Retroviruses

Retroviruses have been studied for over 100 years since the discovery by Ellerman and Bang in 1908 that cell-free tissue filtrates could transmit leukaemia in chickens. The first pathogenic human retrovirus (HTLV) was discovered in 1981 and HIV, the causative agent of AIDS was discovered in 1983, but this presentation concentrates on the basic biology of retroviruses.

Retrovirus particles consist of a core, which contains the RNA genome of the virus plus the nucleocapsid (NC) protein and reverse transcriptase (RT), integrase (IN) and protease (PR) enzymes. The core lies inside an icosahedral capsid (CA protein) which is surrounded by the matrix (MA) which links the capsid to the lipid envelope. The transmembrane protein (TM) and surface glycoprotein (SU) are associated with the envelope.

All retrovirus genomes consist of two molecules of RNA, which are equivalent to mRNA. These range in size from ~7-11kb. Retrovirus genomes have four unique features:

  1. They are the only viruses which are fully diploid.
  2. They are the only RNA viruses whose genome is produced by cellular transcriptional machinery (without any participation by a virus-encoded polymerase).
  3. They are the only viruses whose genome requires a specific cellular RNA (tRNA) for replication.
  4. They are the only plus-sense RNA viruses whose genome does not serve directly as mRNA immediately after infection.

The gene order in all retroviruses is the same:

5′ – gagpolenv – 3′

Some retroviruses have additional genes, such as the tax and rex genes in HTLV and tat and rev in HIV.

To initiate infection, the SU envelope glycoprotein binds to a specific receptor on the surface of the host target cell. The specificity of this interaction does much to determine the cell-tropism of different retroviruses, or even different isolates of the same virus (e.g. in HIV). Receptor binding results in conformational changes in the glycoprotein spike, revealing the (previously masked) fusion domain in the TM protein and resulting in fusion of the virus envelope with the cell membrane. Penetration and uncoating are poorly understood, but it is now known that uncoating is only partial, resulting eventually in a core (nucleocapsid) particle within the cytoplasm. Reverse transcription occurs inside the ordered structure of this core particle. During reverse transcription, the two single-stranded genome RNA molecules are converted into one double-stranded DNA version of the virus genome, which has the addition of long terminal repeats (LTRs).

The double-stranded DNA form of the virus genome is integrated into the chromatin of the host cell by the integrase (IN) enzyme, where it is known as a provirus. Promoter sequences in the upstream LTR direct expression of virus genes using host cell RNA polymerase. Alternative splicing is used to express virus genes gag, pol and env. In addition to encoding the gag proteins, the full length mRNA transcript also forms new genomes which are packaged into virus particles.

The genetics of retroviruses are complex:

  • High mutation rate – reverse transcription is an error-prone process.
  • Recombination – occurs during reverse transcription, promoted by the combination of two strands of RNA into one double-stranded DNA provirus.
  • Interactions with the host cell – insertional mutagenesis, transduction.

In addition to infectious viruses, retrotransposons are endogenous retrovirus-like genetic elements which make up much of the human genome.

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So what have retroviruses ever done for us?
Apart from forming much of our genome: Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. 2000 Nature 403: 785-9.

Retroviruses are responsible for a wide range of diseases:

  • Paralysis
  • Wasting
  • Ataxia
  • Arthritis
  • Dementia
  • Neuropathy
  • Transformation
  • Immunodeficiency

Retroviruses have been studied intensively for over 100 years as causes of disease and more recently as gene vectors.

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