attack hiv at that phase of its life cycle. protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places. improved protease inhibitors are now in development. protease inhibitors have also been seen in nature. a protease inhibitor was isolated from the shiitake mushroom (lentinus edodes). the presence of this may explain the shiitake mushrooms' noted antiviral activity in vitro. long dsrna helix targeting most viruses produce long dsrna helices during transcription and replication. in contrast, uninfected mammalian cells generally produce dsrna helices of fewer than 24 base pairs during transcription. draco (double-stranded rna activated caspase oligomerizer) is a group of experimental antiviral drugs initially developed at the massachusetts institute of technology. in cell culture, draco was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, amapari and tacaribe arenavirus, guama bunyavirus, h1n1 influenza and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. it was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. draco effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. the procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell. assembly rifampicin acts at the assembly phase. release phase the final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. two drugs named zanamivir (relenza) and oseltamivir (tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains. immune system stimulation main article: immunostimulant rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system to attack a range of pathogens. one of the best-known of this class of drugs are interferons, which inhibit viral synthesis in infected cells. one form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis b and c, and other interferons are also being investigated as treatments for various diseases. a more specific approach is to synthesize antibodies, protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system. once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. a monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, and antibodies purified from infected individuals are also used as a treatment for hepatitis b. antiviral drug resistance antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. in cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus. the issue inevitably remains a major obstacle to antiviral therapy as it has developed to almost all specific and effective antimicrobials, including antiviral agents. the centers for disease control and prevention (cdc) inclusively recommends anyone six months and older to get a yearly vaccination to protect them from influenza a viruses (h1n1) and (h3n2) and up to two influenza b viruses (depending on the vaccination). comprehensive protection starts by ensuring vaccinations are current and complete. however, vaccines are preventative and are not generally used once a patient has been infected with a virus. additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent the effectiveness of herd immunity, making effective antivirals a necessity. the three fda-approved neuraminidase antiviral flu drugs available in the united states, recommended by the cdc, include: oseltamivir (tamiflu), zanamivir (relenza), and peramivir (rapivab). influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. currently, neuraminidase inhibitors (nais) are the most frequently prescribed antivirals because they are effective against both influenza a and b. however, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent nai binding. this was seen in the h257y mutation, which was responsible for oseltamivir resistance to h1n1 strains in 2009. the inability of na inhibitors to bind to the virus allowed this strain of virus with the resistance mutation to spread due to natural selection. furthermore, a study published in 2009 in nature biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir. this finding was based on a performance evaluation of these drugs supposing the 2009 h1n1 'swine flu' neuraminidase (na) were to acquire the oseltamivir-resistance (his274tyr) mutation, which is currently widespread in seasonal h1n1 strains. origin of antiviral resistance the genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments. viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment. immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at the highest risk of developing oseltamivir resistance during treatment. subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance. the mechanisms for antiviral resistance development depend on the type of virus in question. rna viruses such as hepatitis c and influenza a have high error rates during genome replication because rna polymerases lack proofreading activity. rna viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain a high frequency of mutations. dna viruses, such as hpv and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. dna viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than rna viruses. in both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. billions of viruses are produced every day during the course of an infection, with each replication giving another chance for mutations that encode for resistance to occur. multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance. this effect, called the quasispecies model, results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with the highest fitness every time the virus is spread to a new host. recombination, the joining of two different viral variants, and reassortment, the swapping of viral gene segments among viruses in the same cell, also play a role in resistance, especially in influenza. antiviral resistance has been reported in antivirals for herpes, hiv, hepatitis b and c, and influenza, but antiviral resistance is a possibility for all viruses. mechanisms of antiviral resistance vary between virus types. detection of antiviral resistance national and international surveillance is performed by the cdc to determine effectiveness of the current fda-approved antiviral flu drugs. public health officials use this information to make current recommendations about the use of flu antiviral medications. who further recommends in-depth epidemiological investigations to control potential transmission of the resistant virus and prevent future progression. as novel treatments and detection techniques to antiviral resistance are enhanced so can the establishment of strategies to combat the inevitable emergence of antiviral resistance. treatment options for antiviral resistant pathogens if a virus is not fully wiped out during a regimen of antivirals, treatment creates a bottleneck in the viral population that selects for resistance, and there is a chance that a resistant strain may repopulate the host. viral treatment mechanisms must therefore account for the selection of resistant viruses. the most commonly used method for treating resistant viruses is combination therapy, which uses multiple antivirals in one treatment regimen. this is thought to decrease the likelihood that one mutation could cause antiviral resistance, as the antivirals in the cocktail target different stages of the viral life cycle. this is frequently used in retroviruses like hiv, but a number of studies have demonstrated its effectiveness against influenza a, as well. viruses can also be screened for resistance to drugs before treatment is started. this minimizes exposure to unnecessary antivirals and ensures that an effective medication is being used. this may improve patient outcomes and could help detect new resistance mutations during routine scanning for known mutants. however, this has not been consistently implemented in treatment facilities at this time. vaccinations main article: vaccination while most antivirals treat viral infection, vaccines are a preemptive first line of defense against pathogens. vaccination involves the introduction (i.e. via injection) of a small amount of typically inactivated or attenuated antigenic material to stimulate an individual's immune system. the immune system responds by developing white blood cells to specifically combat the introduced pathogen, resulting in adaptive immunity. vaccination in a population results in herd immunity and greatly improved population health, with significant reductions in viral infection and disease. vaccination policy main article: vaccination policy § united states vaccination policy in the united states consists of public and private vaccination requirements. for instance, public schools require students to receive vaccinations (termed "vaccination schedule") for viruses and bacteria such as diphtheria, pertussis, and tetanus (dtap), measles, mumps, rubella (mmr), varicella (chickenpox), hepatitis b, rotavirus, polio, and more. private institutions might require annual influenza vaccination. the centers for disease control and prevention has estimated that routine immunization of newborns prevents about 42,000 deaths and 20 million cases of disease each year, saving about $13.6 billion. vaccination controversy main article: vaccination schedule § united states despite their successes, in the united states there exists plenty of stigma surrounding vaccines that cause people to be incompletely vaccinated. these "gaps" in vaccination result in unnecessary infection, death, and costs. there are two major reasons for incomplete vaccination: vaccines, like other medical treatments, have a risk of causing complications in some individuals (allergic reactions). vaccines do not cause autism; this has been confirmed by national health agencies, such as the us centers for disease control and prevention, the us institute of medicine, and the uk national health service low rates of vaccine-preventable disease, as a result of herd immunity, also make vaccines seem unnecessary and leave many unvaccinated. although the american academy of pediatrics endorses universal immunization, they note that physicians should respect parents' refusal to vaccinate their children after sufficient advising and provided the child does not face a significant risk of infection. parents can also cite religious reasons to avoid public school vaccination mandates, but this reduces herd immunity and increases risk of viral infection. limitations of vaccines vaccines boosts the body's immune system to better attack viruses in the "complete particle" stage, outside of the organism's cells. traditional approaches to vaccine development include an attenuated (a live weakened) or inactivated (killed) version of the virus. attenuated pathogens, in very rare cases, can revert to a pathogenic form. inactivated vaccines have no possibility of introducing the disease they are given against; on the other hand, the immune response may not always occur or it may be short lived, requiring several doses. recently, "subunit" vaccines have been devised containing only the antigenic parts of the pathogen. this makes the vaccine "more precise" but without guarantee that immunological memory will be formed in the correct manner. vaccines are very effective on stable viruses but are of limited use in treating a patient who has already been infected. they are also difficult to successfully deploy against rapidly mutating viruses, such as influenza (the vaccine for which is updated every year) and hiv. antiviral drugs are particularly useful in these cases. antiretroviral therapy as hiv prevention following the hptn 052 study and partner study, there is significant evidence to demonstrate that antiretroviral drugs inhibit transmission when the hiv virus in the person living with hiv has been undetectable for 6 months or longer. public policy