Retroviral Biology: Human Retrovirus

 

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Background
  • Retroviruses (Retroviridae) infect mainly vertebrates.
  • Unique replication cycle -- their genetic information is encoded in RNA, instead of DNA.
  • retroviruses utilizes an RNA-dependent polymerase (reverse transcriptase) that makes a DNA form of the viral genome.
  • the term retrovirus refers to this RNA to DNA direction.
  • The family Retroviridae consists of three subfamilies: Oncovirinae (human T cell lymphotrophic virus (HTLV); Lentivirinae (HIV); and Spumavirinae ("foamy")
  • Retroviruses can alter the function in structure of host cell genetic information;inserting into the host cell germ line its (viral) genetic information
Retroviral Structure and Life Cycle
  • retroviruses are about 70 to 130 nm in diameter with a lipid-containing envelope which surrounds an icosahedral capsid with a dense inner core.
  • The core contains 2 identical copies of single-stranded RNA (retroviruses are diploid)
  • RNA is complexed with reverse transcriptase and transfer RNA.
  • The virion also contains viral proteins, such as integrase.
  • Retroviral RNA has features most normally found in messenger RNA: a cap side at 5' end, and a polyadenylation site at the 3' end.
  • Retroviral RNA is not translated but rather transcribed into DNA. The DNA form of the retroviral genome is called a provirus.
  • Retroviral replication cycles consist of two phases:
    • phase 1:
      • virus enters cytoplasm; following binding to cell surface receptors;
      • viral RNA and reverse transcriptase synthesize a double-stranded DNA version of the viral RNA.
      • This provirus enters the nucleus and permanently integrates into the host cell genome.
      • This integration proceeds randomly for the four known pathogenic human retroviruses (HTLV-I, HTLV-II, HIV-1 and HIV-2)
    • phase 2:
      • synthesis and processing of the viral genome, messenger RNAs, and viral proteins, taking advantage of the host cell's biosynthetic machinery.
      • Virions, following assembly, are released by budding.
      • Host cell membrane proteins may contributed to the viral envelope.
      • Proviral integration usually happens during the S phase; accordingly, nondividing cells are usually resistance to retroviral infection.
      • Lentiviruses (HIV-1, HIV-2, Visna virus) however may infect nondividing cells; the host cell, once infected, is infected for its life.
Retroviral Genome
  • includes coding and non-coding regions
    • non-coding sequences: recognition sites for DNA or RNA synthesis or processing
    • non-coding sequences:localized at 5' and 3' terminal regions
  • Retroviral genomes exhibit terminal redundancy -long terminal repeats (LTRs)
  • Integrated retroviral DNA: LTR sequences repeated in both 5' and 3' viral terminus.
  • LTR is -- sequences involved in:
    • viral protein expression
    • provirus integration
    • viral RNA polyadenylation
  • Primer binding site, required for initiation of reverse transcription, and viral packaging sequences are localized outside LTR regions.
  • Coding Regions (genes):
    • gag (group-specific antigen, core protein)
      • gag gene encodes to polyprotein, later cleaved to form capsid proteins
      • gag gene precursor proteins include a protease that cleaves the Gag and Pol polyproteins
      • Gag-Pol polyprotein produces a protease that cleaves Gag-Pol polyprotein;
    • pol (RNA-dependent DNA polymerase)
      • the Pol gene encodes three proteins: (a) reverse transcriptase, (b) integrase (c) protease.
      • Reverse transcriptase copies viral RNA into double stranded DNA provirus. Doubles stranded DNA provirus attaches to host cell DNA due to integrase action.
      • Protease cleaves Gag-Pol polyprotein into smaller proteins
    • env (envelope)
      • encodes envelope glycoproteins: 1 protein binding to specific host cell surface receptors, responsible for viral tropism.
      • Additional encoded protein anchors the complex to the envelope.

     HIV-1 contains a larger genome then other retroviral pathogens.

    • additional proteins encoded include:
      • TAT which enhances viral expression from LTR region;
      • REV regulates RNA splicing/transport;
      • NEF down regulates host cell CD4 (host cell receptor for HIV-1);
      • Vif protein required for HIV nucleoprotein core assembly;
      • the ability of HIV and other lentiviruses to infect nondividing cells is due to the activity of vpr.
        • Vpr enhances proviral transport to the nucleus, inducing G2 arrest.
Fauci, A.S. and Longo, D.L RNA Viruses . In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1105 - 1107.