Lecture 10 VIROLOGY Assistant prof.dr. Baheeja A. alkhalidi

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1 Lecture 10 VIROLOGY Assistant prof.dr. Baheeja A. alkhalidi Viruses are microbes that REQUIRE a host cell to replicate. By themselves they cannot replicate. They border on the edge of living and non-living. Without a host cell, they cannot reproduce or do anything. With a host cell, they can make more of themselves. Viruses are composed of several components: 1) Nucleic Acid (either DNA or RNA) which holds the genetic information for the virus 2) A capsid (protein coat) to protect the nucleic acid 3) An envelope When a virus exits the cell, it does so by exocytosis in which the virus buds out through the plasma membrane and thus creates a surrounding bubble of plasma membrane 4) Spikes (outer surface projections) These are glycoproteins in the envelope that allow the virus to interact with a host cell and begin its entry (by receptor endocytosis) Viruses can infect animals, plants or bacteria (bacteriophage) Cell specificity: Just because a virus is near a cell, does not mean a virus can infect the cell. If it does not have the right type of receptor to interact with the spike, it will not enter. If it does not have the right cell machinery it will not infect. Host range is the types of cells inside an organism that a virus can infect. Host range also means what animals a virus can infect. Not all viruses can infect all animals. Classification: The old scheme was based on the host range. All neurotropic viruses are the same, all lung-tropic viruses are the same Tropism is where a virus can infect.

2 Now, classification is based on the genetic material (DNA or RNA) inside a virus. Viruses can have either RNA or DNA (but rarely both). It can be double stranded (ds) or single stranded (ss) Positive Stranded vs Negative stranded (+) RNA is like mrna: It can be directly translated to proteins (-) RNA is the reverse complement of mrna: It CANNOT be directly translated into proteins; it must be turned into a (+) RNA Naked versus Enveloped Naked: Just a protein coat around nucleic acid of the virus Enveloped: a sphere of plasma membrane surrounding the protein coat that is surrounding the nucleic acid of the virus. RNA families of viruses : Picorna Virus +RNA, naked Enteroviruses Polio virus: Caused severe paralysis due to nerve damage (Remember FDR, the president, he was in a wheel chair) Hepatovirus Hepatitis A: Causes liver damage. Hepatitis is a general term for Liver damage, thus each Hepatitis virus is in a different family Rhinovirus Causes the common cold, more than a 100 types Toga viruses +RNA, enveloped Rubella Common in children, MMR has stopped commonality in USA Flavi viruses +RNA, enveloped

3 Yellow fever Causes a hemorrhagic fever, which is uncontrolled bleeding Major problem in central America during panama canal Hepatitis C Causes severe liver damage and influences liver cancer Paramxyo viruses -RNA, enveloped Mumps, Measles gone in US due to MMR (measles mumps rubella vaccine for young children) Rhabdo viruses -RNA, enveloped, looks like a bullet Rabies is major disease Orthomyxo viruses -RNA, enveloped, has multiple segments of RNA (segmented genome) Influenza A different strains infect different animals and birds. Influenza B mainly infects humans Filo viruses -RNA, enveloped, long filaments Marburg and Ebola viruses are the only two members of this family Highly pathogenic hemorrhagic viruses (causes a lot of bleeding) Filo viruses can infect MANY cell types their receptor for the spikes are on many cells throughout the body and thus cause a lot of damage. Bunya virus -RNA, enveloped Hantavirus- causes hantavirus pulmonary syndrome (HPS). Arena viruses -RNA, enveloped Lassa fever and hemorrhagic fevers. Reo viruses dsrna, naked Rotaviruses cause severe diarrhea in infants and young children

4 DNA Families of viruses: Adeno viruses Linear dsdna Causes acute (quick) respiratory and other infections. Herpesviruses Large, linear dsdna characterized by Latency Herpes Simplex 1 Mouth Sores Herpes Simplex 2 Genital Sores Varicella Zoster Chicken Pox (varicella)and Shingls(zoster). Cytomegalovirus Dangerous for children at birth if mother is secreting virus from vagina during birth (birth defects). Roseolla virus causes roseolla (fever and rash)in children. Epstein-Barr virus cause of infectious mononucleosis, also linked with cancers such as Burkitt s lmphoma and Hodgkin s disease. Kaposi s Sarcoma Associated Virus cause of Kaposi s Sarcoma in AIDS patients and also causes other cancers in the elderly as well Poxviruses Large dsdna viruses Cause of Smallpox Smallpox is eradicated except for two vials in the world Vaccine was made from vaccinia, a virus that infected cows Vaccinia is also a pox virus Cause of Moscullum Contagium A relatively uncommon disease,, it presents as small raised white tissue on gentials, especially the penis and is especially common in AIDS patients Papova viruses Small dsdna Papilloma- common infection of woman (and men) but targets the cervix and vaginal walls and some papilloma strains are highly associated with cervical cancer. Vaccination against these cancerinducing strains can reduce the incidence of cervical cancer,other strains cause warts in humans. Polyoma viruses cause renal disease in immunodeficient.

5 Vacuolatis SV40 causes cancer in monkeys, used in research. Hepadna viruses ONLY member is Hepatitis B Virus dsdna enveloped Persistant infections of the liver Long term causes a lot of liver damage, can lead to hepatocellar carcinoma. Parvo virus Naked, linear ssdna Adeno associated virus can make adeno virus infections worse Erythro(B19) virus Cause of fifth disease Hepatitis D only seen in Hepatitis B infected patients, caused by the additional infection of Hepatitis delta, a viroid (the only human one) Hepatitis D, causes massive, rapid liver damage IV: Viral Carcinogenesis (Mainly from Notes) Development of Cancer Cancer is a disease of uncontrolled growth of our cells. Normally our cells only grow enough for what is needed in the body. The growth of cells is controlled by two types of proteins in our cells (1) protooncogenes and (2) tumor suppressors. These proteins either allow a cell to grow right (for the proto-oncogenes) or stop the cell from growing wrong (tumor suppressors). Mutations that develop in one particular cell in our body could affect the function of either of these two types of proteins and lead to uncontrolled growth of the cell. This leads to massive growth of the cell over many years and the inability for our body to handle it. This process of cancer development if oncogenesis or neoplastic transformation. A neoplasm is another word for a cancer. Multiple mutations are required for cancer development. Some retroviruses can actually start the process of oncogenesis directly. Examples of human cancer causing retroviruses are HTLV1 and HTLV2 (Human T Cell Leukemia Virus). A cancer causing retrovirus transduces cells and begins producing its own genetic information, BUT it also

6 brings in its own genes. There are two ways it can start oncogenesis (1) is by making proteins that bind to tumor suppressors or (2) by bringing in mutant forms of proto-oncogenes, theses mutated proteins are called oncogenes. Thus the virus is making a cell grow uncontrolled. This allows for an indirect expansion of the virus because now there are more cells that have the virus and thus more copies of the virus around. But, this also leads to more cells and later to mutations in those cells that lead to full blown cancer. Viruses usually only initiate cancer, cancer takes a long time to develop and usually becomes a major disease after many mutations. There are other types of cancer causing viruses. Examples are te Herpesviruses such as Epstein-Barr Virus (EBV) and Kaposi s Sarcoma Virus (KSHV). EBV causes Burkitt s Lymphoma and KSHV causes Kaposi s Sarcoma (a cancer like disease of the skin) and other lymphomas. Herpesviruses do not transduce the cells they infect, but rather, they often setup a Latent infection where their genomes (DNA genomes already) persist in the nucleus of the infected cells. When the cells are stressed, they exit the Latent form and switch to a Lytic form that kills the cell, but produces many new virions. Latency often enhances cells growth by virus made oncogenes, These proteins enhance cell growth to make more of the latent virus and often will lead to cancer as well. Here we focus on HPV-16, a very oncogenic form of papilloma virus. Recently, a vaccination against this virus has been developed which is very efficacious against the development of HPV-16 induced cancers. Cancer will not develop just with a viral infection, a second hit or mutation is required for full blown cancer. How do you stop cancer? Even though mutations started cancer, enough mutations in a cell will eventually lead to the cancer cell s death. Thus the drugs that are given cause mutations in cells that grow very fast. Unfortunately, this includes

7 the cells of our hair, intestinal tract and our white blood cells. Cancer therapy is a balance between killing our cells and killing the cancer. V: AIDS and HIV (Mainly from Notes) Human Immunodeficiency Virus is the virus that causes AIDS (acquired immuno deficiency syndrome). AIDS patients were first reported in 1981 as five men in Los Angeles. In the early 1980's AIDS was a very deadly disease, which was manifested as people coming down with VERY rare diseases. AIDS is the state where the immune system is so weak that it cannot fight off infections (viral, bacterial, fungal, etc) or cancer (leukemias, lymphomas, Kaposi's Sarcoma) that it normally could fight off. In 1986, HIV was discovered. It is a retrovirus that is able to infect immune cells. The cellular tropism, or cellular specificity of HIV is for T cells, or CD4 Cells of the immune system. In addition, HIV can infect all CD4 cells. Another CD4 cell is a macrophage. Macrophages as you remember are able to phagocytoze and degrade bacteria in their lysosomes. HIV has three main genes, (1)gag, (2)pol, and (3)env. gag is the gene for the protein coat, pol is the gene for the reverse transcriptase and env is the gene for the outer spike that attach to the receptor on the cell it will infect. In 1987, the first anti-hiv drug was released: AZT (Azidothymidine) AZT targets the reverse transcription step of the HIV replication. There it forces the reverse transcription to make a lot of errors and thus mutate the virus beyond its ability to function.

8 Over time, many of these reverse transcription inhibitors, or nucleoside inhibitors were developed, but in time, the virus was able to mutate to avoid this drug. The second class of anti-hiv drugs developed, in 1996, were the protease inhibitors. These drugs target the HIV protease, which is a HIV protein that changes the proteins coat from the initial immature form that is released from an infected cell, to a mature form. Without the protease, the immature HIV is not able to infect as well. These two types of drugs were in a combinatorial, or cocktail type of treatment (2 nucleoside inhibitors, 1 protease inhibitor) to target multiple genes and stop the ability for HIV to mutate against the drugs. This was called HAART, Highly Active Anti-Retroviral Therapy. The biggest problem with this therapy is that the virus can in fact mutate over time, and this is often due to patients unable to follow the treatment (nonadherance) or unable to pay for so many drugs. Thus mutant forms of HIV exist that are resistant to HAART. A third target of anti-hiv drugs is the fusion step. When a virus s spikes attach to the receptors of the cell that it will be infecting, HIV gets closer and allows the spikes to fuse the envelope and the plasma membrane of the cell that it is infecting. Fusion inhibitors have been developed which bind to the spikes right before they start fusion and freeze the virus in place. No fusions occur and thus no infection happens. The first fusion inhibitor was released a couple of years ago and is called Fuzeon. The major problem is that this drug is only injectable because it is a protein and proteins are degraded by the stomach. Thus this drug is

9 effective but used only after HAART fails.as of yet, there is no cure for HIV, only the ability to control the virus.