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College of Medicine Microbiology Medical Virology Control on viral infections: Dr. Jawad K. AL-Khafaji ----------------------------------------------------------------------------Control on viral infections and diseases by the following main methods: 1. 2. 3. 4. Host defenses. Viral vaccines. Antiviral chemotherapy. Public hygiene (include personal and community). 1-Host defenses: Host defenses against viruses fall into two major categories: 1. Non specific defenses (innate immunity) , of which the most important are anatomic barriers, interferon (IFN) and natural killer(NK)cells. 2. Specific defenses(acquired immunity), including both humoral and cellular immunity . A-Non specific host defenses: 1. Anatomic barriers : Anatomic barriers are located at body surface (skin and mucosa) or within the body (endothelial cell). They are partly effective in preventing viral infection. 2. Interferon : Interferon is glycoprotein produced by any type of cell (all vertebrate species) after viral infection . Interferons are produced from infected cell with virus to protect other cells from viral infection. Interferon does not protect the virus-infected cell that is produce it. Interferons are divided into three types based on the cell of origin: 1. IFN-alpha is produced by leukocytes. 2. IFN-beta is produced by fibroblasts. 3. IFN-gamma is produced by lymphocytes . •IFN-alpha and beta are induced by viruses , whereas IFN-gamma is not produced in response to most viruses but is induced by mitogen stimulation. The induction of IFN is not specific to any virus. •Action of IFN: IFN inhibits replication of widely viruses range. IFN don’t interact directly with virus but move to other cells , and bind to receptor on cell surface which induces the cells to activate specific 1 signals for synthesis of antiviral proteins (AVP)that are usually result in an inhibit viral replication. IFN inhibit the growth of virus by blocking the translation of viral mRNA into proteins without affecting the translation of cellular mRNA. 3. NK cells and phagocytosis : NK cells are important parts of the innate defenses against virus-infected cells. They kill virus-infected cells by secreting some enzymes, which cause death of the infected cells. Viruses may be phagocytosed by different PMN leukocytes and macrophages. The effect of phagocyosis may be virus inactivation ,and result in clearance of virus. 4. Inflammation and Fever: Inflammation inhibits viral replication through (i)elevated local temperature (ii)reduced oxygen tension (iii) metabolic alteration, and (iv)acid production. Fever may act in two ways(1)higher body temperature may inactivate the virus particle , particularly enveloped viruses , which are more heatsensitive than non enveloped viruses.(2)fever may inhibit replication of some viruses. B-Specific host defenses: Specific defenses, including both humoral and cell-mediated immunity (CMI). The most important type of host defense is acquired immunity, either actively acquired by exposure to the virus , or passively acquired by transfer of immune serum (such as : transfer of IgG from mother to fetus across placenta, or transfer of IgA from mother to newborn in the colostrums). The first exposure to virus stimulates the production of antibodies and activation of cytotoxic T-cell. The IgM and IgG confer protection against viruses that enter or are spread through the blood. Secretory IgA is important in protecting against infection by virus that enters through mucosa of respiratory and gastrointestinal tracts . How does Ab inhibit virus? Two main mechanisms for kill virus by antibodies: • First; neutralization of infectivity of virus by Abs binding to viral antigens(proteins on the surface of virus). This binding lead to prevent the interaction of virus with cellular receptor and inhibit viral replication . The Ab-coated virus is more rapidly phagocytized than normal virus. • Second; is lysis of virus-infected cell in presence of Ab and complement. Ab binds to virus antigens and then binds complement, which enzymatically degrades the cell membrane of virus-infected cell. 2 Because the cell is killed before yield of virus is produced, the spread of virus is significantly reduced. Action of cellular immunity : Lyses of virus-infected cell by cytotoxic Tcell. The T-cell recognizes viral antigens only when it is presented in association with classI MHC. They kill virus-infected cell by three methods : (1) releasing perforins ,which make holes in cell membrane of infected cell . (2) releasing proteolytic enzymes into infected cell, which degrade the contents of the cell. 2-Viral vaccines: Prevention of viral diseases can be achieved by use of vaccines that induce active immunity. Main types of viral vaccines are ; (i) attenuated live-virus vaccine, and (ii) killed-virus vaccine. Attenuated-virus vaccines: The vaccines contain live virus whose pathogenicity has been attenuated (weakened) .The pathogenicity of virus is attenuated either by serial passages in animals or by repeated subculturing in cell cultures. The live vaccine is preferred to vaccine containing killed virus because the live vaccine has several advantages. 1.The virus in such vaccine can be replicate in the host and tend to : (i)stimulate Ab production (IgG) in longer duration, and induce local Ab production(IgA) , therefore resistance at portal of entry. (ii)induce a good cell-mediated response, and stimulate cytotoxic T-cell. 2. In vaccination with live vaccines lead to herd immunity because the attenuated viruses can replicate in immunized persons and spread to other members of population, thereby increasing the number of people protected. Disadvantages of these vaccines ; (1) the attenuated virus has risk reversion , the virus can revert to virulence during vaccine preparation or in immunized person . For this reason, live vaccine should not be given to immunocompromised peoples or pregnant women because the fetus may become infected .(2) Interference may occur with other viruses result in contamination of vaccine during vaccine preparation. Killed-virus vaccines: The vaccines contain killed virus (killed by chemicals such as formalin or by UV radiation or by heating). 3 The killed vaccines have two advantages,(1) they can not revert to virulent, and(2) they are more heat-stable (at room temperature) , therefore can be used more easily ,especially in tropical climate. The vaccines have many disadvantages ; (1)cell-mediated immunity is poor and don’t stimulate cytotoxic T-cells because the virus in the vaccine does not replicate .(2) stimulate IgG and IgM in shorter duration, but do not induced local resistance (IgA) therefore not resistance at portal of entry. Because they induce shorter duration of Ab production are less protective. The immunity conferred is often brief, and must be boosted. (3)Some killed vaccines may induce hypersensitivity to subsequent infection. Most viral vaccines are usually given before exposure to viral infection (pre-exposure) except two vaccines , rabies and hepatitis-B vaccines are effective when given post-exposure because the incubation period of disease is long enough that the vaccine-induced immunity can prevent the disease. 3-Antiviral Chemotherapy: The viruses are unaffected by antibiotic agents but affected by antiviral chemotherapy agents and interferon . Number of antiviral drugs(AVD) is very few compared with large number of antibacterial drugs. The major reasons for these difference and limitation are due to some problems with viral chemotherapy: 1. All viruses are obligate intracellular parasites. 2. Obligatory dependence upon metabolic of host cell. Therefore , AVD interfere with cellular processes. Antiviral drugs are difficulty in obtaining selective toxicity against viruses without normal cell. 3. Some viruses become latent within host cells, and no antiviral drug can eradicate them. 4. Drug-viral mutants may occur in some viruses , and cause drugresistant viruses. Mode of action : Antiviral chemotherapy drugs are available to treat only a few viral diseases. Antiviral drugs (AVD) specifically inhibit one or more steps of viral replication , which act as target site for AVD. 1. Inhibition of early events of viral infection(attachment ,penetration, uncoating). 2. Inhibition of viral N.A replication . 3. Inhibition of viral proteins synthesis. 4. Inhibition of late events (assembly and release). 4 Inhibition of early events: Antiviral drugs inhibit early events of viral life cycle by removal of binding sites of viruses . Enfuvirtide(Fuseon) : The drug prevents viral infection by inhibiting attachment and penetration process. The drug is used to treat HIV infection. It binds to cellular receptor on cell surface , thereby blocking the entry of HIV into the cell. Amantadine(Symmetrel): It prevents viral infection by inhibiting uncoating of virus by blocking the ion-channel activity of matrix protein in the virion. The absorption(attachment) and penetration occur normally, but transcription of viral mRNA by RNA polymerase does not occur because uncoating can not occur. This drug specifically inhibits influenza A virus, but not inhibit influenza B and C. The main side effects of amantadine are CNS alteration such as dizziness, ataxia, and insomnia. Inhibition of viral N.A synthesis: A. Nucleoside inhibitors: Acyclovir(Zovirax) :Acyclovir is guanosine analogue that active against DNA polymerase of herpes simplex virus-1(HSV-1) and HSV-2,and Varicella-zoster virus(VZV) . Acyclovir must be activated within infected cell by virus-encoded thymidine kinases that phosphorylate the drug. The drug is not phosphorylated in uninfected cell, the cellular DNA synthesis is not inhibited .The drug binds to DNA polymerase, which lead to inhibit viral replication. Selective toxicity is high and there are very few adverse effects. Azidothymidine(AZT, zidovudine, Retrovir) : nucleoside analogue drug . It is particularly effective against DNA synthesis by inhibits DNA polymerase (reverse transcriptase )of HIV and inhibits growth of the virus. The main side effects of AZT are bone marrow suppression and myopathy. B. Non-Nucleoside inhibitors: Foscarnet(Foscavir):is pyrophosphate analogue . It binds to DNA polymerase at pyrophosphate cleavage site and prevents removal of phosphate from nucleoside triphosphate (dNTP). This inhibits the addition of next dNTP to growing DNA chain. Foscarnet inhibits DNA polymerase of all herpes viruses and HIV . It is also used to treat patient infected with acyclovir-resistant of HSV-1 and VZV. 5 Inhibition of viral protein synthesis: Fomivirsen(Vitravene): The drug binds to viral mRNA within infected cell and prevents it from being translated into viral proteins. This drug active in blocks the replication of cytomegaloviruses(CMV). Methisazone: specifically inhibits the protein synthesis of poxviruses by blocking the translation of viral mRNA. Interferon(IFN): Synthetic IFN is used in treatment of some viral viruses. Recombinant alpha-IFN is effective in treatment of patients with chronic HBV and HCV. IFN inhibits translation of viral mRNA into proteins. Inhibition of late events: Zanamivir (Relenza) and Oseltamivir (Tamiflu): These drugs inhibit neuraminidase enzyme . This enzyme is located on surface of the influenza virus and is required for release of the virus from infected cell. Inhibition of release of influenza virus limits the infection by reducing the spread of the virus from cell to another. These drugs are effective against both influenza A and B viruses. Also effective against strains of influenza virus resistant to amantadine. N.B Antibiotic agents are not effected on viruses , therefore it can not used in treatment of viral infection , but they used in cases of viral infections to prevent occurring any secondary infection with bacteria. 6