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Chapter 48 : Retroviral DNA Transposition: Themes and Variations

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Abstract:

Two unique features of retroviruses are their genome organization and strategies for gene expression. While the gene order of retroviruses is conserved, the synthesis of retroviral proteins can be controlled by different mechanisms. Variations include the ways in which RNA splicing is used to produce mRNAs from a single long transcript, a portion of which must remain unspliced to serve as the viral genome. With these general principles in mind, an overview of the retrovirus family follows, along with a description of how the gene organization of its members relates to gene expression and the viral entry process. Detailed descriptions of the molecular aspects of these processes can be found in the comprehensive ( ) an overview chapter in ( ), or a number of recent reviews that focus mainly on the early steps in the reproductive cycle of human immunodeficiency virus type-1 (HIV-1) ( ).

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figures

Image of Figure 1
Figure 1

A phylogenetic tree based on the collection of RT-IN sequences for all retrotranscribing viruses in the NCBI taxonomy and NCBI RefSeq databases. Full-length Pol or Gag-Pol sequences for all viruses were downloaded and truncated based on their alignment with the RT-IN region of HIV-1. ClustalX algorithm with neighbor joining clustering was then used for tree reconstruction. The tree in the illustration is an artistic representation, based on the results. Red boxes identify viral species discussed in this overview: for alpharetroviruses, RSV is Rous sarcoma virus and ALV avian leukosis virus; betaretrovirus MMTV is mouse mammary tumor virus; gammaretrovirus MMLV is Moloney murine leukemia virus; deltaretrovirus HTLV-1 is human T-lymphotropic virus 1; epsilonretrovirus WDSV is walleye dermal sarcoma virus; lentivirus HIV-1 is human immunodeficiency virus type 1; and spumaretrovirus PFV is the prototype foamy virus. The analysis and Figure were kindly provided by Dr. Vladimir Belyi, Rutgers Cancer Institute of New Jersey.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Image of Figure 2
Figure 2

The organization of proviruses in each of the retroviral genera. A generic proviral map is included at the top. Representative genomes have been aligned to allow comparisons, and are not to scale. Viral species are identified in the Figure 1 legend. Origins of the major transcripts of ALV, MLV, and PFV are represented by green arrows below the maps. Translational frameshifts are indicated by descending arrows, and read-throughs by vertical arrows in the gene coding regions.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 3

The single cell reproductive cycle of the alpharetrovirus, ALV. The virus life cycle is divided into an early phase that includes steps from virus infection to establishment of the provirus, and a late phase that includes expression of the provirus and formation of progeny virions. Adapted from: Principles of Virology, 3 edition Vol. I. 2009. S.J Flint, L.W. Enquist V.R Racaniello, and A.M. Skalka ASM Press Washington DC, Appendix A, Figure 20.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 4

Domain and subunit relationships of the RTs of different retroviruses. The organization of open reading frames in the mRNAs of all but the spumavirus PFV, is indicated at the top. PFV RT is expressed from a spliced mRNA ( Fig. 2 ). Protein products (not to scale) are shown below, with arrows pointing to the sites of proteolytic processing that produce the diversity of RT subunit composition. Open red arrows indicate partial (asymmetric) processing, and the solid arrows indicate complete processing. ASLV, avian sarcoma/leucosis viruses; others are identified in Figure 1 . Adapted from: Principles of Virology, 3 edition Vol. I. 2009. S.J Flint, L.W. Enquist V.R Racaniello, and A.M. Skalka, ASM Press Washington DC, Figure 7.9.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 5

Major steps in retroviral reverse transcription. For simplicity, reverse transcription from a single RNA template is shown, and potential (+) strand synthesis from viral RNA fragments other than the ppt are omitted. RNA is represented by green lines, with key regions identified in lower case: pbs, tRNA primer binding site; u5, unique 5′-end sequence; r, repeated sequence; u3, unique 3′-end sequence, ppt, polypurine tract. Light blue lines represent (-) strand DNA, and dark blue, (+) strand DNA: key regions are identified in uppercase. A modified base in the tRNA primer (C.) blocks further reverse transcription of the tRNA. Adapted from: Principles of Virology, 3 edition Vol. I. 2009. S.J Flint, L.W. Enquist V.R Racaniello, and A.M. Skalka, ASM Press Washington DC, Figures 7.3–7.6.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 6

Comparison of the structures of three RTs. Top row: The DNA polymerase domains of lentiviral (HIV-1 p66, ), gammaretroviral (XMRV, ) and LTR-retrotransposon (Ty3 subunit A, ) RTs. Fingers, palm and thumb subdomains are designated F, P and T, respectively. Positions of the RNA (magenta) and DNA strands (teal) of the bound RNA/DNA hybrids are shown. Bottom row: Architectures of the non-catalytic subunits of the dimeric RTs: HIV-1 p51 () and Ty3 subunit B (). Both subunits contain F, P and T subdomains in analogous positions; the p51 connection and Ty3 (subunit B) RNase H domain, denoted C and R respectively, are also in analogous positions. Superposition of the asymmetric p66/p51 HIV-1 RT heterodimer and the symmetric Ty3 (A)/(B) homodimer is shown in the center. HIV RT subunits are in orange and grey, and Ty3 subunits in green and yellow. The illustration was prepared by Drs. Jason Rausch, and Stuart Le Grice, NCI-Frederick, and Dr. Marcin Nowotny, International Institute of Molecular and Cell Biology, Poland. Structure details for HIV-1 RT are in ( ), for XMRV RT in ( ), and for Ty3 RT in ( ).

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 7

Reactions catalyzed by retroviral integrases. Left: Reactions at the retroviral DNA ends produced by RT in infected cells. The processing reaction takes place in the cytoplasm as soon as DNA synthesis is completed at the termini. Following nuclear entry the two processed viral DNA ends are joined to host DNA in concerted cleavage and ligation reactions at staggered positions in the target site. Repair of the resulting gaps is catalyzed by host enzymes. The integrated provirus is flanked by short repeats (indicated by vertical lines) of the host DNA, with length determine by the distance between the staggered cuts made by IN. Right: Reactions as assayed using duplex oligonucleotides containing viral DNA end sequences and target DNAs. Red stars indicate radioactive or fluorescent labels that can be used for distinguishing reactions (A) and identifying recombinant molecules (B–D) following electrophoresis in denaturing or non-denaturing (D) gels.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 8

Domain organization of IN proteins from different retroviruses. Maps for the organization of IN proteins are shown with amino acid numbers that delineate the start and end of each domain. The lengths of linkers that connect the domains are also indicated below the lines between domains. The domain models below are from the crystal structures of the HIV-1 N-terminal domain (NTD), catalytic core domain (CCD), and C-terminal domain (CTD), PDB codes 1K6Y, 1BIU, 1EX4, respectively. The Zn ion in the NTD is shown as a blue sphere, and the Mg ion in the active site of the CCD, as a green sphere. Domains in proteins for which there is no experimentally determined structure from crystallography are shown in muted colors in the maps above. The domain pictures were generated using Chimera software (UCSF) and the figure kindly provided by Dr. M.D. Andrake, Fox Chase Cancer Center, Philadelphia, PA.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 9

Solution models for the PFV IN tetramer in an intasome and the ASV IN reaching dimer. A. The PFV IN tetramer in an intasome, with DNA omitted to draw attention to IN subunit organization of the inner dimer. Color codes for IN domains in the inner dimer are as in Figure 8 , with one subunit in dim pastels for ease of distinction. All three domains of the outer monomers are in yellow. Coordinates for the PFV intasome solution structure were kindly provided by Dr. Kushol Gupta. B. The left side shows the solution structure of the ASV IN reaching dimer structure in the absence of DNA, color coded as in the PFV IN inner dimer. In this structure the CTDs interact with each other, in a “closed” configurations. The right side shows a hypothetical “open” configuration of the reaching dimer formed by rotation of the domain linkers. This open configuration resembles that of the PFV inner IN dimer and could bind viral DNA ends in a similar manner. Pictures were generated using Chimera software (UCSF) and the figure kindly provided by Drs. R. Bojja and M.D. Andrake, Fox Chase Cancer Center, Philadelphia, PA. Structural details are found in ( ).

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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Figure 10

Models for architectures of full length HIV-1 IN protein. Structures for HIV-1 IN protein in the absence of DNA substrates were derived by HADDOCK data-driven modeling of the HIV-1 IN monomer, dimer, and tetramer in solution, based on Small Angle X-Ray Scattering and protein cross-linking data ( ). It is not yet known which of these multimeric forms are competent for viral DNA binding in the formation of an HIV-1 intasome. Figures were generated using Chimera software (UCSF) and kindly provided by Drs. R. Bojja and M.D. Andrake, Fox Chase Cancer Center, Philadelphia, PA.

Citation: Skalka A. 2015. Retroviral DNA Transposition: Themes and Variations, p 1101-1123. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0005-2014
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