Retroviral Replication

Finn Skou Pedersen, Aarhus University, Aarhus, Denmark
Magdalena Pyrz, Aarhus University, Aarhus, Denmark
Mogens Duch, Aarhus University, Aarhus, Denmark

Published online: April 2011

DOI: 10.1002/9780470015902.a0000430.pub3

Retroviruses are enveloped animal ribonucleic acid (RNA) viruses that replicate via a deoxyribonucleic acid (DNA) intermediate, which is integrated into the host genome as a provirus. Interaction of the viral envelope protein with a target cell receptor triggers entry of the viral nucleoprotein core by fusion of viral and cellular membranes. After entry, the viral enzymes reverse transcriptase and integrase mediate reverse transcription of viral RNA and integration of the resulting double-stranded DNA copy of the viral genome, respectively. Expression of viral RNA and proteins from proviral DNA utilises the transcription and translation machinery of the host. Retrovirus particles are assembled through protein–protein and protein–lipid interactions, released from the cell by budding, and subsequently matured by a viral protease. A provirus can be transmitted through the germline from parents to offspring as an endogenous retrovirus. Host cell restriction factors target multiple steps of retroviral replication in a complex interplay of virus–host interactions.

Key Concepts:

  • Reverse transcription and integration into the host genome are hallmarks of retroviral replication.
  • The viral RNA genome contains a packaging signal for selective encapsidation into viral particles and a binding site for a tRNA primer for initiation of reverse transcription.
  • The integrated virus contains long-terminal repeats harbouring signals for transciptional initiation and polyadenylation, which define the retroviral transcription unit.
  • Open reading frames for Gag, Pol and Env are found in all retroviruses, but some retroviruses encode additional proteins such as Tat and Rev of HIV-1.
  • A stop-codon between gag and pol can be bypassed by read-through or frame-shifting during translation of retroviral mRNA to make the Gag–Pol polyprotein.
  • Retroviruses have specialised strategies for export of unspliced genomic-length viral RNA from the nucleus.
  • The metastable retroviral envelope protein drives the fusion of viral and cellular membranes by a type I fusion mechanism to allow retroviral entry in a receptor-dependent manner.
  • The retroviral protease is required for maturation of viral particles after their release from producer cells by budding.
  • A retrovirus can integrate into the genome of germ cells and become part of the genetic material transmitted from parents to offspring.
  • A provirus can be maintained through species diversification as an endogenous retrovirus that may serve as a marker of phylogenetic relationship and evolutionary distance.

Keywords: reverse transcription; integrase; protease; Gag–Pol polyprotein; RNA genome; integration; provirus; enveloped viruses; type I fusion; host restriction; endogenous retrovirus

Figure 1. Retroviral particle and genome structure. (a) Retrovirus particle showing the approximate location of its components using the standardised two-letter nomenclature for retroviral proteins. (b) Genome organisation and gene expression pattern of a simple retrovirus, showing the structure of an integrated provirus linked to flanking host cellular DNA at the termini of its LTR sequences (U3-R-U5) and the full-length RNA that serves as genomic RNA and as mRNA for translation of the gag and pol ORFs into polyproteins. env mRNA is generated by splicing and encodes an Env precursor glycoprotein. LTR, long terminal repeat (U3-R-U5 for proviral DNA, derived from R-U5 downstream of 5¢ cap and U3-R upstream of 3¢ poly(A) in genome RNA); PBS, primer binding site; , packaging signal; PPT, polypurine tract; SD, splice donor site and SA, splice acceptor site.
Figure 2. Replication cycle of a simple retrovirus. The flow of the early part of the replication cycle goes from receptor binding and internalisation at the left through reverse transcription to integration of the proviral DNA. The late part of the replication cycle proceeds from the provirus through transcription and processing and translation of viral RNA to assembly and release of viral particles. Maturation of the released particles involves cleavage of viral polyproteins by PR (protease).
Figure 3. Reverse transcription and integration processes. (a) Reverse transcription. Outline of the reverse transcriptase (RT)-catalysed steps leading from single-stranded genomic RNA (top; black line) to double-stranded proviral DNA (bottom; red line). (b) Integration. The viral DNA (top) is the product of the completed reverse transcription process of (a). Shown are the integrase (IN)-mediated cleavage and religation steps leading to joining of proviral and host DNA. Subsequent repair and ligation are carried out by host factors. Note the loss of two terminal nucleotides of the viral DNA and the generation of a short repeat of host sequences of the integration site.
Figure 4. Examples of host-mediated restriction of retroviral replication. The symbols and text in red denote the point of restriction during the cycle of replication and in most cases the name of the responsible host gene/gene product. The two assembly pathways refer to C-type retroviruses and B-/D-type retroviruses as indicated.
close
 References
    Arnaud F, Caporale M, Varela M et al. (2007) A paradigm for virus-host coevolution: sequential counter-adaptations between endogenous and exogenous retroviruses. PLoS Pathogens 3(11): e170.
    Baltimore D (1970) RNA-dependent DNA polymerase in virions of RNA tumor viruses. Nature 226: 1209–1211.
    Bieniasz PD (2009) The cell biology of HIV-1 virion genesis. Cell Host Microbe 5: 550–558.
    Byun H, Halani N, Mertz JA et al. (2010) Retroviral Rem protein requires processing by signal peptidase and retrotranslocation for nuclear function. Proceedings of the National Academy of Sciences of the USA 107: 12287–12292.
    Delelis O, Lehmann-Che J and Saïb A (2004) Foamy viruses: a world apart. Current Opinion in Microbiology 7(4): 400–406.
    Douglas JL, Gustin JK, Viswanathan K et al. (2010) The great escape: viral strategies to counter BST-2/tetherin. PLoS Pathogens 69(5): e1000913.
    Duch M, Carrasco ML, Jespersen T et al. (2004) An RNA secondary structure bias for non-homologous reverse transcriptase-mediated deletions in vivo. Nucleic Acids Research 32(6): 2039–2048.
    Eggink D, Berkhout B and Sanders RW (2010) Inhibition of HIV-1 by fusion Inhibitors. Current Pharmaceutical Design [Epub ahead of print] PMID: 21128887.
    Fass D, Davey RA, Hamson CA et al. (1997) Structure of a murine leukemia virus receptor-binding glycoprotein at 2.0 angstrom resolution. Science 277: 1662–1666.
    Felts RL, Narayan K, Estes JD et al. (2010) 3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells. Proceedings of the National Academy of Sciences of the USA 107(30): 13336–13341.
    Ganser-Pornillos BK, Yeager M and Sundquist WI (2008) The structural biology of HIV assembly. Current Opinion in Structural Biology 18(2): 203–217.
    Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302: 415–419.
    Hwang CK, Svarovskaia ES and Pathak VK (2001) Dynamic copy choice: steady state between murine leukemia virus polymerase and polymerase-dependent RNase H activity determines frequency of in vivo template switching. Proceedings of the National Academy of Sciences of the USA 98: 12209–12214.
    Kirchhoff F (2010) Immune evasion and counteraction of restriction factors by HIV-1 and other primate lentiviruses. Cell Host Microbe 8(1): 55–67.
    Lauring AS, Cheng HH, Eiden MV and Overbaugh J (2002) Genetic and biochemical analyses of receptor and cofactor determinants for T-cell-tropic feline leukemia virus infection. Journal of Virology 76: 8069–8078.
    Lund AH, Duch M, Lovmand J et al. (1993) Mutated primer binding sites interacting with different tRNAs allow efficient murine leukemia virus replication. Journal of Virology 67(12): 7125–7130.
    Maksakova IA, Mager DL and Reiss D (2008) Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cellular and Molecular Life Science 65(21): 3329–3347.
    Mi S, Lee X, Li X et al. (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403: 785–789.
    Miller M (2010) The early years of retroviral protease crystal structures. Biopolymers 94(4): 521–529.
    Miyauchi K, Kim Y, Latinovic O et al. (2009) HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 137(3): 433–444.
    Murakami T (2008) Roles of the interactions between Env and Gag proteins in the HIV-1 replication cycle. Microbiology and Immunology 52: 287–295.
    Niewiadomska AM and Yu XF (2009) Host restriction of HIV-1 by APOBEC3 and viral evasion through Vif. Current Topics in Microbiology and Immunology 339: 1–25.
    Ono A (2010) Relationships between plasma membrane microdomains and HIV-1 assembly. Biology of the Cell 102(6): 335–350.
    book Pedersen FS and Sørensen AB (2010) "Pathogenesis of oncoviral infections". In: Kurth R and Bannert N (eds) Retroviruses: Molecular Microbiology and Genomics, pp. 237–268. Norfolk, UK: Caister Academic Press.
    Rein A (2010) Nucleic acid chaperone activity of retroviral Gag proteins. RNA Biology 7(6): 61–66.
    Schlecht-Louf G, Renard M, Mangeney M et al. (2010) Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proceedings of the National Academy of Sciences of the USA 107(8): 3782–3787.
    Shah VB and Aiken C (2010) HIV nuclear entry: clearing the fog. Viruses 2: 1190–1194.
    Shun MC, Raghavendra NK, Vandegraaff N et al. (2007) LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes & Development 21(14): 1767–1778.
    Silverman RH, Nguyen C, Weight CJ and Klein EA (2010) The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nature Reviews in Urology 7(7): 392–402.
    Tarlinton R, Meers J and Young P (2008) Biology and evolution of the endogenous koala retrovirus. Cellular and Molecular Life Sciences 65(21): 3413–3421.
    Temin HM and Mitzutani S (1970) RNA-directed DNA polymerase in virions of Rous sarcoma virus. Nature 226: 1211–1213.
    Tremblay MJ (2010) HIV-1 and pattern-recognition receptors: a marriage of convenience. Nature Immunology 11(5): 363–365.
    Warrilow D, Tachedjian G and Harrich D (2009) Maturation of the HIV reverse transcription complex: putting the jigsaw together. Reviews in Medical Virology 19(6): 324–337.
    Wolf D and Goff SP (2009) Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458(7242): 1201–1204.
 Further Reading
    den Boon JA, Diaz A and Ahlquist P (2010) Cytoplasmic viral replication complexes. Cell Host Microbe 8(1): 77–85.
    book Coffin JM, Hughes SH and Varmus HE (eds) (1997) Retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    Desfarges S and Ciuffi A (2010) Retroviral integration site selection. Viruses 2: 111–130.
    Douville RN and Hiscott J (2010) The interface between the innate interferon response and expression of host retroviral restriction factors. Cytokine 52(1–2): 108–115.
    Kannian P and Green PL (2010) Human T lymphotropic virus type 1 (HTLV-1): molecular biology and oncogenesis. Viruses 2: 2017–2077.
    book Knipe DM, Howley PM, Griffin DE et al. (eds) (2007) Fields' Virology, 5th edn. Philadelphia, PA: Lippincott-Raven.
    book Kurth R and Bannert N (eds) (2010) Retroviruses: Molecular Microbiology and Genomics. Norfolk, UK: Caister Academic Press.
    Sattentau QJ (2010) Cell-to-cell spread of retroviruses. Viruses 2: 1306–1321.
    book Spearman P and Freed EO (eds) (2009) HIV Interactions with Host Cell Proteins. Berlin: Springer.
    Vareta M and Palmarini M (2010) Multitasking: making the most out of the retroviral envelope. Viruses 2: 1571–1576.

Related Sub-Topics:

RNA Viruses | Virus Replication
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Retroviral Replication
 
How to Cite close
Pedersen, Finn Skou, Pyrz, Magdalena, and Duch, Mogens(Apr 2011) Retroviral Replication. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000430.pub3]