Week 4

• Virus particles contain either RNA or DNA and can only replicate inside host cells
• Some viruses cause lethal acute diseases, such as Smallpox, Ebola, Influenza, Covid, Rabies, Polyoma, EBV, HBV, HTLV-1
• Virus replication follows the 'central dogma' of molecular biology: DNA -> RNA -> Protein
• Retroviruses have a unique replication process involving reverse transcription, where RNA is converted into DNA
• Retroviruses shape our genomes by integrating their DNA intermediate (provirus) into the host genome
• Human T cell Leukaemia viruses (HTLV) origin, transmission, and pathogenesis were discovered by Robert Gallo in the U.S. in 1978
• Human Immunodeficiency Viruses (HIV) also known as Lentiviruses, like HTLV, cause serious diseases and were discovered to have a DNA intermediate integrated into the host genome
• Retroviruses can be classified into different groups based on the Baltimore Classification System:

  • Group I: dsDNA viruses
  • Group II: ssDNA viruses
  • Group III: dsRNA viruses
  • Group IV: (+) ssRNA viruses
  • Group V: (-) ssRNA viruses
  • Group VI: ssRNA-RT viruses (e.g., Retroviruses)
  • Group VII: dsDNA-RT viruses (e.g., Hepadnaviruses)
• Endogenous Retroviruses (ERVs) are integrated proviruses found in the genomes of various species, including humans
• ERV sequences can be exapted for beneficial purposes, such as syncytins that aid in placental morphogenesis
• The first human retrovirus discovered was HTLV-1, which causes adult T-cell leukaemia and is found in regions like Japan, Central and South Africa, Melanesia, South America, and the Caribbean
• HTLV-1 has a global prevalence of around 22 million people, while HTLV-2 has a prevalence of around 7 million people
• Transmission of HTLV can occur through various routes, including vertical transmission, blood transfusions, and sexual contact
• HTLV-1 causes Adult T-cell Leukemia (ATL), a malignancy of CD4+ T lymphocytes
• ATL is a malignancy of CD4+ CD25+ T-helper cells
• HTLV-2 is associated with sporadic cases of myelopathy resembling HAM/TSP and Hairy Cell Leukemia
• HIV-1 causes Acquired Immune Deficiency Syndrome (AIDS)
• Immune deficiency leads to opportunistic infections and cancers
• HIV-1 group M viruses estimated to have entered humans in the 1930s
• HIV-2 is largely restricted to West Africa and less pathogenic than HIV-1
• Individuals with a mutation in the CCR5 gene are largely resistant to HIV infection
• HIV binds to CD4+ cells and dendritic cells for viral dissemination
• Clinical course of HIV infection includes primary infection, clinical latency, and AIDS
• Viral reservoirs are sites where HIV accumulates and persists, potentially leading to viral rebound
• Retroviruses have given molecular biologists insights into cell processes and have implications in diseases like AIDS and leukemia
• Properties of transformed cells:

  • Transformed cells in culture have numerous unusual characteristics
  • Characteristics include altered morphology, lack of contact inhibition, anchorage independence, proliferation in the absence of growth factors, immortalization, and tumorigenicity
• The transformation phenotype induced by Rous Sarcoma Virus (RSV) infection is transmitted to progeny cells and depends on the continued activity of an RSV gene product
• RSV both initiates and maintains the transformed phenotype

  • Cells infected with the temperature-sensitive mutant at its permissive temperature become transformed
  • The transformed cells can be grown for many generations
  • If the temperature of these infected cultures is raised to 41°C (the nonpermissive temperature), these cells quickly revert to a non-transformed phenotype
• Retroviruses:

  • RNA viruses make double-stranded DNA copies of their genomes through reverse transcription
  • The DNA copies are integrated into the host's chromosomal DNA as part of the normal viral replication cycle
  • RNA viruses are called retroviruses because their replication cycle depends on information flowing backward from RNA to DNA
  • The DNA version of their viral genomes is called a provirus
• The life cycle of an RNA tumour virus like RSV involves:

  • Entry
  • Nuclear import
  • Integration
  • Transcription
  • RNA export
  • Translation
  • Assembly
  • Reverse transcription
  • Release
• Working with RSV, researchers found that viral replication and cell transformation were specified by separate genes

  • The transforming function resides in a single gene called src
  • The src oncogene is highly related to a gene in normal chicken cells
• Several classes of DNA viruses, including Papilloma virus, papovavirus, human adenovirus, herpesvirus, and poxvirus, induce cancers in laboratory animals or humans
• DNA viral genomes normally replicate independently of the host cells' DNA

  • Viral genomes lack the DNA segments (centromeres) to properly segregate during mitosis
  • Pieces of DNA tumour virus genomes integrate into host-cell chromosomal DNA
• Formation of integrated SV40 genomes:

  • SV40 DNA genomes recombine at low efficiency with the host-cell chromosomal DNA
  • In some cells, only a portion of the viral genome is present; in others, full, multiple, head-to-tail tandem arrays are present
• Papovavirus genomes integrate into host-cell chromosomal DNA

  • Almost all cervical carcinomas carry fragments of human papillomavirus (HPV) genomes integrated into their chromosomal DNA
  • Only the portion of the viral genome that contains oncogenic information is found in the chromosomal DNA of these cancer cells
• Hepatitis B Virus (HBV) is a DNA virus that can induce tumours