this would also lower the case fatality rate of MERS-CoV. There are also further concerns about the potential for a serious epidemic as there will be an increase in the number of people going to Mecca in Saudi Arabia for the Muslim Haj. While a vaccine could potentially be developed, it might be that the MERS epidemic would burn itself out the same way the SARS epidemic did, thus rendering the development of the vaccine unnecessary and unprofitable.
S. K. P. Lau, P. C. Y. Woo, K. S. M. Li, Y. Huang, H-W. Tsoi, B. H. L Wong, S. S. Y. Wong, S-Y. Leung, K-H. Chan and K-Y. Yuen. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats PNAS Vol. 102 No. 39 14040–14045, doi: 10.1073/pnas.0506735102
Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study The Lancet Infectious Diseases, Volume 13, Issue 10, 859 – 866 doi:10.1016/S1473-3099(13)70164-6
D. Butler Receptor for new coronavirus found
Viruses are so varied because each virus has evolved to specifically infect one particular host. There are so many different types of viruses that it’s difficult to describe them with a generality; what they have in common is merely as I wrote in an earlier post – that they’re obligate intracellular parasites comprising of nucleoprotein complexes with a protective protein coat (and possibly a lipid envelope). However, with classification, we are able to make generalisations within a particular subset of viruses – particularly with respect to how they infect and replicate, then bust out of our cells. If we are able to figure out how viruses replicate and infect our cells, we are then in a better position to prevent them from replicating in, or even better, from entering and infecting our cells in the first place.
Viruses are primarily classified according to their genetic material; that is to say, whether they have DNA or RNA. After splitting into these two groups, there are further subsets, such as whether the genetic material is single- or double-stranded; if the viral genome is whole or segmented – amongst others.
This method of classification is called the Baltimore classification, after its developer David Baltimore. The genetic nature of a virus is important because it determines where and how the replication of the DNA or RNA takes place (either the nucleus or the cytoplasm), which in turn partially determines what steps the virus must take to get its genome there. Thus, it is possible for us to predict certain features of a virus’s replication cycle based purely on its genetic nature.
The stages in viral replication are so closely linked that it is difficult to separate them sometimes, and the number of stages range from seven to eight, or even nine, depending on who you are talking to. Nevertheless, they can be grouped into three main areas dealing with Entry into, Replication in, and Exit from host cells. Adsorption & Attachment, Entry, and Uncoating are stages in how the viruses enter cells; Transcription, Expression/Synthesis, and Replication are stages in viral replication; Assembly, Maturation, and Release are stages in how viruses exit cells.
As viruses don’t have any means of moving around, they depend on collisions with other things moving around in our bodies to push them along, causing random movement (also known as Brownian motion). Viruses are adsorbed onto the surface of the cells they are trying to infect, where they attach to the host cell by inserting their protein key into the host protein/sugar-chain lock, and thus gain entry into the cell.
The virus then enters the host cell via one of three methods. First, the translocation of the entire virus particle across the cell membrane; not much is known about this process, unfortunately. The second and third methods both involve endocytosis, which is the process by which our cells engulf particles such as nutrients (and in this case, viruses) from outside the cell. Endocytosis causes the formation of little pockets called vesicles, which go on to merge with larger pockets (containing fairly hostile environments) called lysosomes, which break down the particles that are brought into the cell for use throughout the cell. Triggered by the change in environment in lysosomes, viruses undergo uncoating, where the viral genome is exposed to the cellular environment. In the second method of entry, no further direct virus-host interactions are required, whereas in the third method, often employed by enveloped viruses, the viral lipid envelope and the cell membrane fuse to allow entry of the viral genome into the cell.
Upon entry, the virus then takes over the cell machinery and uses the cells’ enzymes to start transcribing and replicating its genome, and synthesizing the protein components of more viral particles. The precise order and manner of these stages is dependent on the nature of the viral genetic material¹.
Finally, the assembly of the newly-synthesized viral proteins and newly-replicated genetic material forms new viral particles, which is followed by protein cleavage where necessary for the maturation of the new viral progeny, and the release of the new viruses into the world again, usually by budding from the cell, or causing the cell to burst.
By deciphering how the various steps of any particular virus’s replication cycle happens, we are better able to prevent and/or treat a viral infection; for instance, the various drugs available in HIV therapy are based around the steps HIV takes to replicate itself. HIV is a class VI virus, meaning that it requires reverse transcriptase to replicate; one of the first HIV treatments was zidovudine (commonly known as AZT), which was aimed at inhibiting reverse transcriptase. Many other HIV drugs have continued to be developed in the same vein, and research has gone into finding drugs that can inhibit virus entry, maturation and exit as well.
Class I and Class II have DNA for their genetic material. Class I viruses are able to express their genes upon entry as the genes are made of double-stranded DNA; replication of the genome and expression/synthesis of proteins are then carried on concurrently. Replication is almost exclusively nuclear in Class I viruses, with the exception of poxviruses, which are able to replicate their DNA in the cytoplasm. Class II viruses, with single-stranded DNA, typically have to undergo genome replication in the cell nucleus first before protein expression can be carried out.
Class III, IV and V have RNA for their genetic material. Class III viruses have segmented double-stranded RNA genomes, which are transcribed separately to produce mRNA and synthesize proteins in the cell cytoplasm. Class IV viruses’ (+)sense RNA are able to synthesize viral proteins immediately after infection in the cell cytoplasm, as they use their genomes like mRNAs; Class V viruses, on the other hand, have to make a (+)sense RNA from their (-)sense RNA genome first.
Class VI and VII viruses both use reverse transcription in their replication, although the point in the viral replication cycle at which reverse transcription is carried out is different for both classes. Class VI has diploid single-stranded (+)sense RNA, but this genetic material does not serve as mRNA immediately after infection. Instead, they use viral reverse transcriptase to create a DNA intermediate for replication and protein synthesis after infection. Class VII has double-stranded DNA, much like our own cells, which can be transcribed into mRNA, and the resulting mRNA read to make viral proteins. Reverse transcriptase comes in near the end of the replication cycle, to re-create the virus DNA from its mRNA.
Ebola is caused by a virus that causes viral hemorrhagic fever – that is to say, it results in fever and bleeding disorders, shock, and eventually, death. Other symptoms include edema, migraine, fatigue, vomiting, and diarrhea. Occurring most often in the African continent, ebolavirus outbreaks happen when the virus jumps from its animal reservoir to a human, thus spreading through the human population; however, it is still unknown which animal harbours ebolavirus, although a strong suspect is bats.
The first ebolavirus (EBOV) was isolated in 1976, in what was then known as Zaire (now called the Democratic Republic of the Congo), when it caused an outbreak in the local population, and was thus named the Zaire ebolavirus, or the Zaire virus. Almost simultaneously, a second species of ebola virus was isolated in Sudan, and thus was called Sudan ebolavirus (SUDV); at first it was thought to be of the same species as EBOV, but later studies proved it to be of a different species. Later, animal laboratory workers in Reston, Virginia, got a scare, when ebolavirus was identified in the sick primates that they had been handling. Luckily for them, this turned out to be an Asian species of ebolavirus that did not cause disease in humans. All in all, five genetically and immunologically distinct species of ebolavirus have been isolated, with each species having several different strains. The most virulent species is EBOV, or Zaire virus, with an average case fatality rate of approximately 83%, and there have been more outbreaks of EBOV than any other ebolavirus.
EBOV and its kin are RNA viruses that are unusually genetically stable, allowing researchers to determine that most outbreaks were caused by different strains of different species of ebolavirus, indicating that these outbreaks were probably from different viral reservoirs. Ebolaviruses are unusual in that they are one of the only species of filamentous animal viruses in the world; filamentous viruses are more usually found in plants, so it has been posited that ebolaviruses may have evolved from plant viruses. Ebolaviruses have an outer lipid envelope, which technically means that the virus can be disrupted via alcohol-based agents; however, very low levels of virions are needed for infection to occur in humans (in the range of 1-10 virions). As transmission from humans to humans is via contact with an infected person’s blood or other body fluids, practicing the barrier nursing (or these days, the standard precautions) method, involving the use of protective equipment such as gloves, masks, gowns and so on, is more effective and useful in preventing transmission.
It has been problematic to elucidate the mechanism of ebolavirus infection because of a lack of samples and the difficulty of culturing the virus in the laboratory. However, researchers finally figured out the structure of the EBOV glycoprotein (GP) as derived from a human survivor of an outbreak. EBOV GP is the only virally expressed protein on the surface of the virion; it is important in the replication cycle of EBOV because it is responsible for the attachment of the EBOV virion to host cells, as well as virion-cell membrane fusion. Hence, it is a vital target of vaccines against EBOV. Various types of vaccines, including live attenuated and DNA subunit vaccines, have been developed against EBOV, and thus far they have had some promising success in animal models such as mice, guinea pigs, and macaques.
EBOV and its kin primarily attack endothelial cells, white blood cells and red blood cells, and overwhelms the protein synthesis mechanism in these cells. It is also able to interfere with our adaptive immune system by inhibiting the activation of neutrophils, a type of white blood cell. After entering these cells, these viruses replicate in the cytoplasm, then cause the host cell to burst, spreading their virions even further throughout the body. When enough cells burst, this causes the patient’s organs to break down, and their blood to stop clotting, leading to death, if the virus is not expelled from the body by the immune system in time.
Unfortunately, there is no curative treatment available for ebolaviruses; there is only supportive treatment that helps to mitigate the symptoms. Although there is a promising drug target called Niemann–Pick C1(NPC) present in the cell membrane, which is important in helping EBOV bind to our cells, a drug that can successfully target NPC is still under development. Thus the best way to avoid being infected would be to avoid contact with bats or non-human primates, and to wear protective equipment when taking care of people who have been infected with ebolaviruses. Frighteningly, it seems that EBOV can be transmitted between species through the air via large droplets, although the range of such transmission is limited.
The Ebola Virus poster (Science Infographics 2011 Honorable Mention)
J E Lee and E O Saphire Ebolavirus glycoprotein structure and mechanism of entry Future Virol. 2009; 4(6): 621–635. doi: 10.2217/fvl.09.56
N Sullivan, Z-Y Yang, and G J Nabel Ebola Virus Pathogenesis: Implications for Vaccines and Therapies J. Virol Sept 2003 vol. 77 no. 18 9733-9737 doi: 10.1128/JVI.77.18.9733-9737.2003
Influenza is a viral infection that generally affects the upper respiratory tract; that is to say, the mouth, nose and throat. Symptoms often last a week or so, and range from a sudden high fever, coughing, headache, muscle and joint pain, severe fatigue, to sore throat and runny nose. Although the virus can be transmitted at all times, it is typically a seasonal infection that peaks during winter in temperate countries, presumably because more people are packed closer together in winter; the influenza virus is also able to survive for longer outside the body in cold weather. Influenza is passed from person to person via aerosolized droplets i.e. by sneezing and coughing, and contact with contaminated surfaces. It is also able to infect people of all ages; however, the most vulnerable are the very young, the very old, and those with suppressed immune systems. Special care should be taken in these cases, as severe illness or death may result. In the United States, seasonal influenza epidemics have caused the deaths of more than 30,000 people yearly, and the hospitalization of more than 100,000. More virulent strains may claim the lives of 10,000 – 15,000 more people each year. Influenza pandemics are caused by strains that are so virulent that in the 1918 flu pandemic, more than 2.5% of those that fell ill died, compared to a case fatality rate of less than 0.05% for the more typical virus strain; these pandemic strains are also able to spread rapidly even in the summer, during what is supposedly their “off” season.
There are three types of influenza virus (A, B & C), but the one that we are most concerned about is the influenza A virus. When we’re talking about H1N1, H2N3, and H7N9, we are talking about the influenza A virus – an RNA virus of the orthomyxoviridae (influenza virus) family that is able to infect birds, pigs, and humans, amongst other animals. Variants of the virus that are endemic in birds are called avian influenza; variants that are endemic in pigs are called swine influenza.
In the naming of the subtypes of influenza A virus, ‘H’ stands for hemagglutinin, and ‘N’ for neuraminidase, both of which are antigens embedded on the lipid envelope surface of influenza A virus particles. HA is a protein that mediates binding of the virion to, and entry of the viral genome into, the host cell, while NA is involved in the release of new influenza virions from infected cells. There are 17a different known hemagglutinin (HA) antigens, and 11 different known neuraminidase (NA) antigens; therefore, there are 187 possible different combinations of HA and NA antigens that can theoretically be expressed on the surface of an influenza A virus particle. The genome of the influenza A virus is segmented; that is to say, the genome is broken up into different segments, and each segment codes for different parts of the viral particle.
Several small details are all that differentiate avian flu from human flu; for example, avian flu HA binds to alpha 2–3 sialic acid receptors on the avian cell surface, while human flu HA binds to alpha 2–6 sialic acid receptors on the human cell surface. Unfortunately, swine flu viruses have the ability to bind both types of sialic acid receptors on swine cell surfaces – this makes them dangerous because virulent avian flu viruses could jump into pigs, undergo reassortment and gain the ability to bind to alpha 2-6 sialic acid receptors, then jump into humans and consequently cause a pandemic. This sudden change in the genetic makeup of the influenza virus is known as antigenic shift.
The best way to prevent being infected by the influenza virus is, of course, by getting the flu vaccine. Typically available as a seasonal trivalent vaccine (that means that it is protective against three viruses, usually two influenza A viruses and one influenza B virus), the seasonal flu vaccine is recommended for people at high risk of getting flu, particularly during its peak season in the winter months. It is also only provides protection for one season (one year) because the surface protein antigens on the influenza viruses mutate over time such that the antibodies put out by our immune system against one year’s vaccine will no longer recognize next year’s viral antigens. In fact, the genes for an influenza virus evolve at a rate which is approximately a million times faster than that of animal (including human) genes. This gradual mutation of antigens is known as antigenic drift.
To decide which influenza viruses to include in each year’s trivalent vaccine, scientists study influenza viruses in the wild to determine which are the most predominant, or most likely to become predominant, in the following year; these viruses are then cultivated, then inactivated or attenuated, and included in the following year’s influenza vaccine. There are three types of inactivated vaccines (with decreasing risk of the virus regaining virulence if the inactivation is carried out improperly): whole virus vaccines, split virus vaccines, and subunit vaccines. Whole and split virus vaccines have names that are mostly self-explanatory, while subunit vaccines make use of only certain antigens from the influenza virus; in this case, primarily HA and NA. Live, attenuated influenza vaccines, on the other hand, are weaker and avirulent strains of the live influenza virus. Live, attenuated vaccines are the most effective, but they are also the ones that are most likely to revert to the virulent strain of influenza.
Influenza viruses that are suspected to be able to cause pandemics are used to create monovalent influenza vaccines; this is primarily to allow for control of manufacture, transport, and administration of the vaccine, so as to reduce the risk of the virus regaining its virulence and spreading throughout the population.
Deaths from pandemics were caused by both the virus (and the immune system’s reaction to the virus) as well as secondary infections that turned lethal when the infected person’s immune system was too busy fighting off the virus. When antibiotics were discovered, the mortality rate of pandemic influenza viruses fell as secondary bacterial pneumonia could now be treated effectively. Antivirals such as Tamiflu, a neuraminidase inhibitor, are a recent development, but they have been shown to be effective against influenza in the most recent 2009 H1N1 influenza pandemic, causing the case fatality rate to fall further to 0.03% – very close to the case fatality rate for seasonal influenza.
J D Parvin, A Moscona, W T Pan, J M Leider, and P Palese Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1.
Hepatitis, which has the defining feature of liver inflammation, can be due to a variety of reasons, including consuming excessive amounts of alcohol and/or other toxins, bacteria, and viruses. One of the most important viruses in hepatitis is the hepatitis B virus (HBV).
Hepatitis B is endemic in many parts of the world, including sub-Saharan Africa, East Asia, and eastern and central Europe. Transmitted by body fluids and blood, HBV causes liver inflammation, vomiting, fatigue, fever, and jaundice; in less than 1% of cases, HBV causes fulminant hepatitis, which has a high mortality rate. Approximately 5%, or 350 million, are chronic carriers who go on to develop cirrhosis of the liver, and liver cancer. In endemic areas, transmission of HBV most frequently occurs from mother to her unborn child; this is known as vertical transmission. In non-endemic areas, HBV is transmitted from person to person most frequently by unprotected sex or needle sharing; this is known as horizontal transmission. The infection early on in life occurring from vertical transmission is correlated with a higher chance of chronic infection, possibly because the baby’s immune system gets used to the HBV antigen, and does not recognize it as a foreign protein; thus the immune system is unable to clear the virus from the body.
HBV is a hepadnavirus, with a partial double-stranded DNA genome and a viral envelope. It is also one of the smallest animal viruses, measuring just 42nm across. To infect us, the HBV binds to the surface of a hepatocyte (liver cell), and enters the cell. It then moves to the cell nucleus, and delivers the partial double-stranded genome into the nucleus. In the nucleus, the genome is completed so as to become fully double-stranded, and thus the complete genome can now serve as the template for the four viral RNAs that will eventually produce more copies of HBV viral particles and its genome. After more copies have been produced, the various parts that make up a HBV virion self-assemble, forming many more virions, and exit the cell to infect more hepatocytes.
HBV is unusual; it is a pararetrovirus – that is to say, it is one of the few known non-retroviruses that use reverse transcription in its replication. Reverse transcription is noteworthy because it reverses the usual flow of information from DNA to RNA, and instead goes from RNA to DNA. However, HBV is not a retrovirus because it has an RNA intermediate instead of a DNA intermediate, meaning that the genetic information flow in HBV replication goes from DNA à RNA à DNA, instead of RNA à DNA à RNA, as in retroviruses.
In the process of replication, HBV produces a large amount of excess viral particles, so much so that one of the first instances that viral particles were detected was from the blood serum of HBV infected people; they are non-infectious because they do not have a genome. These genome-less viral particles are known as virus-like particles (VLPs), and have become important in vaccine creation because of they are very immunogenic, while at the same time being non-infectious. HBV VLPs are commonly spherical or filamentous, compared to the spherical HBV virion.
HBV has four serotypes, and eight genotypes. Different serotypes produce different antibody reactions from our adaptive immune system; however, the genotype of a HBV virion has no relation with which serotype is presented on its surface. Genotypes are correlated with the geographical distribution of HBV, with some genotypes being more predominant in some regions; we are also able to trace the evolution of HBV through its genotypes.
Although HBV does cause cell damage upon infection, a lot of damage is done by the reaction of our immune system to infection. After being activated by antiviral cytokines, white blood cells, particularly virus-specific cytotoxic T cells, set about destroying infected hepatocytes, thus causing liver inflammation, and other liver-related symptoms, such as jaundice and liver cancer. When T cells die as a result of responding to the infection, more antiviral cytokines are produced. The higher the level of antiviral cytokines, the stronger the signal to recruit more T cells, resulting in more hepatocytes destroyed, and more severe liver inflammation.
Treatment primarily deals with interfering with DNA synthesis via nucleoside and nucleotide analogues, thus interrupting HBV replication. Unfortunately, there is no drug available that will help infected persons clear HBV from their bodies faster.
The first vaccines were essentially injections of HBsAg (HBV surface antigen) that would induce the production of antibodies to counteract HBsAg, and consequently HBV virions themselves. They were initially purified from the blood of people already infected with HBV; all viruses were destroyed, leaving behind the HBsAg. This was withdrawn over fears of HIV contamination, as the people most likely to have HBV were also at high risk for HIV. Recombinant vaccines were then developed, where the gene for HBsAg was transfected into yeast, thus producing HBsAg without the risk of contamination from other pathogens. Because HBsAg is able to self-assemble into VLPs, these vaccines are also considered the first VLP vaccines. This is also one of the first vaccines against cancer, due to the link between chronic HBV carriers and liver cancer.
D. Grimm, R. Thimme, and H. E. Blum. HBV life cycle and novel drug targets Hepatol Int. 2011 June; 5(2): 644–653. doi: 10.1007/s12072-011-9261-3
A. J. Cann. Principles of Molecular Virology, 4th Edition. Elsevier 2005
Dengue is endemic today in over 100 countries in Asia, the Pacific, the Americas and Africa, affecting mostly urban and sub-urban tropical and sub-tropical areas. It typically causes a flu-like illness known as dengue fever; the “dengue triad” of symptoms is a fever, a headache, and a rash. It also causes severe joint and muscle pain – thus it has also been called “bonebreak fever”. The more severe version is known as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), where patients experience blood loss and shock. There are four fivea serotypes of the dengue virus in humans – DENV-1, DENV-2, DENV-3, and DENV-4; each of them with different viral protein antigens on the surface of the virus.
The transmission of the dengue virus involves both its human host and the Aedes aegypti mosquito vector; when a female mosquito sucks blood from a dengue-infected person, the virus goes along. The virus then infects the mosquito, eventually reaching its salivary glands. Then just before the infected mosquito sucks blood from another person, it injects its anesthetic saliva into the person, thus passing the virus to the second person. And the cycle repeats.
Although A. aegypti is primarily found in tropical and sub-tropical areas, secondary Aedes vectors are able to survive in colder climates like those of the United States and Europe. As a consequence, the dengue virus is quickly gaining a foothold in these regions.
The dengue virus is a single-stranded RNA flavivirus.The dengue virus envelope protein, found on the surface of the virus, attaches to the surface of our cells, and causes our cells to take in the virus. It would be useful to block this action in treating dengue; unfortunately, the precise way the envelope protein is binding to the surface of our cells is still not known, so we are unable to develop any drugs in this direction.
Flaviviruses like dengue are also able to block our immune system from responding during infection by inhibiting signaling within the response of our innate immune system, leading to a slower clearance of the virus from our bodies.
Because there is currently no drug or vaccine available for dengue, doctors can only offer symptomatic relief to patients. One of the main problems with developing a vaccine for dengue is because of its four five serotypes. Our immune system fights off viral infections by producing antibodies in response to viral antigens; because the immune system retains these antibodies, there is long-term protection against the serotype we were originally infected with. However, cross-protection between serotypes is only transient, depending on antibody levels, which decrease with time. When antibody levels are high, antibodies against one serotype can cross-protect against other serotypes; when antibody levels are low, the effects of the antibodies are negligible. However, when antibody levels are in the mid-range, antibody-dependent enhancement kicks in, and then people who have initially been infected with one dengue virus serotype have a higher chance of developing DHF or DSS if infected with another serotype. Thus any vaccine developed has to protect against all fourb serotypes simultaneously so as to minimize the chance of DHF or DSS developing in people who have been given a vaccine protecting against one serotype but not another. These types of vaccines are known as tetravalent vaccines, because they counter all four serotypes at the same time. At this point in time, the most promising vaccine is being developed by Sanofi Pasteur, which is currently in Phase III of clinical trials.
Vaccines against dengue virus currently under development
|Sanofi Pasteur||Live attenuated chimeric tetravalent vaccine, phase 3 clinical trials|
|Inviragen||Live attentuated tetravalent vaccine, phase 2 clinical trials|
|Butantan||Live attenuated tetravalent vaccine, phase 2 clinical trials|
|Merck||Subunit protein tetravalent vaccine, phase 1 clinical trials|
|Glaxosmithkline||Purified inactivated tetravalent vaccine, phase 1 clinical trials|
|Naval Medical Research Center||Plasmid DNA vaccine, phase 1 clinical trials|
The best way to prevent infection by the dengue virus is to stop its vectors – namely, the Aedes mosquitos; the easiest way to do this is by reducing the number of places where it can lay its eggs, by clearing any standing water.
R. Perera and R. J. Kuhn. Structural Proteomics of Dengue Virus Curr Opin Microbiol. 2008 August; 11(4): 369–377. doi: 10.1016/j.mib.2008.06.004
Michael S.Diamond. Mechanisms of Evasion of the Type I Interferon Antiviral Response by Flaviviruses Journal of Interferon & Cytokine Research. September 2009, 29(9): 521-530. doi:10.1089/jir.2009.0069.
B. Adams, E. C. Holmes, C. Zhang, M. P. Mammen, Jr, S. Nimmannitya, S. Kalayanarooj, and M. Boots.Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok Proc Natl Acad Sci U S A. 2006 September 19; 103(38): 14234–14239. doi: 10.1073/pnas.0602768103
Footnote a: In October 2013, scientists announced the discovery of a fifth dengue serotype, found in the blood of a dengue patient from Malaysia.
Footnote b: As there has only been one case of the fifth serotype being found in humans, it is likely that primates other than humans still remain as the hosts for the fifth serotype – meaning that the infection of the patient in Malaysia with the fifth serotype was accidental. However, if more cases are found, we will have to factor this fifth serotype into our vaccines.
This is a dialogue-form essay I wrote for a Coursera.org course on AIDS a couple of months ago, sort of in reply to a friend. As part of the assignment, I asked around for common (or not so common) myths about AIDS, and got a reply from a friend who was indignant about why gay men were banned from donating blood. So this was the essay I ended up writing. The requirement was that the essay should debunk the myth, in script form. Of course, I took liberties with imagining my friend’s replies XD I’ve removed the references that referred to the course lectures, but rest assured that the statements are legitimate. So if you see a number reference but no reference link below the essay, it means I was referring to a course lecture.
L: I don’t understand why gay men aren’t allowed to donate blood just because they are more likely to contract AIDS? Is it even true that they are more likely to contract AIDS? (When pressed) I’m not quite sure about how people contract AIDS, though.
L: I mean, seriously – isn’t that some kind of discrimination or something?
Me: Well, firstly, you say that you don’t know how HIV/AIDS is transmitted, right?
L: Yeeeeeah. And what’s the difference between HIV and AIDS?
Me: Hmm. HIV stands for Human Immunodeficiency Virus, which is what causes AIDS, or Acquired Immunodeficiency Syndrome – kind of like how the influenza virus causes the flu. One is the germ, and the other is the illness.
L: It’s a little confusing, but I think I get it. Why don’t they call it the same thing though?
Me: It’s a history thing. Well, basically HIV is transmitted via body fluids – mostly blood, semen and vaginal fluids. 37% of men who have sex with men (MSM) have had anal sex , and the figure jumps to 42-44% when younger MSM are surveyed [2, 3]. One of the things about anal sex is that first, the inner lining of the anus is more delicate than the vagina, and therefore tears more easily; hence it’s easier for HIV to enter the bottom’s bloodstream from the top’s semen . Second, the anus lacks the mucus produced by the vagina, which provides a small amount of protection from HIV transmission . The virus can also move from the blood, if any, in the bottom’s anus to the exposed parts of the top’s penis , particularly if the top is uncircumsized [5, 6]. In developed countries like ours, unprotected anal sex is 17.5 times as likely to allow for HIV to be transmitted compared to vaginal sex, on a per-act basis . And the crux is, only one in six MSM use condoms consistently when participating in anal sex [7, 8]. So in gay men, there is a higher chance that they will have contracted AIDS. And since one of the ways that HIV is transmitted is via blood, that’s why they’re not allowed to donate blood. However, it is true that 36% of younger women have also had anal sex , so the risk is equally relevant to them. The wording on blood donation forms should probably be changed to reflect that. Actually, there’s lots of things we can do about this issue, but people who have anal sex do tend to be more likely to contract AIDS.