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Basics of VirusesViral Genomes There are over 21 families of viruses. Each of these families will have many strains of viruses within them. Just the Herpes virus has 8 different strains within its family. Others like Flavivirus has strains like Dengue, Zika, West Nile and Yellow Fever. Other then classifying viruses by their family, we can classify them by their genetic makeup. There are 7 different classes of viral genomes. They are classified using the Baltimore scale shown below.  Class I viruses are the double stranded DNA viruses (dsDNA). These are the common viruses that lay latent in humans for many years or even their lifetime. The Herpes viruses are the best example of these viruses. They include HSV1, HSV2, Varicella Zoster Virus (Chicken pox and Shingles), Epstein Barr viruses, and Cytomegalovirus. These viruses will get into cells and live there for the lifetime of the host. They will stay latent unless something happens to activate them.  This often happens in immune suppression like with transplants or chemotherapy. A healthy immune system keeps them in check. Class II viruses are the single stranded viruses (ssDNA). There are very few of these that are in humans. The best example is parvo viruses which affect cats and dogs. The one human example is the famous Parvo B19 virus which can cause aplastic anemia.  Class III is the double stranded RNA viruses (dsRNA). The Rota virus is the classic example of the double stranded RNA viruses. They are part of the many viruses that we call stomach bugs. They cause diarrhea.  The cells of the body have defenses against double stranded RNA (dsRNA) as our bodies do not use this format. This serves as a warning to the cells. Class IV viruses are the + strand single strand RNA viruses (+ssRNA). The positive strand runs from the 5' to the 3' direction while the - strand runs 3' to 5'. This distinguishes the Class IV + strand RNA viruses form the Class V - strand RNA viruses. Our ribosomes recognize mRNA which is the + strand of the RNA. That means many + strand RNA viruses can start being translated by the ribosome as soon as it enters the cell.  Others have to be copied to - strand and then back so they are formatted correctly for the ribosome. The best example of a + strand RNA virus is the Rhinovirus that makes up the common cold. Class V viruses are the - strand RNA viruses (-ssRNA). They often bring their own polymerase into the cell for copying their - stand genome into a + strand RNA that can be used with the ribosomes. The most famous of - strand viruses is Influenza.  The influenza virus is completely unique in that it has 8 segments of single stranded RNA that is of the - strand. This allows influenza strains to swap segments to crate completely new strains. Class VI viruses are called the Retroviruses. They are an RNA virus that copies its RNA genome into DNA using a reverse transcriptase and inserts it into the human DNA using integrase.  The most famous retrovirus is HIV. This enters human CD4 T cells and integrates into the cells genome. There is an acute period of infection as the virus invades the host's T cells. Then it enters a latent period where it can stay for years or even decades. Lentivirus is a close relative to HIV that is a retrovirus. It is used in labs to insert genes into cells for gene editing. This is used in many T cell therapies to make edits to the cell's genome. Class VII viruses are hybrid viruses. These viruses use a combination of both double stand and single stranded DNA genomes. The most famous of Class VII viruses is Hepatitis B.  This is another virus that can enter cells and remain latent for many years or decades. Hepatitis B is a liver virus that leads to many of the cases of liver cancer over time. Understanding the viral genomes of any virus will tell you a lot about that virus. It will determine what kind of immune response will be activated. Innate cells have Toll Like Receptors designed to detect these different kinds of RNA or DNA of these pathogens. Viral Capsids The capsid is a strong protein structure that encloses and protects the viral genome. The most basic viruses will use a single protein produced many times to build the capsid. The more complex viruses will use multiple proteins to build their capsid structure.  The basic structure of the viral capsid comes in 3 basic designs. They are Icosahedral, Helical and Complex. The Helical symmetry of capsids takes 1 protein and links them together into a very long string. That string is then wrapped into a helical structure like a tube.  An example of a helical capsid virus is Ebola. This virus actually looks like a worm because of its helical capsid. The Icosahedral capsid is made up of triangles to form a sphere like shape. If you ever seen a 20 sided die from the D&D game, that is a perfect example of an icosahedral shape.  The basic unit of the icosahedral capsid is a single viral protein often designated as Viral Protein 1 (VP1). Some viruses will use multiple proteins to form its basic triangle structure and will designate them VP1, VP2 and VP3.  This small structure is the most basic building block of the icosahedral structure. When 3 of these proteins come together, they form the basic triangle of the icosahedral capsid. The single triangle is called a facet.  The most basic virus is made up of only 20 facets. This is also called its T number. A T-1 virus would have 20 facets. A T-2 virus would have 40 facets and a T-3 virus would have 60 facets.  Since each facet is made up of the 3 basic proteins, the T number that represents the facets gets multiplied by 3 to find out the total proteins in the capsid. For example a T-1 capsid has 20 facets with 3 proteins per facet = 60 total proteins. A T-3 capsid would have 20 x 3 facets or 60 total facets with 3 proteins to make up every facet. That would be 60 x 3 = 180 total proteins. When a capsid falls into icosahedral symmetry, it will have specific shapes if forms. There are 2 fold, 3 fold and 5 fold axes in each 20 facet capsid.  As the virus capsid gets bigger into the T scale, the number of 5 fold axes increase so that the capsid goes from a basic of triangle faces to pentagon shaped faces made up of these 5 fold triangles shown below.  In a large enough capsid, you will begin to see 6 fold axes of symmetry. They begin to look like the pattern on a soccer ball.  The last Capsid is the Complex which is made up of both helical and icosahedral parts. The classic example of this type of virus is the bacteriophage.  The head of the bacteriophage is made up of a basic icosahedral shape which is attached to a long tube that is made up of a helical structure. These do not harm humans and prey on bacteria hence their names. The Adeno Associated Virus (AAV) is a basic T-1 icosahedral capsid. Its made up of 20 facets. The most basic uses only 1 protein VP1 with 60 copies to make up the capsid. Others will use 3 different proteins with VP1, VP2 and VP3 in 20 copies of each to build the capsid.  The AAV capsid is the smallest you can find. It only holds about 4,500 bases (4.5kb) of RNA or DNA genetic material. Binding proteins and Membranes We looked at the viral genome and the protein capsid. There are 2 other major structural components of the virus with the binding proteins and a membrane.  All viruses come with proteins that project from their surface. These are ligands that bind to specific receptors on cells to gain entry. These proteins give the virus its tropism.  The concept of tropism means a virus will only be able to infect cells of tissues that display the receptor for the proteins it has on its surface. Each virus will have different proteins on its surface which will make it able to infect specific tissues. The influenza virus has a protein called Hemagglutinin which binds to the Sialic Acid receptor in the upper and lower respiratory tract. This gives influenza tropism for the respiratory tract.  The HIV virus has a protein called the glycoprotein that binds to CD4 on helper T cells and Dendritic cells to make entry. It also uses a co-receptor of the T cell with CCR5 or CXCR5 to bind. This gives HIV tropism for Helper T cells.  The Hepatitis B virus (HBV) has 3 proteins on its surface with an L, M and S protein. The HBV virus will make binding to the heparin sulfate receptor with one protein then use others to make binding to the NTCP and EFGR receptors. This gives Hepatitis B tropism to the liver.  For a cell to become infected with a virus, it must be susceptible and permissible for infection. Susceptible means that cell has the receptor for that virus to make entry. Permissible means that cell is capable of allowing the virus to replicate inside.  Susceptible is the idea of tropism, but permissible is a factor of the cell itself. Not every cell will be able to allow viral replication. This can often be related to cellular host defenses like Interferons and the Antiviral state. The last part of the virus is the membrane. Not every virus will have a membrane. When the virus only has a protein shell, we call it a capsid. When the virus has a membrane, we call it a nucleocapsid. We call a virus with a membrane and enveloped virus.  When a virus has no membrane the protein structure is very strong. This makes these viruses very hardy. They can survive on surfaces for long periods of time. They can also survive the low Ph of the stomach. All enteroviruses are this kind of structure. They make up one of the many families that cause Gastroenteritis. Another is the Norovirus which is commonly called the Cruise ship virus. This baby is even resistant to hand sanitizers. Always wash your hands before eating.  The membrane gives viruses benefits. It makes them slippery so they are harder to target by host immunity. They have lipid membranes which helps them blend in with the cells of the host. The membrane makes them less hardy outside the body. They don't live as long before they dry out. They also don't survive the Ph of the stomach. The Corona virus is an example of an enveloped virus.  |
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