MIC3MPD Mid-Semester

• In the MIC3MPD lectures this semester, three main topics will be covered: Molecular Virology, Viral Immunology, and Viral Pathogenesis
• Molecular Virology

  Discusses how viruses interact with host cells, including processes of viral attachment, replication, assembly, and exit
• Viral Immunology


  Examines the relationship between the host and the virus, focusing on the body's response to viral infections and the evasion strategies of viruses
• Viral Pathogenesis


  Studies various viruses and the diseases they cause, emphasizing the impact of viruses on human health and society
• Not all viruses are harmful. Some viral genes, remnants of ancient viral infections, have been incorporated into our DNA and used for beneficial purposes, such as the development of the human placenta
• Many viruses are pathogenic and can cause serious diseases, such as HIV, smallpox, influenza, rabies, and Ebola. These viruses pose significant public health challenges
• Virus

  An infectious obligate intracellular parasite that contains either DNA or RNA, is surrounded by a protein coat, and may also have an envelope derived from the host cell membrane
• The study of viruses requires an integrative approach combining cell biology, biochemistry, immunology, genetics, ecology, and zoology. This approach helps reveal the complexity of viruses
• Virion

  The virus itself, as distinct from when it is within an infected cell where the virus undergoes its life cycle
• Virion Components

  • Capsid
  • Nucleocapsid
  • Envelope
• Envelope

  Some viruses are encapsulated by an envelope, which contains proteins known as spike proteins that enable the virus to bind to its host cell receptor
• Viruses are classified based on their nucleocapsid type, its fragmentation, its organization, its sequence, the symmetry of their capsid, the presence or absence of an envelope, and the dimensions of the virion and the capsid. This classification is done by the International Committee on Taxonomy of Viruses (ICTV)
• Virus Life Cycle

  1. Binding

  2. Uncoating

  3. Replication

  4. Translation

  5. Assembly

  6. Release
• Viruses outnumber cellular life by at least 10 to 1 and comprise the greatest biodiversity on Earth. They can be beneficial but are also sources of new pathogens and are constantly evolving. New viruses are found all the time, but we usually only hear about the ones that significantly impact human or animal health, such as SARS-CoV-2
• Viruses are unique in that they are obligate intracellular parasites. This means they are incapable of replicating or carrying out their life cycle outside of a host cell. The reason for this is that viruses lack the necessary cellular machinery for self-replication and instead, they must hijack the host cell's machinery to multiply
• Initial Viral Attachment

  Viruses must first adhere to the cell surface using a viral spike or binding protein, often termed a glycoprotein in enveloped viruses. This binding is mediated by a specific cell receptor(s)
• Susceptible cell

  A cell that has the necessary receptor for the virus
• Permissive cell

  A cell that can support viral replication
• Tropism

  The predilection of a virus for a particular cell or tissue type
• Examples of viral tropism

  • Hepatitis B/C virus has a tropism for liver cells
  • HIV has a tropism for CD4+ T cells & macrophages
  • Influenza virus has a ubiquitous receptor for sialic acid
• Co-receptor

  Some viruses, such as HIV, require a co-receptor in addition to the primary receptor for entry into the host cell
• Mechanisms of Viral Penetration

  • Endocytosis (pH dependent or independent)
  • Fusion at the plasma membrane (pH dependent or independent)
• Viral Fusion

  The merging of the viral membrane of an enveloped virus with a host cell membrane, which can occur at the plasma membrane or the endosomal membrane
• Viral Fusion Proteins

  Proteins encoded by viruses that facilitate the fusion process, containing a small stretch of hydrophobic amino acids that can embed within the cellular membrane
• Class I Fusion Proteins

  Composed of three identical protein subunits, with the C-terminal end of one piece anchored to the viral membrane and the other end having a characteristic stretch of 20 hydrophobic amino acids — the fusion peptide
• Class II Fusion Proteins

  Have different structural features than Class I proteins, with the portion that inserts into the target membrane being the internal hydrophobic fusion loop. pH plays a major role in the structural rearrangement of some Class II proteins to expose the fusion loop
• Cellular Entry of Viruses

  • Hepatitis C Virus binds multiple receptors and undergoes receptor-mediated endocytosis
  • HSV-1 binds receptors and fuses directly with the plasma membrane
• DNA Virus Entry

  DNA viruses, whether enveloped or non-enveloped, have a complex process of entering the host cell and releasing their genetic material, generally involving receptor-mediated endocytosis, release of the viral capsid into the cytoplasm, transport of the viral capsid to the nucleus, and uncoating to release the genetic material within the nucleoplasm for viral replication
• DNA Virus Entry Example

  • Adenovirus binds to the cell receptor, leading to endocytosis. The viral capsid proteins are sequentially removed in the endosome, and the release of the penton base mediates the lysis of the endosome and the release of the capsid, which can then dock with the nuclear pore complex
• All viruses have two main replication objectives: 1) Make plus strand RNA at some stage in their viral lifecycle, and 2) Continuously make genome copies to be packaged into virions for viral egress to help propagate the viral life cycle
• No virus encodes a complete set of genes for translating proteins, making them dependent on the translational machinery of the host cell
• Replication Considerations

  • RNA genomes are generally smaller than DNA genomes, up to a maximum of about 30 KB
  • DNA genomes are much larger, up to 1.2 megabases
• Location of Replication

  The genome type and size dictate the location of replication. As a general rule, RNA viruses replicate in the cytoplasm, while DNA viruses generally replicate in the nucleus
• Viral genomes are heavily condensed to maximize their gene coding capacity. Overlapping genes and alternate reading frames are common features of many small viral genomes
• Genome Replication Rules

  • Always require a template for replication
  • Replication always occurs in a five prime to three prime direction for new synthesis
  • The strands will be anti-parallel
• Types of RNA Genomes

  • Plus Stranded RNA
  • Negative Stranded RNA
  • Double Stranded RNA
• Plus Stranded RNA Viruses

  Do not carry a polymerase in their virion. Upon infection, the plus sense genome acts as a messenger RNA template for protein translation
• Negative Stranded RNA Viruses

  Carry an RNA polymerase in their virion. Upon infection, the first activity that occurs is transcription, followed by translation and production of proteins
• Double Stranded RNA Viruses

  Also carry a polymerase in their virion. Upon infection, the double-stranded RNA genome separates, and the plus strand is used either to manufacture protein templates or act as a messenger RNA
• Replication in the Cytoplasm

  Plus sense RNA viruses set up replication factories by rearranging organelles within a cell, providing a concentrated and unique microenvironment in the cell cytoplasm for replication to take place