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General Virology (contin.) CLASSIFICATION OF VIRUSES Virus classification according to envelope 1. Enveloped viruses: Enveloped DNA viruses, e.g. Herpes viruses Enveloped RNA viruses, e.g. Togaviruses 2. Non-enveloped viruses: Non-enveloped DNA viruses, e.g. Adenoviruses Non-enveloped RNA viruses, e.g. Picornaviruses All RNA viruses are enveloped except: picornaviruses, reoviruses and caliciviruses. All DNA viruses are enveloped except: Adenoviruses, human papilloma viruses and parvoviruses. : Virus classification according to the genome 1. DNA viruses: Enveloped-DNA viruses: e.g. Herpes viruses, Poxviruses and Hepadnaviruses. Non-enveloped DNA viruses: e.g. Adenoviruses, Parvoviruses, and Papillomaviruses. 2. RNA viruses: Enveloped RNA viruses:e.g. Myxoviruses, Rhabdoviruses, Togaviruses, Arboviruses, Retroviruses and Coronaviruses Non-enveloped RNA viruses: e.g. Reoviruses Virus classification according to host 1. Human: e.g.Varicella zoster. 2. Arthropod: e.g.Yellow fever virus. 3. Animal: e.g. Rabies virus. 4. Plants: e.g.Tobacco mosaic virus Virus classification according to disease produced by the virus 1. Respiratory viruses 2. Enteric viruses 3. Hepatitis viruses VIRAL REPLICATION Viruses are metabolically inert, so they are obligate intracellular parasites replicating only inside living cells. Virus Replication Cycle It can be divided into the following stages: 1. Attachment 2. Penetration 3. Uncoating 4. Transcription 5. Translation 6. Assembly 7. Release Virus growth cycle 1. Attachment: This is a specific interaction where the virus attaches by viral surface proteins to specific receptors on the host cell plasma membrane e.g. human immunodeficiency virus attaches to CD4 receptors. 2. Penetration: The entire virus (or sometimes only the genome) enters the cell by two ways: Endocytosis: the cell membrane invaginates around the adsorbed virus particle. Fusion may occur between the viral envelope and host cell membrane releasing the naked nucleocapsid into the host cell cytoplasm. 3. Uncoating: The protein coat of the virus is removed. This is mainly carried out by host cell enzymes contained in lysozymes. 4. Transcription: Production of virus mRNA occurs using the virus genome as a template. In positive sense RNA viruses the genome itself acts as mRNA. 5. Translation: Virus mRNA attaches to the host ribosomes and directs the synthesis of virus-specific proteins. This period of synthetic activity (synthesis of viral nucleic acid and proteins) is called the eclipse period because no viral particles are detected inside the host cell. 6. Assembly: Newly synthesized nucleic acid molecules and structural proteins assemble to form particles of the new virus progeny. 7. Release: The new particles are released from the cell by one of two ways: Budding: a gradual process of extrusion through the cell membrane. Viruses released by budding are enveloped viruses. Rupture of the host cell (cytolysis): usually occurs in non enveloped viruses. ANTIVIRAL CHEMOTHERAPY Limitations Because viruses are obligate intracellular parasites, antiviral agents must be capable of selectively inhibiting viral functions without damaging the host. This makes the development of such drugs very difficult. Another limitation is that many rounds of virus replication will have occurred during the incubation period and the virus will have therefore spread before symptoms appear, making a drug relatively ineffective. Sites of action of major antiviral drugs The Mechanisms of Action of Antiviral Drugs I-Inhibition of Attachment and Uncoating of the Virus A. Fusion Inhibitor It blocks the virus and cellular membrane fusion step e.g. Fuzeon used in human immunodeficiency virus (HIV) infection. B. Inhibitors of Uncoating Amantadine and Rimantadine: specifically inhibit influenza A viruses by blocking viral uncoating. They must be administered prophylactically to have a significant protective effect. II- Inhibition of Nucleic Acid Synthesis A. Agents that inhibit polymerase These are nucleoside-like molecules that inhibit DNA or RNA polymerases. Examples: Acyclovir: It acts on virus encoded DNA polymerase. It is effective against Herpes simplex virus (HSV) and varicella-zoster virus (VZV). It is only activated in viral infected cells because the viral thymidine kinase is required to activate the drug by placing the first phosphate on the drug. Ganciclovir: A derivative of acyclovir and it is effective in infections caused by Cytomegalovirus (CMV). B. Reverse Transcriptase Inhibitors i.Nucleoside analogues Examples: 1- Azidothymidine (AZT): It inhibits HIV replication by blocking synthesis of proviral DNA. 2-Dideoxyinosine (DDI): It also inhibits HIV as AZT, but it is less toxic. 3- Lamivudine: Used in treatment of HIV and HBV infections. ii.Non-nucleoside analogues They act by binding directly to reverse transcriptase (RT). Nevirapine: effective against HIV. C. Drugs interfering with mRNA synthesis Ribavirin: Effective against DNA and RNA viruses. It is used in treatment of HCV and respiratory syncytial virus (RSV). D. Interferons Synthetic interferons are now available and are prepared by recombinant technology (e.g. alpha interferon used in chronic hepatitis C). III- Inhibition of Cleavage of Precursor Polypeptides Such drugs inhibit the viral protease that is required at the late stage of the replicative cycle to form the mature virion. Inhibition of the protease yields noninfectious viral particles e.g. saquinavir and indinavir which inhibit proteases encoded by HIV. IV- Inhibition of Release of Virus Neuraminidase Inhibitors These drugs are effective against both influenza A & B viruses. They act by inhibiting the release of virus from infected cells. This limits the infection by reducing the spread of the virus from one cell to another. Two drugs are available which are given either by inhalation or orally (Oseltamivir & Zanamavir). Thank You