Vaccines have so far held the center position in efforts to stop viruses. They are inexpensive and secure, and the protection can last for a long time. But some viruses because of a number of reasons, aren’t compatible with this method like retroviruses, influenza as well as rhinoviruses and arboviruses.
Some of the obstacles to the use of vaccines are (1) the variety of serotypes e.g. rhinoviruses togaviruses, rhinoviruses (2) alteration in the gene e.g. retroviruses, influenza as well as (3) Infections that are latent. It has been a while since notable results on a large scale been made with antiviral medications like Acyclovir and AZT when there is no vaccine.
However. Acyclovir and AZT are not penicillin-like in their spectrums of activity, or in the degree of inhibition. They’re more like some of the antibacterial drugs that first came out like salvarsan. None of the antiviral compounds tested has been able of stopping completely the replication of any virus, and certain viruses always seem to be able to bypass the blockade induced by drugs.
There aren’t many limitations on the kinds of molecules that block virus replication, at the very least within the lab. They are diverse in terms of quantity and complexity. They include natural products that are found in plants, synthetic oligonucleotides polysaccharides, basic inorganic and organic compounds, and nucleoside analogs. Some examples of antiviral compounds that are that are currently used include:
- Nucleoside analogues: Thousands and thousands of analogues of natural nucleosides are now being created and tested in the lab initially as anti-herpesvirus agents and a large number are being tested for anti-HIV drugs. Alongside purine and pyrimidine nucleosides amino, ara- nucleotides or aza-nucleosides are being synthesized. One atomic shift could transform an active molecule into an inactive molecular.
- Pyrophosphate analogues: Forscarnet is an example of an analogue to pyrophosphate. It specifically blocks herpesvirus DNA polymerase on the binding sites of pyrophosphates and also has anti-HIV activities.
- Amantidine molecules: Amantidine chemical compounds is approved for cure of the an influenza A infection. The addition of the grouping of methyl (rimantidine) changes the chemical profile of the drug and blocks its entry into the brain, which can reduce the adverse effect known as “jitteriness”.
Resistance of viruses to inhibitors
One disappointing aspect of antiviral therapy is the inability to date of any antiviral drug to stop virus replication completely. Antiviral activity is known to cause an increase of 100-1000 percent reduction in the virus’s titre that, while significant, permits some virus-causing particles to persist. This can have serious implications for patients with immunocompromised bodies who may not be able to eradicate residual viruses. It isn’t known to be certain if these virions are drug-resistant or if they differ biologically or genetically distinct from the main parts of the population.
Many compounds hinder viral replication in cell culture. The more complicated the regulatory mechanism of a virus are, the more straightforward it is to identify molecules that stop it. It can be very difficult to choose which molecules should be further studied. A general estimate of percentages of activity of antiviral compounds in cell cultures as well as animal models and in humans is 1000:10:1.
1. Cell-free virus
A few antiviral drugs inhibit or block the extracellular virus in living cells. One exception is the line of WIN compounds that bind to the picornavirus’s external proteins. They are able to bind to and integrate into the canyons that are present at the top of picornavirus viruses, consequently stabilize the particles and preventing the coating from slipping away.
2. Virus Adsorption
There is an enormous amount of research in the development of compounds that can prevent the virus from adhering to cells that are susceptible. For HIV that binds with CD4 receptors, peptides that are short have been created to correspond with the sequence of receptor binding site on the CD4 molecule, as well as the binding protein Gp120. These peptides will hinder the interaction between the receptor region with Gp120, without affecting other receptor functions of CD4.
Maraviroc, the anti-HIV drug, acts as an inhibitor of entry. The Chemokine receptor CCR5 is a crucial co-receptor of the majority of HIV strains. Maraviroc is a receptor that binds to CCR5 which blocks HIV’s HIV Gp120 protein from joining with the receptor in cellular cells and makes it ineffective to be absorbed by human macrophages and T cells. Since HIV may also utilize other coreceptors like CXCR4 and CXCR4, the HIV tropism test like trofile tests must be conducted to determine if the drug is efficient.
3. Virus entry and uncoating
The influenza virus and certain flaviviruses are introduced via viropexis or the engulfment. Then, immediately after, in a cytoplasmic endocyst (vacuole) it initiates fusion between the virus’s lipid-rich membrane and the vacuole’s intracellular membrane.
The process is controlled by an amino acids, or by one of glycoproteins that the virus produces. A substance that disrupts the process of fusion could stop replication in this early stage. If it is influenza A the fusion sequence of the HA molecules is only able to act in response to a structural three dimension rearrangement of the HA molecules.
The major change, which causes the HA trimer expands as if it were the petals of a flower is likely to occur only at a lower pH5.5 that is found in lysosomal vacuoles. Amantidine is believed to block the replication of influenza A by increasing the pH in the vacuole’s cytoplasm, which prevents virus-induced fusion, and thus preventing the virus from dissolving.
Other enveloped viruses, like paramyxoviruses as well as HIV can enter cells via virus-induced fusion with plasma membrane of cells. It is possible that this “fusion from without” may be susceptible to peptides with short chains that could act on the fusion sequence in extracellular ways.
The majority of antiviral medications are currently in use because they block the transcription or replication in viral nucleic acids.
- Herpes DNA inhibitors Polymerase – is by far, the most palatable drug for antiviral therapy is the DNA polymerase of herpes simplex. The most efficient antiviral substance that has been developed is acyclovir, which blocks the functions in this enzyme. The most effective antiviral drug must (1) be absorbed only by cells infected with the virus (2) the inhibitory molecule has to be created in the cell that is affected by enzyme activity (3) The inhibitor must be able to exert a specific impact on the virus enzyme. Acyclovir exhibits all of the above properties.
- Inhibitors of the reverse transcriptase in viral DNA – AZT and many other compounds function in the role of chain terminators. The triphosphate of AZT is able to bind to and blocks viral RT better than standard DNA polymerases within cells and an antiviral specificity can be obtained. However, it is not as effective as Acyclovir with regard to the antiviral properties. This can be seen in the toxic effects caused by AZT in clinical use. The cell-mediated toxicity can be explained in part due to the normal cell enzymes phosphorylate AZT , and are therefore activated in infected and non-infected cells.
It could be possible to alter the viral mRNA. Small anti-sense oligonucleotides are created that are compatible with specific genes, for example, that of the rev gene. Fomivirsen (Vitravene) is an anti-sense oligonucleotide with 21 bases that is that is compatible with the early region two mRNAs of CMV. It is approved for regional treatment of CMV Retinitis for AIDS patients.
HIV protease is essential for the cleavage of gag-pol protein fusion. The inhibitors of this enzyme could cause blockage of the assembly of HIV.
Acyclovir is an analogue of synthetic guanine nucleoside. The first phase of phoshorylation ACV monophosphate is executed by virus-specific thymidine Kinase, rather than the cellular Kinases. Monophosphate is unable to escape from the infected cells and the non-phosphorylated compound is able to replenish the loss of intracellular concentration and then it’s converted into the monophosphate.
This way this way, the drug builds up in the cells infected with herpes rather than in uninfected counterparts. Monophosphate is then transformed into di – and tri-phosphate forms via cells’ enzymes. ACV triphosphate, the most pharmacologically active version that the medication. It blocks herpes DNA polymerase but has little impact on the host cell DNA polymerase.
It also has a chain termination activities, which means that it acts as an “suicide inhibitor” Acyclovir resistant strains of HSV contain variants of either the viral thymidine or thymidine kinase gene or the DNA polymerase of the virus. Acyclovir is also antiviral properties against other herpesviruses, such as VZV CMV, VZV, and EBV however the mechanism isn’t as well understood in these instances. Forscarnet is the drug of choice for the treatment of acyclovir resistant strains.
Valacylovir is an ester of acyclovir which is well-absorbed. Its bioavailability is 2-5* more than that of acyclovir. It is employed for the treatment and control of genital herpes.
Famiciclovir is the prodrug for penciclovir, which is the active version and an analog to guanosine. It has a high bioavailability of 77 percent. It is converted to penciclovir in a two step process. The first step takes place in the gut, and the second one is occurs in the liver. It has a prolonged half-life within the gut. It has a greater affinity for HSV Thymidine kinase over acyclovir however, it has a lower affinity to HSV DNA polymerase than Acyclovir.
It is an inhibitor of the viral DNA polymerase enzyme and is also chain terminator. Presently, famciclovir is approved for treatment of shingles. The dosage is 250mg TDS. It is also used in the treatment and prevention of genital herpes infections.
Ganciclovir is a guanine-based nucleoside chemically connected to Acyclovir. It functions as chain terminator and then the termination of viral DNA replication. Its active version is believed to be triphosphate. CMV doesn’t specify TK as the first phosphorylation process of ganciclovir is believed to be controlled by other enzymes in the cell.
Ganciclovir is an extremely potent in vitro action against all herpesviruses, which includes CMV. It is also active in other DNA virus, such as adenovirus and vaccinia. Ganciclovir is more effective against CMV than Acyclovir. Ganciclovir has been proven to be beneficial for treating serious CMV infections in immunocompromised patients particularly when combined with immuneglobulin that is hyperimmune. Reversible neutropenia is one of the most frequently reported adverse reaction.
Ganciclovir resistance is documented in patients with immunocompromised conditions receiving treatment for CMV disease. This is thought to be caused by the lack of the drug’s phosphorylation process through CMV affected cells. A recent study conducted in a prospective manner found that 8percent of patients who received ganciclovir over a period of more than three months were diagnosed with resistant CMV.
Ribavirin is an artificial triazole nucleoside, and the active form is called ribavirin triphosphate. It isn’t incorporated into the basic DNA or RNA structure during the cellular process of synthesizing nucleic acid. In the instance of influenza viruses, it blocks the 5′ caps that are found on viral mRNAs.
It’s also been proven to block the influenza viral RNA polymerase. It is further believed that ribavirin triphosphate interferes with various steps of viral replication and could be the reason for the inability to identify virus strains that are not resistant to ribavirin.
Ribavirin has been found to be effective against DNA and RNA viruses within infected cells. It was found to be active against adenoviruses Herpesviruses, herpesviruses, CMV. vaccinia. influenza A and B, parainfluenza 1, 2, 3, measles, mumps, RSV, rhinovirus. Ribavirin is a significant contribution to the treatment of children who are infected by RSV that is administered as an aerosol during hospitalization.
It has also been proven effectiveness against both influenza B. It is also reported to be useful for treating Lassa fever Hantavirus disease, hepatitis C.
6. Zidovudine (AZT)
AZT is a synthetic analog of the chemical thymidine. It requires conversion into the triphosphate form via cells’ enzymes. It blocks viral reverse transcriptase through acting as a chain termination agent. The reverse transcriptase of viral origin can be 100-fold more vulnerable for inhibition via zidovudine triphosphate compared to host cell DNA polymerase.
When the virus is incorporated into its DNA chain, the synthesis of viral DNA ceases as no further phosphodiester bonds are formed. AZT is effective in vitro against a variety of retroviruses in the human body, including HTLV-I as well as HIV. The current indication for AZT is the treatment of patients with HIV infection that have diminished immunity. (T4 count of cells is 400-500 or less) It has been proven to prolong the life of patients suffering from HIV. It has also been proven to benefit patients who are not suffering from symptoms, however this is not a consensus.
Lamivudine is a potent inhibitor of reverse transcriptase. It is typically well tolerated by patients. It’s now often an integral part of the therapy combination of HIV patients. Recently, it was approved to treat chronic Hepatitis B.
Forscarnet is a pyrophosphate-based analog and, unlike nucleoside analogs forscarnet doesn’t need to activate cell or viral Kinases. Forscarnet binds directly on the pyrophoshate binding sites of DNA polymerases and RNA.
Forscarnet is difficult to administer since it needs to be administered continuously via intravenously using an infusion pump. It is employed to treat CMV retinitis among AIDS patients who are receiving AZT therapy, because it doesn’t have any overlap adverse effects with AZT. It is also used for treating AZT resistive HSV infections. Its most significant adverse effect is on renal function.
The compound blocks the growth of influenza viruses the culture of cells as well as in experiments with animals. Amantidine is effective only against influenza A and some naturally produced forms of the influenza A are not affected by it. The mechanism by which amantidine works amantadine isn’t understood. It is believed to work in the form of uncoating virus.
The drug has been proven to have beneficial and therapeutic effects. Amantidine significantly decreased the time of the fever (51 hours, compared the 74-hour duration) and also illness. The drug also gave 70 percent protection against influenza A when it was administered as a prophylactic.
Amantidine may trigger mild neurological symptoms, such as anxiety, insomnia, and mental confusion. But, these symptoms rapidly develop in those who are susceptible and disappear when treatment is removed. The therapeutic and prophylactic action of amantidine is currently widely recognized and a variety of analogues of the compound have been created.
Rimantadine isn’t as efficient as amantadine, but it is less harmful. One reason that hinders the effectiveness of amantidine and rimantidine is their rapid development of resistance to their molecules, which is seen in about 30 percent of patients. These mutants that are resistant are believed to be just as susceptible to being infecting others and causing illness as wild viruses.
An empirical approach to drug development can lead to development of several powerful inhibitors for influenza neuraminidase. Of these, two are oseltamivir and zanamivir. They are approved for treatment of influenza A and B.
Clinical trials have shown that both drugs have shown efficacy, with no adverse consequences. Because of its insufficient bioavailability, Zanamivir must be given via inhalation, while oseltamivir can be administered orally. Because the development of drug-resistant mutants characterised through changes to NA is a process that requires a long time in tissue culture, the development of zanamivir-resistant virus is not likely to be a common occurrence in patients.
The information available suggests that mutants could be less stable in the vivo. The impact of these changes on the hemagglutinin receptor is still to be assessed. Overall , the NA class of anti-influenza medications has shown great promise. resistant variants are not found often and could result in biologically crippling.
Immunoglobulins are offered in three forms: intramuscular, IVIG and hyperimmuneglobulins to fight specific virus. Immunoglobulins have more efficacy when they are used for prevention rather than therapeutically.
At present, HNIG is used primarily to prevent the hepatitis A. HNIG can also be administered to non- measles-infected contacts. Hyperimmune globulins can be used in the prevention of postexposure the hepatitis B as well as chickenpox and rabies. They also have been utilized in the treatment of Arenavirus infections, Crimean-Congo haemorrhagic Fever along with Rift valley fever. CMV Ig is prescribed as a preventative treatment to renal recipients who are seronegative from donors with seropositive status.
The application for prophylactic CMV Ig within BMT patients is not a consensus. CMV IVIG is used in conjunction with ganciclovir in therapy of pneumonitis caused by CMV. IVIG is also employed for the treatment of chronic enteroviral meningoencephalitis among children suffering from agammablobinaemia.
Anti-HIV Therapy Introduction
The massive amount of money that been devoted to HIV research led to the development of a vast amount of anti-HIV medications. The rapid pace of progress in this area is unparalleled in the time of medicine and is among the most significant achievements. As of today, with the right treatment, there is absolutely no reason to believe that HIV-infected people cannot enjoy the same life expectancy as a healthy person.
Treatment for HIV is complicated due to due to the fact that HIV genome is integrated into the genome of the host cell and is able to remain in a dormant condition for long periods of time before it is activated. While it might not be feasible to remove the virus completely it is possible that the disease could be kept indefinitely under control to ensure that the person suffering from HIV is likely to die from HIV disease, rather than because of it.
Zidovudine (AZT) was first antiviral medication that was used to treat HIV and was approved in 1987. However, it was evident in the Concorde research in the year 1994, that monotherapy using AZT didn’t provide lasting efficacy and barely made a difference in the rate of mortality. In 1995, the findings from studies like the European DELTA and the American ACTG 175 studies became available and demonstrated that the combination therapy of two nucleoside analogs was more effective than monotherapy using one.
Another breakthrough was the development of HIV protease inhibitors that were specifically designed to combat HIV protease. They have been shown to have the greatest effective HIV-related effect currently available. An early clinical study revealed that the use of oral ritonavir reduced HIV deaths from 38 percent to 22 percent. Combination therapy, also known by the name of HAART (highly actively antiretroviral treatment) with three or more agents was introduced.
The reason for this strategy can be derived from the idea that by using medications that are synergistic, cross-resistant and with no overlapping toxicities It is possible to lower toxicity, enhance effectiveness and stop resistance from developing. The ultimate breakthrough came in 1996 when David HO (Time Magazine Man of the Year 1996) finally identified the causes of HIV the disease.
He proved that, instead of being latent in”latent phase “latent phase” as previously believed, there is huge replication in this time. David Ho had coined the phrase “hit hard and early”. The result of this new method were evident quickly. within four years, from 1994 to 1998 the rate in AIDS in Europe dropped to 30.7 from 30.7 to 2.5/100 year-olds i.e. to less than 10 percent.
Less hopeful is the chance of eliminating HIV out of the human body i.e. complete cure. At first it was believed that continuous treatment for three years is sufficient to eliminate all remaining cancerous cells that were not yet infected. However, the duration of treatment needed to be kept being adjusted upwards as more research came into existence. The most recent estimate of elimination of all cells that are latently infected has been 73.3 years.
It is therefore evident that it’s not feasible to attain a complete cure in the near term. It is important to be able to comply when treatment is to last for a lifetime. There is a clear necessity to develop formulations in which the number of tablets that must be consumed daily is reduced to an absolute minimal amount. The development of adverse effects with the long-term use of the drug is another problem.
As the scientific community gains knowledge about the dangers and effectiveness of various regimens and drugs the recommendations for HIV are continually updated. Therefore rather than “hit hard and early” it is now a shift to “hit hard, but only when necessary”. There’s much debate over the best time to begin therapy.
Two criteria are employed to determine if it is time to begin HIV treatment: CD4 counts and viral load. There is general agreement that HIV therapy should begin whenever you’re CD4 count is lower than 200. Certain experts suggest treatment for anyone who’s CD4 count is lower than 350. It isn’t as clear for patients who have CD4 counts of 300-500 , and moderate viral loads. The decision to begin treatment must be made in a private manner with the patient after a lengthy discussions and counselling.
A. Nucleoside Reverse Transcriptase Inhibitor
- Zidovudine (Retrovir, AZT)
- Didanosine (Videx, Videx EC, ddI)
- Stavudine (Zerit, d4T)
- Lamivudine (Epivir, 3TC)
- Abacavir (Ziagen, ABC)
- Tenofovir, a nucleotide analog (Viread, TDF)
- Combivir (combination of zidovudine and lamivudine)
- Trizivir (combination of zidovudine, lamivudine and abacavir)
- Emtricitabine (Emtriva, FTC)
- Truvada (combination of emtricitabine and tenofovir)
- Epzicom (combination of abacavir and lamivudine)
B. Non-Nucleoside Reverse Transcriptase Inhibitor
- Nevirapine (Viramune, NVP)
- Delavirdine (Rescriptor, DLV)
- Efavirenz (Sustiva or Stocrin, EFV, also part of Atripla)
- Etravirine (Intelence, ETR)
- Rilpivirine (Edurant, RPV, also part of Complera or Epivlera).
C. HIV Protease Inhibitors
- Saquinavir (Invirase, SQV)
- Indinavir (Crixivan, IDV)
- Ritonavir (Norvir, RTV)
- Nelfinavir (Viracept, NFV)
- Amprenavir (Agenerase, APV)
- Lopinavir/ritonavir (Kaletra or Aluvia, LPV/RTV)
- Atazanavir (Reyataz, ATZ)
- Fosamprenavir (Lexiva, Telzir, FPV)
- Tipranavir (Aptivus, TPV)
- Darunavir (Prezista, DRV)
D. HIV Entry Inhibitors
- Enfuvirtide (Fuzeon, ENF, T-20)
- Maraviroc (Selzentry or Celsentri, MVC)
E. HIV integrase inhibitors
- Raltegravir (Isentress, RAL)
- Elvitegravir (EVG, part of the combination Stribild)
- Dolutegravir (Tivicay, DTG)
There are a number of combination preparations on the market e.g. CBV (AZT+3TC), TZV (AZT+3TC+ABC), TVD (FTC+TDF), Kaletra (Lopinavir/ritonavir). The use of combination preparations will reduce the numbed of tablets that need to be taken each time.
Monitoring anti-HIV therapy
a. Viral Load
- Initiation: Initiation of a viral load is the most commonly used method for monitoring treatment. There must be more than one log decrease in viral burden at least 10,000 copies per milliliter of HIV-RNA within the first 2 to 4 weeks following the start of treatment. If there is <0.5 percent reduction of viral load, or HIV-RNA, remains over 100,000, the treatment plan should be adjusted either adding or switching medications.
- Monitoring: measurement of viral load is recommended every 4-6 months, if the patient’s condition is stable. If the level of viral load increases to 0.3-0.5 log of levels prior to treatment and the treatment is not working anymore and the treatment should be modified.
b. CD4 count
- Initialization: within 2-4 weeks after starting the treatment CD4 number should be up by at minimum 30 cells/mm3. If this isn’t the case The treatment should be modified.
- Monitoring: The monitoring of CD4 count should be checked every 3 to 6 months during periods of stability in clinical conditions and more often if symptoms of disease develop. If CD4 count falls below level of baseline (or less than 50% growth from pre-treatment) and the treatment must be altered.
c. Anti-HIV Drug Resistance Testing
Testing for resistance to antiretroviral drugs is now a part of managing patients throughout N. America and W. Europe. Many studies on treatment-experienced patients have demonstrated strong correlations with the presence of drug resistance and inability of an treatment regimen for antiretroviral to reduce HIV replication.
- Genotypic Assays: Genotypic assays find mutations in the drug resistance gene found in pertinent viral gene (i.e. the protease and RT genes). Certain genotyping tests require analysis of the complete RT and protease gene, other methods employ the oligonucleotide probe to find specific mutations known to confer resistance to drugs. Genotyping tests can be conducted fairly quickly, so that results are available within a couple of weeks after sampling. Interpretation of the results from tests is dependent on understanding the variety of mutations that are screened for by different antiretroviral medications as well as the possibility of cross-resistance to other medications resulting from the mutations.
- Phenotypic Assays: phenotypic tests test the capacity of viruses to develop in different dosages of antiretroviral medication. Automated, recombinant phenotyping tests are now available commercially with turnaround times of 2-4 weeks, however the phenotyping tests are typically more expensive to conduct in comparison to genotypic assays. Recombinant phenotyping test involves the introduction of RT or protease genes that are derived from plasma of patients HIV the RNA into a lab replica of HIV. The replication of the recombinant virus at different drug concentrations is monitored via the expression by a gene called a reporter. The result is compared to replication of an unrelated version of HIV. The levels of the drugs that block 50 percent and 90% in viral replication (i.e. those with IC50 or IC90) are calculated. The percentage of the IC50s of both the tests and the reference virus is identified as the percentage increase in IC50 or the fold resistance. The interpretation of the phenotyping results can be complicated due to the lack of information on the precise degree of resistance (fold increase in the IC50) which is associated with the failure of various medications.
- In clinical settings, resistance tests can be beneficial in the event of the occurrence of virological failure in antiretroviral therapy. Recent research-based evidence support the application of resistance tests in clinical practice are derived from studies in which the efficacy of tests for resistance were evaluated in the case of the virological failing. In the VIRADAPT AND GART studies examined the virological response to treatment regimens that included antiretroviral therapy in the case of genotyping tests used to guide treatment and those that were observed when treatment changes were solely based on the clinical judgement. The findings of both studies showed that the virological response to treatment was significantly greater when the results of tests for resistance were made available. In addition, a recent multicenter, prospective, randomized study has demonstrated that treatment that is selected based on the phenotypic test for resistance significantly enhances the antiretroviral virological response treatment, when compared to therapy that is not based on tests for phenotypes. Therefore, resistance testing is believed to be an effective tool for determining active medications when switching antiretroviral regimens as a result of an underlying virological problem.
The speed at which developments are made in anti-HIV therapies means it is nearly impossible for this website to keep up to date. For the most current information on HIV and anti-retroviral treatment I would recommend the HIV page on Medscape.com
- There are three types of interferons: Alpha beta, gamma and alpha.
- Interferon-a is present in at least 15 subtypes, and the genes that are associated with it show 85percent homology. IFN b1 exhibits 30% homology to IFNa.
- IFNb2 is now referred to as IFN-6. It has no homology to alpha or B1 types.
- IFN Gamma is an inflammatory lymphokine, and has no similarity to the other types.
- IFNs are responsible for their actions by activating specific receptors that are activated at hormone-like levels. Interferon-inducible response elements within the genome of cells are activated.
- There are two main kinds of IFN receptors. One is for beta1 and alpha, and another for the gamma.
- IFNs are released from different cell types as a response to viral infection Endotoxin, dsRNA, stimuli that are mitogenic or antigenic.
- DsRNA is believed to be an especially significant inducer. Most often, the best IFN inducers are those which are slow to multiply and do not hinder the production of host protein quickly or cause significant damage to the cells.
- IFN is typically measured by analyzing its impact on the multiplicity of a test virus typically vesicular stomatitis virus one of the rhabdoviruses.
- Viral strains that can produce high IFN production cause autointerference during endpoint assays. In general IFN Gamma is different from others because it’s released in the form of a lymphokine in activated T-cells , and sometimes from macrophages.
Mechanism of Action of Interferons
The antiviral benefits of IFNs are achieved through multiple channels;
- The increased production of both Class I and Class II MHC glycoproteins, thus facilitating the recognition of antigens of viruses by the immune system.
- Immunoregulatory effects – activation cells that can kill virus-infected cells; these include NK macrophages and NK. IFNs may be responsible for an evolution from the humoral immune system to the cellular.
- Direct suppression of viral replication various mechanisms are involved in the third path.
- Production of specific inhibitory proteins such as. the Mx protein, which is known for its anti-influenza effects. It is possible that additional specifically inhibitory proteins are likely to be discovered.
- the inhibition of viral processes, such as budding, penetration, uncoating and even budding from infected cells has been observed.
- in vitro tests using extracts from IFN-treated cells demonstrate that the principal objective of IFN actions is translation which is blocked by two mechanisms, both of which require the presence of small quantities of dsRNA.
- The activation process of the dsRNA dependent Kinase. This phosphorylates and deactivates the eIF-2 transcription initiation factor. The phosphorylation freezes the beginning complex that is formed by eIF-2, GTP, met-tRNAf and the small ribosomal ribosomal component and the mRNA. Since eIF-2 is not able to be recycled the protein synthesis process is slowed or is stopped.
- The activation process of the 2-5 oligo A synthetases (r) synthesizing 2-5A (r) activates endonuclease (itself activated via IFN) (r) destruction of the mRNA (r) inhibiting the synthesis of proteins.
The combination of cell-growth reduction and the increase of CMI is the reason for the antitumour properties of IFN.
Protective role in virus infections
The protective function that is a protective function IFN on animals has been suggested through a variety of studies;
- In mice recovering from the influenza virus infection, the level of IFN is highest at the time that the virus’s is beginning to diminish and before an increase in Abs is detected. In this phase IFN levels are high enough to ensure that the IFN amount of the mouse is adequate to safeguard them from the deadly effects of togavirus.
- A powerful antiserum to IFN significantly increases the severity of the mouse hepatitis viral infection.
- Suckling mice that can be susceptible to the coxsackievirus produce tiny amounts of IFN as a response this virus however adult mice, who are immune to the virus, produce huge quantities.
These studies indicate that IFN is a key protective function in at the very least certain viral infections. The dynamics of the illness.
Possible therapeutic use of Interferons
Clinically, a highly effective anti-infective has been proven against rhinovirus infections of human volunteers, which resulted in reduced incidence of infection as well as decrease in symptoms. Contacts with patients who are infected are protected with an intranasal sprays with large amounts of IFN. Additionally, it reduces CMV activation in patients with seropositive status receiving kidney transplants.
IFNs may theoretically be excellent antiviral agents since they can be effective against a wide range of viruses and exhibit high activity. However, their effectiveness is limited by several reasons: IFNs work only for a short time and do not affect the process of synthesis of viruses that has already been started within a cell. Furthermore, in high doses they can cause serious adverse impacts on host.
Exogenous IFN to treat human viral illnesses have not had much success. IFN-a has a prophylactic effect against influenza in the course of epidemics. Local administration reduces the pain and severity of respiratory ailments, IFN had also reported to be effective in treating genital warts , as well as the juvenile laryngeal-papillomatosis. Recently, synthetic alpha interferon was approved to treat of the hepatitis B carriers. It is also used in the treatment of the hepatitis C carriers suffering from chronic active Hepatitis.
Interferon Therapy for Chronic HBV Carriers
It is thought that chronic transmission in HBV is due to the lack of production of interferon as well as the inability of the body to react to interferon in the event in chronic HBV infection. Two forms of interferons are available at present such as Alpha-Interfron (Intron A) and Peginterferon (Pegasys).
In early clinical trials interferon therapy has been linked to HBeAg loss in between 30 and 40 percent of patients. in about 10%, patients have lost HbsAg in total. If a patient experiences HBeAg during treatment, the loss of HBsAg is a result of therapy in about 80percent of patients who were that are followed for more than a decade. Additionally, increased survival, non-complication-free survival as well as a decrease in prevalence of hepatocellular carcinoma have been observed in patients who have responded to interferon.
The treatment of interferon is most efficient in patients who have low levels of HBV DNA with 100,000 to 40 million copies per milliliter and elevated ALT (esp when it is greater than 200 IU/mL) as well as immunocompromised patients and healthy liver functions (albumin, the bilirubin, and coagulation) as well as the acquisition of infection later in life. The first studies suggested that the effectiveness of interferon was not as high for patients suffering from pre-core-mutant HBV disease (HBeAg positive strains) however, recent findings have prompted renewed interest in interferon therapy for this reason. Recent research regarding PEG interferon might lead to the first-line usage of PEG products as a stand-alone or in conjunction with oral drugs.
Interferon, however, requires inconvenient injection therapy, comes with numerous adverse negative effects, and is not more effective than lamivudine when it comes to seroconversion eAg. It is also of only a small amount of value for certain subgroups, but it is the only treatment which offers the possibility of an all-encompassing cure.
- Interferon Alpha (Intron A) is administered by injection several times per week for 6 months to 1 year or more frequently. The drug may cause adverse effects like depression, flu-like symptoms and headaches. It was approved in 1991 and is it is available to children as well as adults.
- Pegylated Interferon (Pegasys) Peginterferon an altered form of interferon which has been accepted for treatment of HBV as well as HCV. It has a comparable but more complex chemical structure to interferon-alpha. This enhances the efficacy of the drug to the point it can only be administered weekly and usually lasts for six months or one year. The drug could cause side reactions like flu-like symptoms, depression, and other mental health issues. It was approved for adult use in May 2005.
Interferon therapy of Hepatitis C Carriers
The early studies have shown that ribavirin and interferon are effective in the treatment of chronic and acute Hepatitis C. Combining interferon and the ribavirin combination could prove effective. There is more evidence in using interferon in the treatment of Hepatitis C.
The current advice is that interferon treatment could be considered for patients suffering from chronic active liver disease that are susceptible to progressing to cirrhosis or HCC. The recommended dosage is 3 MU of tds in sc or im for six months. The rate of response is approximately 50 percent. However, about 50% of those who have responded are relapsed after stopping treatment.
Presently, it’s not known what factors influence the effectiveness of interferon therapy. There are some evidence to suggest that patients who are older and those who have cirrhosis that is established react less effectively. There is increasing evidence that the genotype of the HCV that is infecting affects the response to IFN. Many patients who respond will see a dramatic reductions in SGPT level within the first two months of treatment with interferon.
You can consider a higher dose like five or 10 milligrams for non-responders, but it isn’t certain if the higher doses are effective. Presently, it’s not known what factors are the most likely to cause the possibility of relapse following treatment. If someone relapses after treatment, they could receive a second course followed by maintenance treatment for six up to twelve months.
There is evidence that the combination of interferon and ribavirin can be superior to interferon on its own. In actual fact, a drug preparation that combines both of these agents is available to aid in this. It’s now routine to check for the HCV genotype prior to the start of the Interferon/Ribavirin treatment. Types 1 and 4 have an unfavorable prognosis as well as a lower treatment response. Typically, these patients receive treatment for 48 weeks rather than 24 weeks for the other genotypes.