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Chapter 46 : Reverse Transcription of Retroviruses and LTR Retrotransposons

Author: Stephen H. Hughes1
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Affiliations: 1: HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute at Frederick, 1050 Boyles St., Building 539 Rm. 130A, Frederick, MD 21702
Content Type: Monograph
Publication Year: 2015

Category: Clinical Microbiology

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Abstract:

The conversion, well over a billion years ago, of the RNA world into the modern configuration, in which genetic information is maintained primarily in DNA, required reverse transcriptases (RTs), enzymes that were able to copy genetic information from RNA into DNA, a process called reverse transcription. With minor (but important) exceptions, for example telomerases, normal cellular processes no longer require reverse transcription, which is now primarily employed in the replication of hepadnaviruses, retroviruses, and retrotransposons. This chapter will cover the process of reverse transcription, and the RTs that are involved in the replication of retroviruses and the related long terminal repeat (LTR) retrotransposons, which have lifestyles that are similar to a retrovirus that has either lost, or never acquired, the ability to be transmitted horizontally from one cell to another. The RTs of, and reverse transcription by, non-LTR retrotransposons will be considered in the chapters that describe these elements (49–55). A substantial fraction of the work that has been done on reverse transcription and RT has focused on human immunodeficiency virus type 1 (HIV-1); this is entirely appropriate given the extent of the HIV epidemic and the fact that HIV-1 RT is the target of two important classes of anti-HIV drugs. Thus, a substantial portion of this review will describe data and insights obtained in experiments that were done with HIV-1 and HIV-1 RT. However, there are some important differences in the RTs, and the process of reverse transcription, among the different retroviruses and LTR retrotransposons; these differences will also be considered, at least briefly. The literature on RT and reverse transcription is both vast and complex. Any review, including this one, can present no more than a superficial overview of what is known. Much that is important has been omitted, some intentionally, some inadvertently; for these omissions, the author apologizes. For those who are interested, a number of helpful reviews have already been published, most of which are focused on retroviral RTs ( ).

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. 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.MDNA3-0027-2014
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Reverse Transcription of Retroviruses and LTR Retrotransposons
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Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. 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.MDNA3-0027-2014
/content/10.1128/9781555819217.chap46.fig46-1
Figure 1
Reverse transcription of the genome of HIV-1. This figure shows, in cartoon form, the steps that are involved in the conversion of the ssRNA genome found in virions into dsDNA. In the figure, RNA is shown in green and DNA in purple. For simplicity, the 5′ cap and the poly(A) tail, which are present on the viral genomic RNA, have been omitted. The various sequence elements in the viral genome, including the genes, are not drawn to scale. The tRNA primer (green arrow on the left) is base paired to the primer-binding site (PBS). RT has initiated minus-strand DNA synthesis from the tRNA primer, and has copied the U5 and R sequences at the 5′ end of the genome. This creates an RNA/DNA duplex, which allows RNase H to degrade the RNA that has been copied (dotted green line). The minus-strand DNA (see text) has been transferred, using the R sequence found at both ends of the viral RNA, to the 3′ end of the viral RNA, and minus-strand DNA synthesis can resume. The HIV-1 genome has two purine-rich sequences (polypurine tracts, or PPTs, one immediately adjacent to U3; the other, the central PPT [cPPT] is in the gene). The two PPTs are relatively resistant to RNase H and they serve as primers for plus-strand DNA synthesis . Once plus-strand DNA synthesis has been initiated, RNase H removes the PPT from the plus-strand DNAs . The plus-strand that is initiated in U3 is extended until the first 18 bases to the tRNA primer are copied (see text); RNase H then removes the tRNA primer . It appears that the entire PPT primers are removed by RNase H; however, RNase H leaves a single riboA on the 5′ end of the minus-strand . Removing the tRNA primer sets the stage for the second-strand transfer . Both the plus- and minus-strand DNAs are then elongated. The plus-strand that was initiated at the U3 junction (on the left in the figure) displaces a segment of the plus-strand that was initiated from the cPPT, creating a small flap, called the central flap (cFLAP).
10.1128/9781555819217/fig46-1_thmb.gif
10.1128/9781555819217/fig46-1.gif
Image of Figure 1
Figure 1

Reverse transcription of the genome of HIV-1. This figure shows, in cartoon form, the steps that are involved in the conversion of the ssRNA genome found in virions into dsDNA. In the figure, RNA is shown in green and DNA in purple. For simplicity, the 5′ cap and the poly(A) tail, which are present on the viral genomic RNA, have been omitted. The various sequence elements in the viral genome, including the genes, are not drawn to scale. The tRNA primer (green arrow on the left) is base paired to the primer-binding site (PBS). RT has initiated minus-strand DNA synthesis from the tRNA primer, and has copied the U5 and R sequences at the 5′ end of the genome. This creates an RNA/DNA duplex, which allows RNase H to degrade the RNA that has been copied (dotted green line). The minus-strand DNA (see text) has been transferred, using the R sequence found at both ends of the viral RNA, to the 3′ end of the viral RNA, and minus-strand DNA synthesis can resume. The HIV-1 genome has two purine-rich sequences (polypurine tracts, or PPTs, one immediately adjacent to U3; the other, the central PPT [cPPT] is in the gene). The two PPTs are relatively resistant to RNase H and they serve as primers for plus-strand DNA synthesis . Once plus-strand DNA synthesis has been initiated, RNase H removes the PPT from the plus-strand DNAs . The plus-strand that is initiated in U3 is extended until the first 18 bases to the tRNA primer are copied (see text); RNase H then removes the tRNA primer . It appears that the entire PPT primers are removed by RNase H; however, RNase H leaves a single riboA on the 5′ end of the minus-strand . Removing the tRNA primer sets the stage for the second-strand transfer . Both the plus- and minus-strand DNAs are then elongated. The plus-strand that was initiated at the U3 junction (on the left in the figure) displaces a segment of the plus-strand that was initiated from the cPPT, creating a small flap, called the central flap (cFLAP).

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. 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.MDNA3-0027-2014
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Figure 2
HIV-1 RT in a complex with dsDNA and an incoming dNTP. RT is shown as a ribbon diagram; the DNA and the incoming dNTP are shown as space filling models. The p51 subunit (at the bottom) is shown in gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are shown in different colors: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template strand (the strand that is being copied) is dark red and the primer strand (the strand that is being extended) is purple. The incoming dNTP is light blue.
10.1128/9781555819217/fig46-2_thmb.gif
10.1128/9781555819217/fig46-2.gif
Image of Figure 2
Figure 2

HIV-1 RT in a complex with dsDNA and an incoming dNTP. RT is shown as a ribbon diagram; the DNA and the incoming dNTP are shown as space filling models. The p51 subunit (at the bottom) is shown in gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are shown in different colors: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template strand (the strand that is being copied) is dark red and the primer strand (the strand that is being extended) is purple. The incoming dNTP is light blue.

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. 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.MDNA3-0027-2014
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Figure 3
Movement of HIV-1 RT during polymerization. The colors used for the various subunits, domains, and subdomains of RT, and for the two DNA strands, are as in Fig. 2 . The p51 subunit is gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are as follows: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template is dark red and the primer strand is purple. The incoming dNTP is light blue. The structural changes in RT can be correlated with specific steps in the binding of the substrates and the incorporation of the incoming dNTP. In unliganded RT, the fingers and thumb are closed (A). Before the dsDNA (or other nucleic acid substrate) can be bound, the thumb must move (A → B); this allows the dsDNA to be bound (B). This sets the stage for the binding of the incoming dNTP. When the incoming dNTP binds, the fingers close, which allows the dNTP to be incorporated, with the release of pyrophosphate (PPi). The incorporation of the dNTP temporarily leaves the end of the primer stand in the N or nucleoside triphosphate-binding site (see text). Translocation moves the nucleic acid by 1 bp, which allows the next dNTP to be bound and incorporated.
10.1128/9781555819217/fig46-3_thmb.gif
10.1128/9781555819217/fig46-3.gif
Image of Figure 3
Figure 3

Movement of HIV-1 RT during polymerization. The colors used for the various subunits, domains, and subdomains of RT, and for the two DNA strands, are as in Fig. 2 . The p51 subunit is gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are as follows: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template is dark red and the primer strand is purple. The incoming dNTP is light blue. The structural changes in RT can be correlated with specific steps in the binding of the substrates and the incorporation of the incoming dNTP. In unliganded RT, the fingers and thumb are closed (A). Before the dsDNA (or other nucleic acid substrate) can be bound, the thumb must move (A → B); this allows the dsDNA to be bound (B). This sets the stage for the binding of the incoming dNTP. When the incoming dNTP binds, the fingers close, which allows the dNTP to be incorporated, with the release of pyrophosphate (PPi). The incorporation of the dNTP temporarily leaves the end of the primer stand in the N or nucleoside triphosphate-binding site (see text). Translocation moves the nucleic acid by 1 bp, which allows the next dNTP to be bound and incorporated.

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. 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.MDNA3-0027-2014
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References

/content/book/10.1128/9781555819217.chap46
1. Telesnitsky A,, Goff GP, . 1997. Reverse transcriptase and the generation of retroviral DNA, p 121– 160. In Coffin JM,, Hughes SH,, Varmus HE (ed), Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
2. Sarafianos SG,, Marchand B,, Das K,, Himmel DM,, Parniak MA,, Hughes SH,, Arnold E . 2009. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol 385 : 693– 713.[PubMed] [CrossRef]
3. Hu W,, Hughes SH, . 2012. HIV-1 Reverse Transcription, p 37– 58. In Bushman FD,, Nabel GJ,, Swanstrom R (ed), HIV from Biology to Prevention and Treatment. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [CrossRef]
4. Skalka AM,, Goff SP . 1993. Reverse Transcriptase. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
5. Gilboa E,, Mitra SW,, Goff S,, Baltimore D . 1979. A detailed model of reverse transcription and tests of crucial aspects. Cell 18 : 93– 100.[PubMed] [CrossRef]
6. Shank PR,, Hughes SH,, Kung HJ,, Majors JE,, Quintrell N,, Guntaka RV,, Bishop JM,, Varmus HE . 1978. Mapping unintegrated avian sarcoma virus DNA: termini of linear DNA bear 300 nucleotides present once or twice in two species of circular DNA. Cell 15 : 1383– 1395.[PubMed] [CrossRef]
7. Hughes SH,, Shank PR,, Spector DH,, Kung HJ,, Bishop JM,, Varmus HE,, Vogt PK,, Breitman ML . 1978. Proviruses of avian sarcoma virus are terminally redundant, co-extensive with unintegrated linear DNA and integrated at many sites. Cell 15 : 1397– 1410.[PubMed] [CrossRef]
8. Nikolaitchik OA,, Dilley KA,, Fu W,, Gorelick RJ,, Tai SH,, Soheilian F,, Ptak RG,, Nagashima K,, Pathak VK,, Hu WS . 2013. Dimeric RNA recognition regulates HIV-1 genome packaging. PLoS Pathog 9 : e1003249. [PubMed] [CrossRef]
9. Ke N,, Gao X,, Keeney JB,, Boeke JD,, Voytas DF . 1999. The yeast retrotransposon Ty5 uses the anticodon stem-loop of the initiator methionine tRNA as a primer for reverse transcription. RNA 5 : 929– 938.[PubMed] [CrossRef]
10. Lin JH,, Levin HL . 1998. Reverse transcription of a self-primed retrotransposon requires an RNA structure similar to the U5–IR stem–loop of retroviruses. Mol Cell Biol 18 : 6859– 6869.[PubMed]
11. Isel C,, Lanchy JM,, Le Grice SF,, Ehresmann C,, Ehresmann B,, Marquet R . 1996. Specific initiation and switch to elongation of human immunodeficiency virus type 1 reverse transcription require the post-transcriptional modifications of primer tRNA3Lys. EMBO J 15 : 917– 924.[PubMed]
12. Lanchy JM,, Ehresmann C,, Le Grice SF,, Ehresmann B,, Marquet R . 1996. Binding and kinetic properties of HIV-1 reverse transcriptase markedly differ during initiation and elongation of reverse transcription. EMBO J 15 : 7178– 7187.[PubMed]
13. Telesnitsky A,, Goff SP . 1993. Two defective forms of reverse transcriptase can complement to restore retroviral infectivity. EMBO J 12 : 4433– 4438.[PubMed]
14. Julias JG,, Ferris AL,, Boyer PL,, Hughes SH . 2001. Replication of phenotypically mixed human immunodeficiency virus type 1 virions containing catalytically active and catalytically inactive reverse transcriptase. J Virol 75 : 6537– 6546.[PubMed] [CrossRef]
15. Driscoll MD,, Golinelli MP,, Hughes SH . 2001. In vitro analysis of human immunodeficiency virus type 1 minus-strand strong-stop DNA synthesis and genomic RNA processing. J Virol 75 : 672– 686.[PubMed] [CrossRef]
16. Purohit V,, Roques BP,, Kim B,, Bambara RA . 2007. Mechanisms that prevent template inactivation by HIV-1 reverse transcriptase RNase H cleavages. J Biol Chem 282 : 12598– 12609.[PubMed] [CrossRef]
17. Panganiban AT,, Fiore D . 1988. Ordered interstrand and intrastrand DNA transfer during reverse transcription. Science 241 : 1064– 1069.[PubMed] [CrossRef]
18. Hu WS,, Temin HM . 1990. Retroviral recombination and reverse transcription. Science 250 : 1227– 1233.[PubMed] [CrossRef]
19. van Wamel JL,, Berkhout B . 1998. The first strand transfer during HIV-1 reverse transcription can occur either intramolecularly or intermolecularly. Virology 244 : 245– 251.[PubMed] [CrossRef]
20. Wilhelm M,, Boutabout M,, Heyman T,, Wilhelm FX . 1999. Reverse transcription of the yeast Ty1 retrotransposon: the mode of first strand transfer is either intermolecular or intramolecular. J Mol Biol 288 : 505– 510.[PubMed] [CrossRef]
21. Hungnes O,, Tjotta E,, Grinde B . 1992. Mutations in the central polypurine tract of HIV-1 result in delayed replication. Virology 190 : 440– 442.[PubMed] [CrossRef]
22. Charneau P,, Alizon M,, Clavel F . 1992. A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication. J Virol 66 : 2814– 2820.[PubMed]
23. Swanstrom R,, Varmus HE,, Bishop JM . 1981. The terminal redundancy of the retrovirus genome facilitates chain elongation by reverse transcriptase. J Biol Chem 256 : 1115– 1121.[PubMed]
24. Yu H,, Jetzt AE,, Ron Y,, Preston BD,, Dougherty JP . 1998. The nature of human immunodeficiency virus type 1 strand transfers. J Biol Chem 273 : 28384– 28391.[PubMed] [CrossRef]
25. Kung HJ,, Fung YK,, Majors JE,, Bishop JM,, Varmus HE . 1981. Synthesis of plus strands of retroviral DNA in cells infected with avian sarcoma virus and mouse mammary tumor virus. J Virol 37 : 127– 138.[PubMed]
26. Hsu TW,, Taylor JM . 1982. Single-stranded regions on unintegrated avian retrovirus DNA. J Virol 44 : 47– 53.[PubMed]
27. Miller MD,, Wang B,, Bushman FD . 1995. Human immunodeficiency virus type 1 preintegration complexes containing discontinuous plus strands are competent to integrate in vitro. J Virol 69 : 3938– 3944.[PubMed]
28. Klarmann GJ,, Yu H,, Chen X,, Dougherty JP,, Preston BD . 1997. Discontinuous plus-strand DNA synthesis in human immunodeficiency virus type 1-infected cells and in a partially reconstituted cell-free system. J Virol 71 : 9259– 9269.[PubMed]
29. Thomas JA,, Ott DE,, Gorelick RJ . 2007. Efficiency of human immunodeficiency virus type 1 postentry infection processes: evidence against disproportionate numbers of defective virions. J Virol 81 : 4367– 4370.[PubMed] [CrossRef]
30. Burdick RC,, Hu WS,, Pathak VK . 2013. Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc Natl Acad Sci U S A 110 : E4780– E4789.[PubMed] [CrossRef]
31. Ao Z,, Yao X,, Cohen EA . 2004. Assessment of the role of the central DNA flap in human immunodeficiency virus type 1 replication by using a single-cycle replication system. J Virol 78 : 3170– 3177.[PubMed] [CrossRef]
32. Van Maele B,, De Rijck J,, De Clercq E,, Debyser Z . 2003. Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction. J Virol 77 : 4685– 4694.[PubMed] [CrossRef]
33. Hu C,, Saenz DT,, Fadel HJ,, Walker W,, Peretz M,, Poeschla EM . 2010. The HIV-1 central polypurine tract functions as a second line of defense against APOBEC3G/F. J Virol 84 : 11981– 11993.[PubMed] [CrossRef]
34. Wurtzer S,, Goubard A,, Mammano F,, Saragosti S,, Lecossier D,, Hance AJ,, Clavel F . 2006. Functional central polypurine tract provides downstream protection of the human immunodeficiency virus type 1 genome from editing by APOBEC3G and APOBEC3B. J Virol 80 : 3679– 3683.[PubMed] [CrossRef]
35. Whitcomb JM,, Kumar R,, Hughes SH . 1990. Sequence of the circle junction of human immunodeficiency virus type 1: implications for reverse transcription and integration. J Virol 64 : 4903– 4906.[PubMed]
36. Pullen KA,, Ishimoto LK,, Champoux JJ . 1992. Incomplete removal of the RNA primer for minus-strand DNA synthesis by human immunodeficiency virus type 1 reverse transcriptase. J Virol 66 : 367– 373.[PubMed]
37. Smith JS,, Roth MJ . 1992. Specificity of human immunodeficiency virus-1 reverse transcriptase-associated ribonuclease H in removal of the minus-strand primer, tRNA(Lys3). J Biol Chem 267 : 15071– 15079.[PubMed]
38. Pullen KA,, Rattray AJ,, Champoux JJ . 1993. The sequence features important for plus strand priming by human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 268 : 6221– 6227.[PubMed]
39. Julias JG,, McWilliams MJ,, Sarafianos SG,, Arnold E,, Hughes SH . 2002. Mutations in the RNase H domain of HIV-1 reverse transcriptase affect the initiation of DNA synthesis and the specificity of RNase H cleavage in vivo. Proc Natl Acad Sci U S A 99 : 9515– 9520.[PubMed] [CrossRef]
40. Rausch JW,, Lener D,, Miller JT,, Julias JG,, Hughes SH,, Le Grice SF . 2002. Altering the RNase H primer grip of human immunodeficiency virus reverse transcriptase modifies cleavage specificity. Biochemistry 41 : 4856– 4865.[PubMed] [CrossRef]
41. Dash C,, Rausch JW,, Le Grice SF . 2004. Using pyrrolo-deoxycytosine to probe RNA/DNA hybrids containing the human immunodeficiency virus type-1 3′ polypurine tract. Nucleic Acids Res 32 : 1539– 1547.[PubMed] [CrossRef]
42. Yi-Brunozzi HY,, Le Grice SF . 2005. Investigating HIV-1 polypurine tract geometry via targeted insertion of abasic lesions in the (–)-DNA template and (+)-RNA primer. J Biol Chem 280 : 20154– 20162.[PubMed] [CrossRef]
43. Swanstrom R,, Willis JW, . 1997. Synthesis, assembly, and processing of viral proteins, p 263– 334. In Coffin JM,, Hughes SH,, Varmus HE (ed), Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
44. Linial ML . 1999. Foamy viruses are unconventional retroviruses. J Virol 73 : 1747– 1755.[PubMed]
45. Yu SF,, Baldwin DN,, Gwynn SR,, Yendapalli S,, Linial ML . 1996. Human foamy virus replication: a pathway distinct from that of retroviruses and hepadnaviruses. Science 271 : 1579– 1582.[PubMed] [CrossRef]
46. Roth MJ,, Tanese N,, Goff SP . 1985. Purification and characterization of murine retroviral reverse transcriptase expressed in Escherichia coli . J Biol Chem 260 : 9326– 9335.[PubMed]
47. Boyer PL,, Stenbak CR,, Clark PK,, Linial ML,, Hughes SH . 2004. Characterization of the polymerase and RNase H activities of human foamy virus reverse transcriptase. J Virol 78 : 6112– 6121.[PubMed] [CrossRef]
48. Nowak E,, Miller JT,, Bona MK,, Studnicka J,, Szczepanowski RH,, Jurkowski J,, Le Grice SF,, Nowotny M . 2014. Ty3 reverse transcriptase complexed with an RNA–DNA hybrid shows structural and functional asymmetry. Nat Struct Mol Biol 21 : 389– 396.[PubMed] [CrossRef]
49. Hizi A,, Gazit A,, Guthmann D,, Yaniv A . 1982. DNA-processing activities associated with the purified α, β2, and αβ molecular forms of avian sarcoma virus RNA-dependent DNA polymerase. J Virol 41 : 974– 981.[PubMed]
50. Hizi A,, Leis JP,, Joklik WK . 1977. RNA-dependent DNA polymerase of avian sarcoma virus B77. II. Comparison of the catalytic properties of the α, β2, and αβ enzyme forms. J Biol Chem 252 : 2290– 2295.[PubMed]
51. Hizi A,, Leis JP,, Joklik WK . 1977. The RNA-dependent DNA polymerase of avian sarcoma virus B77. Binding of viral and nonviral ribonucleic acids to the α, β2, and αβ forms of the enzyme. J Biol Chem 252 : 6878– 6884.[PubMed]
52. Lightfoote MM,, Coligan JE,, Folks TM,, Fauci AS,, Martin MA,, Venkatesan S . 1986. Structural characterization of reverse transcriptase and endonuclease polypeptides of the acquired immunodeficiency syndrome retrovirus. J Virol 60 : 771– 775.[PubMed]
53. Kohlstaedt LA,, Wang J,, Friedman JM,, Rice PA,, Steitz TA . 1992. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256 : 1783– 1790.[PubMed] [CrossRef]
54. Jacobo-Molina A,, Ding J,, Nanni RG,, Clark AD Jr,, Lu X,, Tantillo C,, Williams RL,, Kamer G,, Ferris AL,, Clark P,, Hizi A,, Hughes SH,, Arnold E . 1993. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc Natl Acad Sci U S A 90 : 6320– 6324.[CrossRef]
55. Poch O,, Sauvaget I,, Delarue M,, Tordo N . 1989. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 8 : 3867– 3874.[PubMed]
56. Malik HS,, Eickbush TH . 2001. Phylogenetic analysis of ribonuclease H domains suggests a late, chimeric origin of LTR retrotransposable elements and retroviruses. Genome Res 11 : 1187– 1197.[PubMed] [CrossRef]
57. Gao G,, Goff SP . 1998. Replication defect of moloney murine leukemia virus with a mutant reverse transcriptase that can incorporate ribonucleotides and deoxyribonucleotides. J Virol 72 : 5905– 5911.[PubMed]
58. Boyer PL,, Sarafianos SG,, Arnold E,, Hughes SH . 2000. Analysis of mutations at positions 115 and 116 in the dNTP binding site of HIV-1 reverse transcriptase. Proc Natl Acad Sci U S A 97 : 3056– 3061.[PubMed] [CrossRef]
59. Esnouf R,, Ren J,, Ross C,, Jones Y,, Stammers D,, Stuart D . 1995. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol 2 : 303– 308.[PubMed] [CrossRef]
60. Rodgers DW,, Gamblin SJ,, Harris BA,, Ray S,, Culp JS,, Hellmig B,, Woolf DJ,, Debouck C,, Harrison SC . 1995. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 92 : 1222– 1226.[PubMed] [CrossRef]
61. Hsiou Y,, Ding J,, Das K,, Clark AD Jr,, Hughes SH,, Arnold E . 1996. Structure of unliganded HIV-1 reverse transcriptase at 2.7 Å resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure 4 : 853– 860.[PubMed] [CrossRef]
62. Sarafianos SG,, Clark AD Jr,, Das K,, Tuske S,, Birktoft JJ,, Ilankumaran P,, Ramesha AR,, Sayer JM,, Jerina DM,, Boyer PL,, Hughes SH,, Arnold E . 2002. Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J 21 : 6614– 6624.[PubMed] [CrossRef]
63. Sarafianos SG,, Das K,, Tantillo C,, Clark AD Jr,, Ding J,, Whitcomb JM,, Boyer PL,, Hughes SH,, Arnold E . 2001. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J 20 : 1449– 1461.[PubMed] [CrossRef]
64. Lapkouski M,, Tian L,, Miller JT,, Le Grice SF,, Yang W . 2013. Complexes of HIV-1 RT, NNRTI and RNA/DNA hybrid reveal a structure compatible with RNA degradation. Nat Struct Mol Biol 20 : 230– 236.[PubMed] [CrossRef]
65. Huang H,, Chopra R,, Verdine GL,, Harrison SC . 1998. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282 : 1669– 1675.[PubMed] [CrossRef]
66. Lansdon EB,, Samuel D,, Lagpacan L,, Brendza KM,, White KL,, Hung M,, Liu X,, Boojamra CG,, Mackman RL,, Cihlar T,, Ray AS,, McGrath ME,, Swaminathan S . 2010. Visualizing the molecular interactions of a nucleotide analog, GS-9148, with HIV-1 reverse transcriptase–DNA complex. J Mol Biol 397 : 967– 978.[PubMed] [CrossRef]
67. Tu X,, Das K,, Han Q,, Bauman JD,, Clark AD Jr,, Hou X,, Frenkel YV,, Gaffney BL,, Jones RA,, Boyer PL,, Hughes SH,, Sarafianos SG,, Arnold E . 2010. Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol 17 : 1202– 1209.[PubMed] [CrossRef]
68. Tuske S,, Sarafianos SG,, Clark AD Jr,, Ding J,, Naeger LK,, White KL,, Miller MD,, Gibbs CS,, Boyer PL,, Clark P,, Wang G,, Gaffney BL,, Jones RA,, Jerina DM,, Hughes SH,, Arnold E . 2004. Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir. Nat Struct Mol Biol 11 : 469– 474.[PubMed] [CrossRef]
69. Lansdon EB,, Brendza KM,, Hung M,, Wang R,, Mukund S,, Jin D,, Birkus G,, Kutty N,, Liu X . 2010. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J Med Chem 53 : 4295– 4299.[PubMed] [CrossRef]
70. Das K,, Bauman JD,, Clark AD Jr,, Frenkel YV,, Lewi PJ,, Shatkin AJ,, Hughes SH,, Arnold E . 2008. High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci U S A 105 : 1466– 1471.[PubMed] [CrossRef]
71. Das K,, Ding J,, Hsiou Y,, Clark AD Jr,, Moereels H,, Koymans L,, Andries K,, Pauwels R,, Janssen PA,, Boyer PL,, Clark P,, Smith RH Jr,, Kroeger Smith MB,, Michejda CJ,, Hughes SH,, Arnold E . 1996. Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. J Mol Biol 264 : 1085– 1100.[PubMed] [CrossRef]
72. Esnouf RM,, Ren J,, Hopkins AL,, Ross CK,, Jones EY,, Stammers DK,, Stuart DI . 1997. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proc Natl Acad Sci U S A 94 : 3984– 3989.[PubMed] [CrossRef]
73. Ren J,, Esnouf R,, Hopkins A,, Ross C,, Jones Y,, Stammers D,, Stuart D . 1995. The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure 3 : 915– 926.[PubMed] [CrossRef]
74. Ren J,, Nichols C,, Bird LE,, Fujiwara T,, Sugimoto H,, Stuart DI,, Stammers DK . 2000. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J Biol Chem 275 : 14316– 14320.[PubMed] [CrossRef]
75. Ren J,, Esnouf RM,, Hopkins AL,, Stuart DI,, Stammers DK . 1999. Crystallographic analysis of the binding modes of thiazoloisoindolinone non-nucleoside inhibitors to HIV-1 reverse transcriptase and comparison with modeling studies. J Med Chem 42 : 3845– 3851.[PubMed] [CrossRef]
76. Doublie S,, Tabor S,, Long AM,, Richardson CC,, Ellenberger T . 1998. Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution. Nature 391 : 251– 258.[PubMed] [CrossRef]
77. Palaniappan C,, Wisniewski M,, Jacques PS,, Le Grice SF,, Fay PJ,, Bambara RA . 1997. Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. J Biol Chem 272 : 11157– 11164.[PubMed] [CrossRef]
78. Gao HQ,, Boyer PL,, Arnold E,, Hughes SH . 1998. Effects of mutations in the polymerase domain on the polymerase, RNase H and strand transfer activities of human immunodeficiency virus type 1 reverse transcriptase. J Mol Biol 277 : 559– 572.[PubMed] [CrossRef]
79. Powell MD,, Ghosh M,, Jacques PS,, Howard KJ,, Le Grice SF,, Levin JG . 1997. Alanine-scanning mutations in the “primer grip” of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity. J Biol Chem 272 : 13262– 13269.[PubMed] [CrossRef]
80. Sevilya Z,, Loya S,, Adir N,, Hizi A . 2003. The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is modulated by residue 294 of the small subunit. Nucleic Acids Res 31 : 1481– 1487.[PubMed] [CrossRef]
81. Sevilya Z,, Loya S,, Hughes SH,, Hizi A . 2001. The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is affected by the thumb subdomain of the small protein subunits. J Mol Biol 311 : 957– 971.[PubMed] [CrossRef]
82. Ghosh M,, Jacques PS,, Rodgers DW,, Ottman M,, Darlix JL,, Le Grice SF . 1996. Alterations to the primer grip of p66 HIV-1 reverse transcriptase and their consequences for template-primer utilization. Biochemistry 35 : 8553– 8562.[PubMed] [CrossRef]
83. Powell MD,, Beard WA,, Bebenek K,, Howard KJ,, Le Grice SF,, Darden TA,, Kunkel TA,, Wilson SH,, Levin JG . 1999. Residues in the αH and αI helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer. J Biol Chem 274 : 19885– 19893.[PubMed] [CrossRef]
84. Yang W,, Steitz TA . 1995. Recombining the structures of HIV integrase, RuvC and RNase H. Structure 3 : 131– 134.[CrossRef]
85. Nowotny M,, Gaidamakov SA,, Crouch RJ,, Yang W . 2005. Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis. Cell 121 : 1005– 1016.[PubMed] [CrossRef]
86. Dunn LL,, McWilliams MJ,, Das K,, Arnold E,, Hughes SH . 2009. Mutations in the thumb allow human immunodeficiency virus type 1 reverse transcriptase to be cleaved by protease in virions. J Virol 83 : 12336– 12344.[PubMed] [CrossRef]
87. Dunn LL,, Boyer PL,, Clark PK,, Hughes SH . 2013. Mutations in HIV-1 reverse transcriptase cause misfolding and miscleavage by the viral protease. Virology 444 : 241– 249.[PubMed] [CrossRef]
88. Huang W,, Gamarnik A,, Limoli K,, Petropoulos CJ,, Whitcomb JM . 2003. Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. J Virol 77 : 1512– 1523.[PubMed] [CrossRef]
89. Takehisa J,, Kraus MH,, Decker JM,, Li Y,, Keele BF,, Bibollet-Ruche F,, Zammit KP,, Weng Z,, Santiago ML,, Kamenya S,, Wilson ML,, Pusey AE,, Bailes E,, Sharp PM,, Shaw GM,, Hahn BH . 2007. Generation of infectious molecular clones of simian immunodeficiency virus from fecal consensus sequences of wild chimpanzees. J Virol 81 : 7463– 7475.[PubMed] [CrossRef]
90. Huang M,, Zensen R,, Cho M,, Martin MA . 1998. Construction and characterization of a temperature-sensitive human immunodeficiency virus type 1 reverse transcriptase mutant. J Virol 72 : 2047– 2054.[PubMed]
91. Wang J,, Bambara RA,, Demeter LM,, Dykes C . 2010. Reduced fitness in cell culture of HIV-1 with nonnucleoside reverse transcriptase inhibitor-resistant mutations correlates with relative levels of reverse transcriptase content and RNase H activity in virions. J Virol 84 : 9377– 9389.[PubMed] [CrossRef]
92. Thomas DC,, Voronin YA,, Nikolenko GN,, Chen J,, Hu WS,, Pathak VK . 2007. Determination of the ex vivo rates of human immunodeficiency virus type 1 reverse transcription by using novel strand-specific amplification analysis. J Virol 81 : 4798– 4807.[PubMed] [CrossRef]
93. Fassati A,, Goff SP . 2001. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J Virol 75 : 3626– 3635.[PubMed] [CrossRef]
94. Forshey BM,, von Schwedler U,, Sundquist WI,, Aiken C . 2002. Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J Virol 76 : 5667– 5677.[PubMed] [CrossRef]
95. Nermut MV,, Fassati A . 2003. Structural analyses of purified human immunodeficiency virus type 1 intracellular reverse transcription complexes. J Virol 77 : 8196– 8206.[CrossRef]
96. Iordanskiy S,, Berro R,, Altieri M,, Kashanchi F,, Bukrinsky M . 2006. Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 3 : 4. [PubMed] [CrossRef]
97. Dismuke DJ,, Aiken C . 2006. Evidence for a functional link between uncoating of the human immunodeficiency virus type 1 core and nuclear import of the viral preintegration complex. J Virol 80 : 3712– 3720.[PubMed] [CrossRef]
98. Hulme AE,, Perez O,, Hope TJ . 2011. Complementary assays reveal a relationship between HIV-1 uncoating and reverse transcription. Proc Natl Acad Sci U S A 108 : 9975– 9980.[PubMed] [CrossRef]
99. Summers J,, Mason WS . 1982. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29 : 403– 415.[PubMed] [CrossRef]
100. Yu SF,, Sullivan MD,, Linial ML . 1999. Evidence that the human foamy virus genome is DNA. J Virol 73 : 1565– 1572.[PubMed]
101. Rasaiyaah J,, Tan CP,, Fletcher AJ,, Price AJ,, Blondeau C,, Hilditch L,, Jacques DA,, Selwood DL,, James LC,, Noursadeghi M,, Towers GJ . 2013. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503 : 402– 405.[PubMed] [CrossRef]
102. Pornillos O,, Ganser-Pornillos BK,, Yeager M . 2011. Atomic-level modelling of the HIV capsid. Nature 469 : 424– 427.[PubMed] [CrossRef]
103. Li S,, Hill CP,, Sundquist WI,, Finch JT . 2000. Image reconstructions of helical assemblies of the HIV-1 CA protein. Nature 407 : 409– 413.[PubMed] [CrossRef]
104. Tang S,, Murakami T,, Agresta BE,, Campbell S,, Freed EO,, Levin JG . 2001. Human immunodeficiency virus type 1 N-terminal capsid mutants that exhibit aberrant core morphology and are blocked in initiation of reverse transcription in infected cells. J Virol 75 : 9357– 9366.[PubMed] [CrossRef]
105. Arhel NJ,, Souquere-Besse S,, Munier S,, Souque P,, Guadagnini S,, Rutherford S,, Prevost MC,, Allen TD,, Charneau P . 2007. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J 26 : 3025– 3037.[PubMed] [CrossRef]
106. Brown PO,, Bowerman B,, Varmus HE,, Bishop JM . 1987. Correct integration of retroviral DNA in vitro. Cell 49 : 347– 356.[CrossRef]
107. Brown PO,, Bowerman B,, Varmus HE,, Bishop JM . 1989. Retroviral integration: structure of the initial covalent product and its precursor, and a role for the viral IN protein. Proc Natl Acad Sci U S A 86 : 2525– 2529.[PubMed] [CrossRef]
108. Taylor JM,, Cywinski A,, Smith JK . 1983. Discontinuities in the DNA synthesized by an avian retrovirus. J Virol 48 : 654– 659.[PubMed]
109. Lochelt M,, Flugel RM . 1996. The human foamy virus pol gene is expressed as a Pro-Pol polyprotein and not as a Gag-Pol fusion protein. J Virol 70 : 1033– 1040.[PubMed]
110. Konvalinka J,, Lochelt M,, Zentgraf H,, Flugel RM,, Krausslich HG . 1995. Active foamy virus proteinase is essential for virus infectivity but not for formation of a Pol polyprotein. J Virol 69 : 7264– 7268.[PubMed]
111. Feng YX,, Copeland TD,, Henderson LE,, Gorelick RJ,, Bosche WJ,, Levin JG,, Rein A . 1996. HIV-1 nucleocapsid protein induces “maturation” of dimeric retroviral RNA in vitro. Proc Natl Acad Sci U S A 93 : 7577– 7581.[CrossRef]
112. Zhang WH,, Hwang CK,, Hu WS,, Gorelick RJ,, Pathak VK . 2002. Zinc finger domain of murine leukemia virus nucleocapsid protein enhances the rate of viral DNA synthesis in vivo. J Virol 76 : 7473– 7484.[PubMed] [CrossRef]
113. Driscoll MD,, Hughes SH . 2000. Human immunodeficiency virus type 1 nucleocapsid protein can prevent self-priming of minus-strand strong stop DNA by promoting the annealing of short oligonucleotides to hairpin sequences. J Virol 74 : 8785– 8792.[PubMed] [CrossRef]
114. Buckman JS,, Bosche WJ,, Gorelick RJ . 2003. Human immunodeficiency virus type 1 nucleocapsid Zn 2+ fingers are required for efficient reverse transcription, initial integration processes, and protection of newly synthesized viral DNA. J Virol 77 : 1469– 1480.[PubMed] [CrossRef]
115. Thomas JA,, Gagliardi TD,, Alvord WG,, Lubomirski M,, Bosche WJ,, Gorelick RJ . 2006. Human immunodeficiency virus type 1 nucleocapsid zinc-finger mutations cause defects in reverse transcription and integration. Virology 353 : 41– 51.[PubMed] [CrossRef]
116. Thomas JA,, Bosche WJ,, Shatzer TL,, Johnson DG,, Gorelick RJ . 2008. Mutations in human immunodeficiency virus type 1 nucleocapsid protein zinc fingers cause premature reverse transcription. J Virol 82 : 9318– 9328.[PubMed] [CrossRef]
117. Thomas JA,, Gorelick RJ . 2008. Nucleocapsid protein function in early infection processes. Virus Res 134 : 39– 63.[PubMed] [CrossRef]
118. Guo J,, Wu T,, Anderson J,, Kane BF,, Johnson DG,, Gorelick RJ,, Henderson LE,, Levin JG . 2000. Zinc finger structures in the human immunodeficiency virus type 1 nucleocapsid protein facilitate efficient minus- and plus-strand transfer. J Virol 74 : 8980– 8988.[PubMed] [CrossRef]
119. Engelman A,, Englund G,, Orenstein JM,, Martin MA,, Craigie R . 1995. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol 69 : 2729– 2736.[PubMed]
120. Masuda T,, Planelles V,, Krogstad P,, Chen IS . 1995. Genetic analysis of human immunodeficiency virus type 1 integrase and the U3 att site: unusual phenotype of mutants in the zinc finger-like domain. J Virol 69 : 6687– 6696.[PubMed]
121. Leavitt AD,, Robles G,, Alesandro N,, Varmus HE . 1996. Human immunodeficiency virus type 1 integrase mutants retain in vitro integrase activity yet fail to integrate viral DNA efficiently during infection. J Virol 70 : 721– 728.[PubMed]
122. Wu X,, Liu H,, Xiao H,, Conway JA,, Hehl E,, Kalpana GV,, Prasad V,, Kappes JC . 1999. Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex. J Virol 73 : 2126– 2135.[PubMed]
123. Kirchner J,, Sandmeyer SB . 1996. Ty3 integrase mutants defective in reverse transcription or 3′-end processing of extrachromosomal Ty3 DNA. J Virol 70 : 4737– 4747.[PubMed]
124. Nymark-McMahon MH,, Beliakova-Bethell NS,, Darlix JL,, Le Grice SF,, Sandmeyer SB . 2002. Ty3 integrase is required for initiation of reverse transcription. J Virol 76 : 2804– 2816.[PubMed] [CrossRef]
125. Nymark-McMahon MH,, Sandmeyer SB . 1999. Mutations in nonconserved domains of Ty3 integrase affect multiple stages of the Ty3 life cycle. J Virol 73 : 453– 465.[PubMed]
126. Harrich D,, Ulich C,, Garcia-Martinez LF,, Gaynor RB . 1997. Tat is required for efficient HIV-1 reverse transcription. EMBO J 16 : 1224– 1235.[PubMed] [CrossRef]
127. Kameoka M,, Morgan M,, Binette M,, Russell RS,, Rong L,, Guo X,, Mouland A,, Kleiman L,, Liang C,, Wainberg MA . 2002. The Tat protein of human immunodeficiency virus type 1 (HIV-1) can promote placement of tRNA primer onto viral RNA and suppress later DNA polymerization in HIV-1 reverse transcription. J Virol 76 : 3637– 3645.[PubMed] [CrossRef]
128. Liang C,, Wainberg MA . 2002. The role of Tat in HIV-1 replication: an activator and/or a suppressor? AIDS Rev 4 : 41– 49.[PubMed]
129. Apolloni A,, Meredith LW,, Suhrbier A,, Kiernan R,, Harrich D . 2007. The HIV-1 Tat protein stimulates reverse transcription in vitro. Curr HIV Res 5 : 473– 483.[PubMed] [CrossRef]
130. Henriet S,, Sinck L,, Bec G,, Gorelick RJ,, Marquet R,, Paillart JC . 2007. Vif is a RNA chaperone that could temporally regulate RNA dimerization and the early steps of HIV-1 reverse transcription. Nucleic Acids Res 35 : 5141– 5153.[PubMed] [CrossRef]
131. Carr JM,, Coolen C,, Davis AJ,, Burrell CJ,, Li P . 2008. Human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) is part of reverse transcription complexes and acts as an accessory factor for reverse transcription. Virology 372 : 147– 156.[PubMed] [CrossRef]
132. Elder JH,, Lerner DL,, Hasselkus-Light CS,, Fontenot DJ,, Hunter E,, Luciw PA,, Montelaro RC,, Phillips TR . 1992. Distinct subsets of retroviruses encode dUTPase. J Virol 66 : 1791– 1794.[PubMed]
133. Wagaman PC,, Hasselkus-Light CS,, Henson M,, Lerner DL,, Phillips TR,, Elder JH . 1993. Molecular cloning and characterization of deoxyuridine triphosphatase from feline immunodeficiency virus (FIV). Virology 196 : 451– 457.[PubMed] [CrossRef]
134. Lerner DL,, Wagaman PC,, Phillips TR,, Prospero-Garcia O,, Henriksen SJ,, Fox HS,, Bloom FE,, Elder JH . 1995. Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase. Proc Natl Acad Sci U S A 92 : 7480– 7484.[PubMed] [CrossRef]
135. Selig L,, Benichou S,, Rogel ME,, Wu LI,, Vodicka MA,, Sire J,, Benarous R,, Emerman M . 1997. Uracil DNA glycosylase specifically interacts with Vpr of both human immunodeficiency virus type 1 and simian immunodeficiency virus of sooty mangabeys, but binding does not correlate with cell cycle arrest. J Virol 71 : 4842– 4846.[PubMed]
136. Mansky LM,, Preveral S,, Selig L,, Benarous R,, Benichou S . 2000. The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 In vivo mutation rate. J Virol 74 : 7039– 7047.[PubMed] [CrossRef]
137. Chen R,, Le Rouzic E,, Kearney JA,, Mansky LM,, Benichou S . 2004. Vpr-mediated incorporation of UNG2 into HIV-1 particles is required to modulate the virus mutation rate and for replication in macrophages. J Biol Chem 279 : 28419– 28425.[PubMed] [CrossRef]
138. Schrofelbauer B,, Yu Q,, Zeitlin SG,, Landau NR . 2005. Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases. J Virol 79 : 10978– 10987.[PubMed] [CrossRef]
139. Cen S,, Javanbakht H,, Kim S,, Shiba K,, Craven R,, Rein A,, Ewalt K,, Schimmel P,, Musier-Forsyth K,, Kleiman L . 2002. Retrovirus-specific packaging of aminoacyl-tRNA synthetases with cognate primer tRNAs. J Virol 76 : 13111– 13115.[PubMed] [CrossRef]
140. Javanbakht H,, Cen S,, Musier-Forsyth K,, Kleiman L . 2002. Correlation between tRNALys3 aminoacylation and its incorporation into HIV-1. J Biol Chem 277 : 17389– 17396.[PubMed] [CrossRef]
141. Kelly MC,, Kosloff BR,, Morrow CD . 2007. Forced selection of tRNA(Glu) reveals the importance of two adenosine-rich RNA loops within the U5-PBS for SIV(smmPBj) replication. Virology 366 : 330– 339.[PubMed] [CrossRef]
142. Djekic UV,, Morrow CD . 2007. Analysis of the replication of HIV-1 forced to use tRNAMet(i) supports a link between primer selection, translation and encapsidation. Retrovirology 4 : 10. [PubMed] [CrossRef]
143. Li M,, Eipers PG,, Ni N,, Morrow CD . 2006. HIV-1 designed to use different tRNAGln isoacceptors prefers to select tRNAThr for replication. Virol J 3 : 80. [PubMed] [CrossRef]
144. Galvis AE,, Fisher HE,, Nitta T,, Fan H,, Camerini D . 2014. Impairment of HIV-1 cDNA synthesis by DBR1 knockdown. J Virol 88 : 7054– 7069.[PubMed] [CrossRef]
145. Ye Y,, De Leon J,, Yokoyama N,, Naidu Y,, Camerini D . 2005. DBR1 siRNA inhibition of HIV-1 replication. Retrovirology 2 : 63. [PubMed] [CrossRef]
146. Frankel WN,, Stoye JP,, Taylor BA,, Coffin JM . 1989. Genetic analysis of endogenous xenotropic murine leukemia viruses: association with two common mouse mutations and the viral restriction locus Fv-1. J Virol 63 : 1763– 1774.[PubMed]
147. Best S,, Le Tissier P,, Towers G,, Stoye JP . 1996. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382 : 826– 829.[PubMed] [CrossRef]
148. Nisole S,, Lynch C,, Stoye JP,, Yap MW . 2004. A Trim5–cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1. Proc Natl Acad Sci U S A 101 : 13324– 13328.[PubMed] [CrossRef]
149. Sayah DM,, Sokolskaja E,, Berthoux L,, Luban J . 2004. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430 : 569– 573.[PubMed] [CrossRef]
150. Stremlau M,, Owens CM,, Perron MJ,, Kiessling M,, Autissier P,, Sodroski J . 2004. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 427 : 848– 853.[PubMed] [CrossRef]
151. Stremlau M,, Perron M,, Lee M,, Li Y,, Song B,, Javanbakht H,, Diaz-Griffero F,, Anderson DJ,, Sundquist WI,, Sodroski J . 2006. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. Proc Natl Acad Sci U S A 103 : 5514– 5519.[PubMed] [CrossRef]
152. Wu X,, Anderson JL,, Campbell EM,, Joseph AM,, Hope TJ . 2006. Proteasome inhibitors uncouple rhesus TRIM5α restriction of HIV-1 reverse transcription and infection. Proc Natl Acad Sci U S A 103 : 7465– 7470.[PubMed] [CrossRef]
153. Brennan TP,, Woods JO,, Sedaghat AR,, Siliciano JD,, Siliciano RF,, Wilke CO . 2009. Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4 + T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J Virol 83 : 8470– 8481.[PubMed] [CrossRef]
154. Newman RM,, Hall L,, Kirmaier A,, Pozzi LA,, Pery E,, Farzan M,, O’Neil SP,, Johnson W . 2008. Evolution of a TRIM5–CypA splice isoform in old world monkeys. PLoS Pathog 4 : e1000003. [PubMed] [CrossRef]
155. Virgen CA,, Kratovac Z,, Bieniasz PD,, Hatziioannou T . 2008. Independent genesis of chimeric TRIM5–cyclophilin proteins in two primate species. Proc Natl Acad Sci U S A 105 : 3563– 3568.[PubMed] [CrossRef]
156. Wilson SJ,, Webb BL,, Ylinen LM,, Verschoor E,, Heeney JL,, Towers GJ . 2008. Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc Natl Acad Sci U S A 105 : 3557– 3562.[PubMed] [CrossRef]
157. Ahn J,, Hao C,, Yan J,, DeLucia M,, Mehrens J,, Wang C,, Gronenborn AM,, Skowronski J . 2012. HIV/simian immunodeficiency virus (SIV) accessory virulence factor Vpx loads the host cell restriction factor SAMHD1 onto the E3 ubiquitin ligase complex CRL4DCAF1. J Biol Chem 287 : 12550– 12558.[PubMed] [CrossRef]
158. Hrecka K,, Hao C,, Gierszewska M,, Swanson SK,, Kesik-Brodacka M,, Srivastava S,, Florens L,, Washburn MP,, Skowronski J . 2011. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474 : 658– 661.[PubMed] [CrossRef]
159. St Gelais C,, Wu L . 2011. SAMHD1: a new insight into HIV-1 restriction in myeloid cells. Retrovirology 8 : 55. [PubMed] [CrossRef]
160. St Gelais C,, de Silva S,, Amie SM,, Coleman CM,, Hoy H,, Hollenbaugh JA,, Kim B,, Wu L . 2012. SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4 + T-lymphocytes cannot be upregulated by interferons. Retrovirology 9 : 105. [PubMed] [CrossRef]
161. Lahouassa H,, Daddacha W,, Hofmann H,, Ayinde D,, Logue EC,, Dragin L,, Bloch N,, Maudet C,, Bertrand M,, Gramberg T,, Pancino G,, Priet S,, Canard B,, Laguette N,, Benkirane M,, Transy C,, Landau NR,, Kim B,, Margottin-Goguet F . 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13 : 223– 228.[PubMed] [CrossRef]
162. Laguette N,, Sobhian B,, Casartelli N,, Ringeard M,, Chable-Bessia C,, Segeral E,, Yatim A,, Emiliani S,, Schwartz O,, Benkirane M . 2011. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474 : 654– 657.[PubMed] [CrossRef]
163. Rice GI,, Bond J,, Asipu A,, Brunette RL,, Manfield IW,, Carr IM,, Fuller JC,, Jackson RM,, Lamb T,, Briggs TA,, Ali M,, Gornall H,, Couthard LR,, Aeby A,, Attard-Montalto SP,, Bertini E,, Bodemer C,, Brockmann K,, Brueton LA,, Corry PC,, Desguerre I,, Fazzi E,, Cazorla AG,, Gener B,, Hamel BC,, Heiberg A,, Hunter M,, van der Knaap MS,, Kumar R,, Lagae L,, Landrieu PG,, Lourenco CM,, Marom D,, McDermott MF,, van der Merwe W,, Orcesi S,, Prendiville JS,, Rasmussen M,, Shalev SA,, Soler DM,, Shinawi M,, Spiegel R,, Tan TY,, Vanderver A,, Wakeling EL,, Wassmer E,, Whittaker E,, Lebon P,, Stetson DB,, Bonthron DT,, Crow YJ . 2009. Mutations involved in Aicardi–Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 41 : 829– 832.[PubMed] [CrossRef]
164. Rice GI,, Forte GM,, Szynkiewicz M,, Chase DS,, Aeby A,, Abdel-Hamid MS,, Ackroyd S,, Allcock R,, Bailey KM,, Balottin U,, Barnerias C,, Bernard G,, Bodemer C,, Botella MP,, Cereda C,, Chandler KE,, Dabydeen L,, Dale RC,, De Laet C,, De Goede CG,, Del Toro M,, Effat L,, Enamorado NN,, Fazzi E,, Gener B,, Haldre M,, Lin JP,, Livingston JH,, Lourenco CM,, Marques W Jr,, Oades P,, Peterson P,, Rasmussen M,, Roubertie A,, Schmidt JL,, Shalev SA,, Simon R,, Spiegel R,, Swoboda KJ,, Temtamy SA,, Vassallo G,, Vilain CN,, Vogt J,, Wermenbol V,, Whitehouse WP,, Soler D,, Olivieri I,, Orcesi S,, Aglan MS,, Zaki MS,, Abdel-Salam GM,, Vanderver A,, Kisand K,, Rozenberg F,, Lebon P,, Crow YJ . 2013. Assessment of interferon-related biomarkers in Aicardi–Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case–control study. Lancet Neurol 12 : 1159– 1169.[PubMed] [CrossRef]
165. Bishop KN,, Holmes RK,, Sheehy AM,, Davidson NO,, Cho SJ,, Malim MH . 2004. Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Curr Biol 14 : 1392– 1396.[PubMed] [CrossRef]
166. Bishop KN,, Holmes RK,, Sheehy AM,, Malim MH . 2004. APOBEC-mediated editing of viral RNA. Science 305 : 645. [PubMed] [CrossRef]
167. Zheng YH,, Irwin D,, Kurosu T,, Tokunaga K,, Sata T,, Peterlin BM . 2004. Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication. J Virol 78 : 6073– 6076.[PubMed] [CrossRef]
168. Harris RS,, Bishop KN,, Sheehy AM,, Craig HM,, Petersen-Mahrt SK,, Watt IN,, Neuberger MS,, Malim MH . 2003. DNA deamination mediates innate immunity to retroviral infection. Cell 113 : 803– 809.[PubMed] [CrossRef]
169. Harris RS,, Sheehy AM,, Craig HM,, Malim MH,, Neuberger MS . 2003. DNA deamination: not just a trigger for antibody diversification but also a mechanism for defense against retroviruses. Nat Immunol 4 : 641– 643.[PubMed] [CrossRef]
170. Mangeat B,, Turelli P,, Caron G,, Friedli M,, Perrin L,, Trono D . 2003. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424 : 99– 103.[PubMed] [CrossRef]
171. Bishop KN,, Holmes RK,, Malim MH . 2006. Antiviral potency of APOBEC proteins does not correlate with cytidine deamination. J Virol 80 : 8450– 8458.[PubMed] [CrossRef]
172. Bishop KN,, Verma M,, Kim EY,, Wolinsky SM,, Malim MH . 2008. APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathog 4 : e1000231. [PubMed] [CrossRef]
173. Holmes RK,, Malim MH,, Bishop KN . 2007. APOBEC-mediated viral restriction: not simply editing? Trends Biochem Sci 32 : 118– 128.[PubMed] [CrossRef]
174. Mbisa JL,, Barr R,, Thomas JA,, Vandegraaff N,, Dorweiler IJ,, Svarovskaia ES,, Brown WL,, Mansky LM,, Gorelick RJ,, Harris RS,, Engelman A,, Pathak VK . 2007. Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration. J Virol 81 : 7099– 7110.[PubMed] [CrossRef]
175. Keele BF,, Giorgi EE,, Salazar-Gonzalez JF,, Decker JM,, Pham KT,, Salazar MG,, Sun C,, Grayson T,, Wang S,, Li H,, Wei X,, Jiang C,, Kirchherr JL,, Gao F,, Anderson JA,, Ping LH,, Swanstrom R,, Tomaras GD,, Blattner WA,, Goepfert PA,, Kilby JM,, Saag MS,, Delwart EL,, Busch MP,, Cohen MS,, Montefiori DC,, Haynes BF,, Gaschen B,, Athreya GS,, Lee HY,, Wood N,, Seoighe C,, Perelson AS,, Bhattacharya T,, Korber BT,, Hahn BH,, Shaw GM . 2008. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105 : 7552– 7557.[PubMed] [CrossRef]
176. Coffin JM . 1995. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267 : 483– 489.[PubMed] [CrossRef]
177. Meyer PR,, Matsuura SE,, Mian AM,, So AG,, Scott WA . 1999. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 4 : 35– 43.[CrossRef]
178. Boyer PL,, Sarafianos SG,, Arnold E,, Hughes SH . 2001. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol 75 : 4832– 4842.[PubMed] [CrossRef]
179. Mansky LM,, Bernard LC . 2000. 3′-Azido-3′- deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1. J Virol 74 : 9532– 9539.[CrossRef]
180. Koyama H,, Ito T,, Nakanishi T,, Sekimizu K . 2007. Stimulation of RNA polymerase II transcript cleavage activity contributes to maintain transcriptional fidelity in yeast. Genes Cells 12 : 547– 559.[PubMed] [CrossRef]
181. O’Neil PK,, Sun G,, Yu H,, Ron Y,, Dougherty JP,, Preston BD . 2002. Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis. J Biol Chem 277 : 38053– 38061.[PubMed] [CrossRef]
182. Mansky LM,, Temin HM . 1995. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69 : 5087– 5094.[PubMed]
183. Mansky LM . 1996. Forward mutation rate of human immunodeficiency virus type 1 in a T lymphoid cell line. AIDS Res Hum Retroviruses 12 : 307– 314.[PubMed] [CrossRef]
184. Abram ME,, Ferris AL,, Shao W,, Alvord WG,, Hughes SH . 2010. The nature, position and frequency of mutations made in a single-cycle of HIV-1 replication. J Virol 84 : 9864– 9878.[PubMed] [CrossRef]