Table 1.
Integrase history: chronology of selected discoveries and milestones
| Year | Discovery | Virus/notes | Reference(s)a |
|---|---|---|---|
| Viruses as infectious agents; discovery of reverse transcriptase and integrase | |||
| 1904–1936 | Discovery of retroviruses as infectious agents |
EIAV Chicken leukemia (ALV) Sarcomas (ASV) Mouse mammary tumors (MMTV) |
Vallée & Carré (133b) Ellermann & Bang (134) Rous (135) Bittner (136) |
| 1951–1957 | Leukemia virus isolation | MLV | Gross (137, 138) |
| 1954 | Cell culture isolation | PFV | Enders & Peebles (139) |
| 1957–1967 | Many new virus discoveries | Infecting rodents, sheep, chickens, cats, etc. |
— |
| 1958 | Focus assay and cell transformation |
Rous ASV | Temin & Rubin (140) |
| 1959 | X-ray-induced virus | MLV | Lieberman & Kaplan (141) |
| 1963–1964 | Provirus hypothesis | ASV: transformation | Svoboda, Hilgert, and colleagues (8); Temin (7) |
| 1965 | Inherited, endogenous virus | MMTV | Muhlbock (142) |
| 1970 | Reverse transcriptase in virus particles |
MLV ASV |
Baltimore (9) Temin & Mizutani (10) |
| 1978–1980 | Molecular characterization of viral DNA and provirus in infected cells |
MLV MSV ASV |
Hughes, Varmus, and colleagues (143) Dhar, Vande Woude, and colleagues (144) Ju & Skalka (27) |
| 1978 | First integrase purified from virus particles |
ALV: pp32 endonuclease | Grandgenett et al. (145) |
| 1981 | Discovery of the first human retrovirus |
HTLV-1 | Poiesz, Gallo, and colleagues (127) |
| 1983 | Discovery of the AIDS virus | HIV-1 | Gallo et al. (129); Barré-Sinoussi, Montagnier, and colleagues (128) |
| Integrases and their biochemical activities | |||
| 1984 | Integrase is essential for virus propagation |
MLV: integrase mutation MLV: integrase deletion SNV: integrase deletion |
Donehower & Varmus (146) Schwartzberg & Goff (147) Panganiban & Temin (148) |
| 1987 | Integration demonstrated with preintegration complexes from cells |
MLV | Brown, Bishop, and colleagues (149) |
| 1989 | In vitro integrase assays show specificity for DNA ends |
ASLV (ASV and ALV): short oligonucleotides |
Katzman, Leis, and colleagues (35) |
| 1990 | Bacterially produced integrase catalyzes processing and joining in vitro |
MLV ASLV |
Craigie (33) Katz, Skalka, and colleagues (34) |
| Domain structure and integrase functions | |||
| 1991 | Domain organization | Sequence alignments Deletion studies |
Khan, Skalka, and colleagues (56) Bushman, Craigie, and colleagues (54) |
| 1992 | Identification of catalytic residues | Conserved D,D(35)E motif | Kulkosky, Skalka, and colleagues (59) |
| 1992–1993 | Functional form is a multimer | Biochemistry Complementation |
Jones, Skalka, and colleagues (71) van Gent, Plasterk, and colleagues (86); Engelman, Bushman & Craigie (72) |
| 1994–1995 | First crystal structures | HIV: CCD ASLV: CCD |
Dyda, Davies, and colleagues (60) Bujacz, Wlodawer, and colleagues (61) |
| 1995–1997 | NMR structures of the terminal domains |
HIV-1: CTD HIV-1: NTD HIV-2: NTD |
Lodi, Gronenborn, and colleagues (66) Cai, Gronenborn, and colleagues (57) Eijkelenboom, Plasterk, and colleagues (58) |
| 2000–2009 | Two-domain crystal structures | HIV-1: CCD+CTD SIV: CCD+CTD ASLV: CCD+CTD HIV: NTD+CCD MVV: NTD+CCD |
J.C. Chen, Stroud, and colleagues (76) Z. Chen, Kuo, and colleagues (77) Yang, Hyde, and colleagues (78) Wang, Craigie, and colleagues (75) Hare, Cherepanov, and colleagues (79) |
| 2002–2004 | Integration site selection | HIV-1: human cells ASLV: human cells |
Schroder, Bushman, and colleagues (150) Narezkina, Katz, and colleagues (151) |
| 2003–2006 | Integrase tetramer for concerted integration |
Biochemistry/biophysics | Bao, Skalka, Wong, and colleagues (70); Li, Craigie, and colleagues (74) |
| 2003–2005 | Integrase tethering protein | HIV-1: CCD+LEDGF | Cherepanov, Debyzer, and colleagues (152); Cherepanov, Engelman, and colleagues (153) |
| 2007 | First FDA-approved HIV-1 integrase antiviral drug |
Raltegravir (active site inhibitor) | Merck |
| Full-length integrase structures and inhibitor mechanisms | |||
| 2010 | First intasome structure | PFV | Hare, Cherepanov, and colleagues (83) |
| 2010 | Intasome structure with active site inhibitor |
PFV | Hare, Cherepanov, and colleagues (83) |
| 2010 | Intasome with target DNA | PFV | Maertens, Hare & Cherepanov (88) |
| 2011–2013 | First full-length architectures of apo-integrase |
ASLV: monomer and dimer HIV-1: dimers and tetramer |
Andrake, Skalka, and colleagues (94) Bojja, Skalka, and colleagues (93) |
| 2010–2014 | Allosteric inhibitor | HIV-1: CCD | Christ, Debyzer, and colleagues (118); Sharma, Kvaratskhelia, and colleagues (154) |
For space, only the first publication of a specific discovery is cited in this chronology. The many, equally important follow-up and confirmation studies could not be included, but the interested reader is urged to investigate these further.
Domain abbreviations: CCD, core catalytic domain; CTD, C-terminal domain; NTD, N-terminal domain.
Virus abbreviations (and genera): ALV, avian leukosis virus (Alpharetrovirus); ASLV, ALV and ASV family (Alpharetrovirus); ASV, avian sarcoma/leukosis virus (Alpharetrovirus); EIAV, equine infectious anemia virus (Lentivirus); HIV, human immunodeficiency virus (Lentivirus); HTLV-1, human lymphotropic virus type 1 (Deltaretrovirus); MLV, murine leukemia virus (Gammaretrovirus); MMTV, mouse mammary tumor virus (Betaretrovirus); MMV, maedi-visna virus (Lentivirus); MSV, Moloney sarcoma virus (Gammaretrovirus); PFV, prototype foamy virus (Spumavirus); SIV, simian immunodeficiency virus (Lentivirus); SNV, spleen necrosis virus (Gammaretrovirus).