BIOL 4413/5404

RETROVIRIDAE

General Characteristics  

• Retroviruses do not follow the central thesis of biology, which maintains that the direction of flow of information and function is from DNA to RNA.
• The enzyme reverse transcriptase (RT) is packed in the virus.
• First viruses shown to cause cancer and have been studied more extensively for their carcinogenic characteristics.
• Not all retroviruses cause cancer, but tumorigenic retroviruses (sarcomas) are quite common.
• It seems that they possess a transforming gene (viral oncogene) that brings about cellular transformation. 

• Virus genome can become integrated into host genome by way of the DNA intermediate.
• Process studied as a means of introducing foreign genes into a host (gene therapy).
• Retroviruses were the first viruses to be modified for gene therapy, and continue to be used in the majority of gene therapy clinical trials.
• Have properties similar to those of DNA and RNA viruses.
• They resemble movable genetic elements and are sometimes considered to be escaped cellular transposable elements.  
• They resemble bacterial viruses such as Mu.

Taxonomy

Retroviruses are currently classified into 2 Subfamilies and 7 genera.

Family: Retroviridae

Subfamily: Orthoretrovirinidae

Genera

Alpharetrovirus

Rous sarcoma virus

Avian viruses

Betaretrovirus

Mammal viruses

Gammaretrovirus

Mammal viruses

Deltaretrovirus

Human B- or adult T-cell leukemia/lymphoma, HTLV.

Primate lymphotrophic viruses

Bovine leukemia virus

Epsilonretrovirus

Dermal, epidermal and hyperplasia viruses

Lentivirus (HIV) (L., lenti = slow)

Human immunodeficiency viruses (HIV 1&2)

Bovine, caprine, feline, equine, puma, simian and Visna immunodeficiency viruses

Subfamily: Orthoretrospumavirinae

Genus

Spumavirus

African green monkey, bovine, equine, feline, macaque simian and simian foamy viruses.

Structure

• Virions consist of an envelope, a nucleocapsid, and a nucleoid.
• Particle diameter ranges between 80-100 nm.
• The icosahedral nucleoid is concentric or eccentric while the core is spherical.
• Retroviruses have a lipid envelope bilayer with surface proteins.

 

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Source:ICTV Source: Elsevier

 

 

Source: Swiss Institute of Bioinformatics.

 

Genome

 

Notes on the Diploid Condition

• Differ from other viruses in having a diploid genome (dimeric).
• Genome consists of two identical RNA molecules joined together by H bonds.
  • The reason for this feature is not clearly understood.
  • It appears probable that the interaction of the two molecules serves as a regulatory function in reverse transcription.
• Duplication may also permit a higher rate of recombination, particularly if heterozygotes form in which each RNA molecule within a virion core comes from a different virus.

Notes on Reverse Transcriptase (RT)  

• Discovered by David Baltimore and Howard Temin (MIT) in 1970 shattering the so-called 'central dogma' of biology.
• Retrovirions contain approximately 50-100 molecules of RT (an RNA-dependent RNAP).
• Also in the hepatitis B virus (Hepadnaviridae - ds/ss DNA) and in the cauliflower mosaic virus (Caulimovirus -ss DNA).
• Only in retroviruses the intermediate DNA is incorporated into the host genome as a provirus.
  
• RT shows four enzymatic activities:
  • Synthesis of DNA with an RNA template (reverse transcription).
  • Synthesis of DNA with a DNA template.
  • Ribonuclease H activity (an activity that degrades the RNA strand of an RNA:DNA hybrid).
  • A DNA-unwinding activity (helicase-like).
• Like all DNAPs, RT needs a primer for DNA synthesis.
  • Primer molecule (usually a polynucleotide) to which DNAP attaches the first nucleotide during DNA replication.
  • The primer for retrovirus reverse transcription is a specific cellular transfer (tRNA).
• DNA synthesis from RNA commences with the tRNA primer at the 5' terminus of the virion RNA.
  • Remember that nucleic acid synthesis always proceeds from the 3' to the 5' terminus of the template.
  • The type of tRNA used as primer depends on the virus and is brought into the virion from the previous host cell.
  • In the case of the Rous sarcoma virus, the tRNA used is the tryptophan tRNA.

 

Structure of the Genome

• The genome of retroviruses is unique.
• Consists of two identical ssRNA molecules of plus complementarity, each 7-11 kb in length.
• The 5'-end of the genome has a methylated nucleotide cap with a cap sequence type 1 m7G5ppp5'GmpNp.
• The 3'-terminus of each monomer has a poly (A) tract and the terminus has a tRNA-like structure.
• There are also a primer binding site (PBS) at the 5’end and a polypurine tract (PPT) at the 3’end.
• RNA is capable of acting directly as an mRNA but is not used as such.
• There are two long terminal repeats (LTRs) of about 600nt long at the 5’ and 3’ ends.
• The LTRs contain the U3, R, and U5 regions.
• Seven internal proteins, 4 of which are structural and 3 enzymatic {RT, DNA endonuclease (integrase), and a protease}.
• The genetic map includes the following regions and in the same order:
  • gag - encoding internal structural proteins.
  • pol - encoding RT and integrase.
  • env - encoding envelope proteins.
• The Rous sarcoma virus carries a fourth gene located downstream from env and is involved in cellular transformation and cancer.

 

Replication

• GP120 attaches to the CD₄ receptors and a chemokine coreceptor [CCR-5 (fusin)] on the cell membrane of T-helper cells.
• Internalization and integration of the DNA copy into the host genome.
• Integration is not required for retrovirus multiplication (although under natural conditions the virus always integrates).
• RT of one of the two RNA genomes into a ssDNA that is subsequently converted to a linear dsRNA by RT.
• Transcription of the viral DNA, leading to the formation of viral mRNAs and progeny viral RNA.
• A fraction of these new RNAs are spliced to allow expression of some genes, while others are left as full-length RNAs.
• Viral proteins are synthesized by the host cell's translational machinery.
• Assembly of the virion at the host cellular membrane and packaging of the viral RNA genome into the capsid in the cytoplasm.
• Budding of enveloped virions at the cytoplasmic membrane and release from the cell.
• The rate of virus production from the cell is slow and cells continue to divide.

 

 

Source: via Standford University

 

 

 

Source: Microbiology bytes

 

Diseases

Human Pathogenic Retroviruses

HIV (Human immunodeficiency virus)

HTLV (Human T-cell leukemia virus) I and I

Discovered in the southern islands of Japan

HTLV II infects human CD8+ cells

Intravenous drug users

Diseases in Birds and Mammals

Rous sarcoma virus

In chickens -- (sarcomas are malignant tumors of connective tissue, bone, cartilage, or muscle)

Murine sarcoma virus

Simian T-cell leukemia virus

Simian immunodeficiency virus

Cause AIDS in certain monkeys but not in others

Bovine leukemia virus

Equine, bovine and feline lentiviruses