The H1N1 influenza virus outbreak originated in Mexico in early , and then spread rapidly throughout North America. Within a few weeks, the novel swine-origin H1N1 virus extended its reach around the globe. In June , as a result of the global spread of the H1N1 virus, the WHO issued its first pandemic declaration of the 21st century - the first since the flu pandemic of The pandemic declaration acknowledged the inability to contain the virus and recognized its inevitable further spread within affected countries and into new countries.
The new H1N1 virus became the dominant influenza strain in most parts of the world, including the United States. Like other influenza pandemics, the H1N1 outbreak occurred in waves.
The first wave took place in the spring of , with a second wave commencing in late August as children and college students returned to classes. The outbreak peaked in October of , with flu activity reported in all 50 states, as well as numerous other countries and territories.
By January , flu activity had returned to below baseline levels. The H1N1 virus continues to circulate at low levels, but it is no longer the dominant influenza strain, and its behavior more closely resembles a seasonal influenza virus than a pandemic flu. From the time the outbreak began in April through April , the CDC estimated that about 60 million Americans became infected with the H1N1 virus, , Americans were hospitalized and 12, deaths occurred as a consequence of the H1N1 flu.
The highest hospitalization rates occurred in young children. Exact numbers are not known due to the widespread nature of the outbreak and because most patients, especially those with mild cases, were not tested.
The large majority of infections in the United States and most other countries were mild, although pregnant women and individuals with certain underlying medical conditions had an increased risk of severe and fatal illness. There were some differences between the pandemic H1N1 flu and regular, seasonal flu.
First, the H1N1 flu continued to spread during the summer months, which is uncommon for seasonal flu. Second, a much larger percentage of H1N1 patients exhibited symptoms of vomiting and diarrhea than is common with regular seasonal flu.
There were also more reports of severe respiratory disease, especially in young and otherwise healthy people, infected with the new H1N1 virus than with seasonal flu viruses. Significantly, the majority of cases of H1N1 infection, including severe and fatal cases, occurred in young and otherwise healthy individuals generally between the ages of 5 and 50, with relatively few deaths among the elderly.
This is in contrast to the situation with seasonal flu which primarily afflicts the very young and the elderly, and where 90 percent of severe and lethal cases occur in people over the age of Deaths among the elderly accounted for only 11 percent of H1N1 deaths.
Proper use of these drugs can shorten the duration and lessen the severity of the sickness and reduce the chance of spreading the disease. The drugs reduce the risk of pneumonia - a major cause of death from influenza - and the need for hospitalization.
To be most effective, the antiviral drugs should be administered as soon as possible after the onset of symptoms. A vaccine to protect against the H1N1 virus was developed, tested, and approved and became available in October Due to the fact that the virus used to prepare the vaccine grew more slowly than most seasonal flu viruses do, production of the vaccine lagged and widespread distribution of the vaccine occurred later than anticipated.
Priority for the vaccine was initially given to health care and emergency workers and individuals at high risk for severe disease, but by the winter of availability was extended to the general population. Later, some doses went unused. Although some had concerns about the safety of the H1N1 vaccine, flu vaccines have a very good safety profile. While mild side effects, such as soreness at the site of injection, aches, and low-grade fever, may occur as a result of receiving a flu shot, it is not possible to get the flu H1N1 or seasonal from the vaccine.
The flu shot, or inactivated vaccine, is made from only a portion of the virus — a purified protein that makes our immune system develop protection. Likewise, the nasal spray version of the flu vaccine contains attenuated or weakened virus that is not able to cause the flu. Given the potential serious health outcomes from the flu, especially for high-risk population groups, the benefits of vaccination as the best way to prevent influenza infection and its complications far outweigh the risk of relatively minor side effects from the vaccination.
Historically, influenza pandemics arise about three to four times each century. The most recent pandemic , and the first of the 21st century, occurred in , some 40 years after the previous pandemic. The H1N1 flu, commonly known as swine flu, spread around the globe faster than any virus in history, largely due to air travel.
Pandemic flu strains are of deep concern because there is no or only limited natural immunity to novel flu strains, and therefore nearly everyone is susceptible to infection. A high percentage of the population could become ill at any one time and overwhelm public health systems, and a large number of deaths could occur.
We were very fortunate in the case of the H1N1 pandemic. Most people suffered only a mild illness. H1N1 was not an especially virulent virus. Further, the virus remained stable and did not mutate to a more deadly form or to a drug resistant form.
Other influenza strains have been far more lethal. Currently, there is concern about the new avian H7N9 virus. Most patients have experienced severe respiratory illness, with about one-third of the cases resulting in death. Although the virus does not appear to pass easily from person to person, there is always the worry that it could mutate into a form that is more transmissible.
There are drugs that are effective against influenza, but the possibility that a virus could acquire resistance to the drugs is a serious issue. There are four different antiviral drugs, of two different classes, that are effective against influenza. However, influenza viruses can and do develop resistance to these drugs - as one of the main circulating seasonal viruses did during a recent flu season - so that the drugs can no longer be used to treat or prevent infections.
There is a need to develop additional drugs that can prevent or alleviate flu symptoms. Vaccines can be developed to protect humans from influenza viruses. However, as was strikingly obvious during the H1N1 pandemic, vaccine production takes many months. By the time a vaccine was developed, tested, produced, and distributed, many individuals had already been infected. Clearly, a more rapid method of vaccine development is needed.
The goal of developing a universal flu vaccine, one that would provide durable protection against multiple flu strains, remains a challenging feat. The greatest fear is that a new pandemic influenza virus could emerge that could pass from person to person as easily as the H1N1 virus, but be as deadly as the H5N1 virus.
Additional concerns are that an influenza virus could mutate into a form that would be resistant to anti-influenza drugs, such as Tamiflu, or that the virus could change so that a vaccine no longer afforded protection. Even though the H1N1 pandemic was relatively mild, knowing how lethal and unpredictable influenza viruses can be, we must continue to remain alert and prepare for future pandemics.
Investigators in the Department of Molecular Virology and Microbiology MVM have been studying influenza for several decades, with an Influenza Research Center first established in A major focus of the work is directed towards the development and testing of influenza vaccines to find the most effective vaccination dosages, methods, and strategies to protect the population against this deadly disease.
Other projects involve studying the structure and function of important influenza proteins. Research is ongoing on both epidemic influenza also referred to as seasonal or interpandemic influenza and pandemic influenza. Epidemic influenza occurs annually and is attributable to minor changes in genes that encode proteins on the surface of circulating influenza viruses.
Pandemic influenza occurs when more significant changes in the influenza A virus arise as a result of the acquisition of genes from influenza viruses of other animal species by a human virus strain, thus creating a novel virus.
The latter carries a greater risk for the human population. It was previously led by Dr. Wendy Keitel and is currently under the direction of Dr.
Hana El-Sahly. The VTEU network conducts clinical trials that evaluate vaccines and treatments for a wide array of infectious diseases. Following successful penetration inside cells, the virus particles need to get to an appropriate site in the cell for genome replication.
This process is termed intracellular trafficking. In fact, the biological importance of the cytoplasmic trafficking was not realized until the invention of live cell imaging technology. For viruses that replicate in the cytoplasm, the viral nucleocapsids need to be routed to the site for replication. In fact, microtubule-mediated transport coupled with receptor-mediated endocytosis is the mechanism for the transport Fig.
In addition, for viruses that replicate in the nucleus, the viral nucleocapsids need to enter the nucleus. For many DNA viruses, the viral nucleocapsids are routed to the perinuclear area via microtubule-mediated transport. In this process, a dynein motor powers the movement of virus particles. As an analogy, the viral nucleocapsids can be envisioned as a train in a railroad. Two distinct viruses are used to explain how the entry is linked to cytoplasmic trafficking: A adenovirus naked and B herpes virus enveloped.
Incoming viruses can enter cells by endocytosis A or direct fusion B. Following penetration into cytoplasm, either endocytic vesicles or viral capsids exploit dynein motors to traffic toward the minus ends of microtubules. Either the endocytic vesicles A or the capsids B interact directly with the microtubules.
The virus can also lyse the endocytic membrane, releasing the capsid into the cytosol A. As the virus particles approach to the site of replication, from the cell periphery to the perinuclear space, the viral genome becomes exposed to cellular machinery for viral gene expression, a process termed uncoating. Uncoating is often linked with the endocytic route or cytoplasmic trafficking see Fig. For viruses that replicate in the nucleus, the viral genome needs to enter the nucleus via a nuclear pore.
Multiple distinct strategies are utilized, largely depending on their genome size Fig. For the virus with a smaller genome, such as polyomavirus, the viral capsid itself enters the nucleus. For viruses with a larger genome, the docking of nucleocapsids to a nuclear pore complex causes a partial disruption of the capsid eg, adenovirus or induces a minimal change in the viral capsid eg, herpes virus , allowing the transit of DNA genome into the nucleus.
A Polyomavirus capsids are small enough to enter the nucleus directly via the nuclear pore complex without disassembly. Uncoating of the polyomavirus genome takes place in the nucleus. B The adenovirus capsids are partially disrupted upon binding to the nuclear pore complex, allowing the transit of the DNA genome into the nucleus. C For herpesvirus, the nucleocapsids are minimally disassembled to allow transit of the DNA genome into the nucleus.
The viral genome replication strategies are distinct from each other among the virus families. In fact, the genome replication mechanism is the one that defines the identity of each virus family. Furthermore, the extent to which each virus family relies on host machinery is also diverse, ranging from one that entirely depends on host machinery to one that is quite independent.
However, all viruses, without exception, entirely rely on host translation machinery, ribosomes, for their protein synthesis. Exit can be divided into three steps: capsid assembly, release, and maturation. The capsid assembly follows as the viral genome as well as the viral proteins abundantly accumulates.
The capsid assembly can be divided into two processes: capsid assembly and genome packaging. Depending on viruses, these two processes can occur sequentially or simultaneously in a coupled manner. Picornavirus is an example of the former, while adenovirus is an example of the latter Fig. In the case of picornavirus, the capsids ie, immature capsid or procapsid are assembled first without the RNA genome. Subsequently, the RNA genome is packaged or inserted via a pore formed in the procapsid structure.
By contrast, in the case of adenovirus, the capsid assembly is coupled with the DNA genome packaging. Then, a question that arises is how does the virus selectively package the viral genome? A packaging signal , 9 a cis -acting element present in the viral genome, is specifically recognized by the viral capsid proteins, which selectively package either RNA or DNA. A Sequential mechanism. For picornavirus, the procapsid, a precursor of the capsids, is preassembled without RNA genome.
Subsequently, the RNA genome penetrates into the procapsid via a pore. B Coupled mechanism. For adenovirus, the DNA genome is packaged into the capsid during capsid assembly. For naked viruses, the virus particles are released via cell lysis of the infected cells. Thus, no specific exit mechanism is necessary, because the cell membrane that traps the assembled virus particles are dismantled.
Examples of naked viruses are polyomavirus ie, SV40 and adenovirus. By contrast, in cases of enveloped viruses, envelopment , a process in which the capsids become surrounded by lipid bilayer, takes place prior to the release. With respect to the relatedness of the capsid assembly to the envelopment, two mechanisms exist. First, the envelopment can proceed after the completion of capsid assembly Fig. In this sequential mechanism, the fully assembled capsids are recruited to the membrane by interaction of the viral capsids with viral envelope glycoprotein.
Examples of this include herpesvirus and hepatitis B virus. Alternatively, the envelopment can occur simultaneously with the capsid assembly Fig. Retrovirus is the representative of this coupled mechanism. The capsid assembly occurs prior to the envelopment. The assembled capsid is then targeted to the membrane for envelopment. Togavirus constitutes a family of positive-strand RNA viruses see Table Capsid proteins and the viral genome are recruited together to the budding site on the membrane.
Capsid assembly and the envelopment of the capsid proceeds simultaneously. The envelopment process can be divided into three steps: a bud formation, a bud growth, and finally membrane fusion. On the other hand, regarding the membrane for envelopment, two cellular membranes are exploited. The plasma membrane is the site of envelopment for some viruses, such as retrovirus and influenza virus, whereas endosomes, such as endoplasmic reticulum ER and Golgi bodies, are the site of envelopment for others, such as herpesvirus see Fig.
Then, how are the viruses released from the infected cells? Most enveloped viruses are released extracellularly via exocytosis 10 ; often, this process is also called budding , as an analogy of buds in plants. Via budding, the envelopment proceeds in a linked manner with extracellular release. Then a question that arises is how mechanistically is budding triggered? The clue for this was revealed by the identification of a peptide motif termed late L domain , 11 which is instrumental in triggering the budding process Box 3.
Briefly, Gag protein, via its late domain, recruits cellular factors involved in the multivesicular bodies 12 MVBs pathway and subverts the MVB pathway for budding. After all, it is intriguing to learn how viruses exploit cellular mechanisms to produce their own progeny extracellularly.
Late domain, which was first discovered in the Gag polyproteins of retroviruses and M matrix proteins of rhabdoviruses, is involved in the budding process of the enveloped viruses. Intriguingly, a substitution mutation of the late domain motif results in virions attached to the plasma membrane without being released, as if the viral release is blocked at a late stage of budding, a phenotype that is reflected in the nomenclature. It was found that the late domains are involved in recruiting cellular factors involved in the MVBs pathway panel B.
In other words, the retroviral late domains mediate the viral egress from the plasma membrane by coopting the cellular machinery for MVB biogenesis. A alanine , E glutamic acid , P proline , T threonine , and Y tyrosine. Vps4 red is involved in recycling the MVB machinery. For picornavirus and retrovirus, maturation is an essential step to acquire infectivity. In case of retrovirus, the cleavage of the Gag polyprotein by the viral PR protein aspartate protease occurring in the released virion is accompanied with a considerable morphological transition such as the condensation of the capsid structure see Fig.
Importantly, such a maturation process confers the particle its infectivity. Above, we learned the steps involved in the virus life cycle, starting from attachment to target cells to progeny production. However, the virus life cycle is not always fully executed, because the invading virus encounters many obstacles, such as host immune response and host factors, that restrict the viral propagation.
Productive infection refers to a successful execution of the virus infection that leads to the production of progeny virus. Productive infection includes lytic infection and persistent infection. Specifically, lytic infection produces a progeny virus via cell lysis, thus the virus genome replication cannot persist eg, adenovirus and influenza virus.
In contrast, persistent infection continues to produce a progeny virus for a long period either without cell death [eg, hepatitis B virus and hepatitis C virus HCV ] or with cell death but leaving long-lasting reservoir cells eg, HIV see Fig. Five types of virus infections are illustrated with emphasis on the progeny virus production and the state of the viral genome red. The virus life cycle including viral genome replication is fully executed in productive infection, while the virus life cycle is not fully executed in nonproductive infection.
The type of virus infection is determined by the intricate interplay between virus and host interaction. On the other hand, nonproductive infection refers to the type of virus infections that do not lead to the production of a progeny virus. The bacterium reproduces,. Phage DNA integrates into. New phage DNA and proteins. Reproductive Cycles of Animal Viruses.
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