Abstract
Replication of HIV-1 under selective pressure frequently results in the evolution of virus variants that replicate more efficiently under the applied conditions. For example, in patients on antiretroviral therapy, such evolution can result in variants that are resistant to the HIV-1 inhibitors, thus frustrating the therapy. On the other hand, virus evolution can help us to understand the molecular mechanisms that underlie HIV-1 replication. For example, evolution of a defective virus mutant can result in variants that overcome the introduced defect by restoration of the original sequence or by the introduction of additional mutations in the viral genome. Analysis of the evolution pathway can reveal the requirements of the element under study and help to understand its function. Analysis of the escape routes may generate new insight in the viral life cycle and result in the identification of unexpected biological mechanisms. We have developed in vitro HIV-1 evolution into a systematic research tool that allows the study of different aspects of the viral replication cycle. We will briefly review this method of forced virus evolution and provide several examples that illustrate the power of this approach.
References
Abbink T. E. M.& Berkhout B. . 2003A novel long distance base-pairing interaction in human immunodeficiency virus type 1 RNA occludes the gag start codon. J. Biol. Chem. 278, 11601–11611. (doi:10.1074/jbc.M210291200). Crossref, PubMed, ISI, Google ScholarAbbink T. E.& Berkhout B. . 2007RNA structure modulates splicing efficiency at the HIV-1 major splice donor. J. Virol. 82, 3090–3098. (doi:10.1128/JVI.01479-07). Crossref, PubMed, ISI, Google ScholarBaba T. W., Jeong Y. S., Penninck D., Bronson R., Greene M. F.& Ruprecht R. M. . 1995Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267, 1820–1825. (doi:10.1126/science.7892606). Crossref, PubMed, ISI, Google ScholarBaba T. W., 1999Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat. Med. 5, 194–203. (doi:10.1038/8859). Crossref, PubMed, ISI, Google ScholarBack N. K. T., Nijhuis M., Keulen W., Boucher C. A. B., Oude Essink B. B., van Kuilenburg A. B. P., Van Gennip A. H.& Berkhout B. . 1996Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 15, 4040–4049. Crossref, PubMed, ISI, Google ScholarBaldwin C. E.& Berkhout B. . 2006Second site escape of a T20-dependent HIV-1 variant by a single amino acid change in the CD4 binding region of the envelope glycoprotein. Retrovirology 3, 84. (doi:10.1186/1742-4690-3-84). Crossref, PubMed, ISI, Google ScholarBanerjea A., Li M. J., Bauer G., Remling L., Lee N. S., Rossi J.& Akkina R. . 2003Inhibition of HIV-1 by lentiviral vector-transduced siRNAs in T lymphocytes differentiated in SCID-hu mice and CD34+ progenitor cell-derived macrophages. Mol. Ther. 8, 62–71. (doi:10.1016/S1525-0016(03)00140-0). Crossref, PubMed, ISI, Google ScholarBaron U.& Bujard H. . 2000Tet repressor-based system for regulated gene expression in eukaryotic cells: principles and advances. Methods Enzymol. 327, 401–421. (doi:10.1016/S0076-6879(00)27292-3). Crossref, PubMed, ISI, Google ScholarBerkhout B. . 2009A new Houdini act: multiple routes for HIV-1 escape from RNAi-mediated inhibition. Future Microbiol. 4, 151–154. (doi:10.2217/17460913.4.2.151). Crossref, PubMed, ISI, Google ScholarBerkhout B.& de Ronde A. . 2004APOBEC3G versus reverse transcriptase in the generation of HIV-1 drug-resistance mutations. AIDS 18, 1861–1863. (doi:10.1097/00002030-200409030-00022). Crossref, PubMed, ISI, Google ScholarBerkhout B.& Haasnoot J. . 2006The interplay between virus infection and the cellular RNA interference machinery. FEBS Lett. 580, 2896–2902. (doi:10.1016/j.febslet.2006.02.070). Crossref, PubMed, ISI, Google ScholarBerkhout B.& Klaver B. . 1993In vivo selection of randomly mutated retroviral genomes. Nucleic Acids Res. 21, 5020–5024. (doi:10.1093/nar/21.22.5020). Crossref, PubMed, ISI, Google ScholarBerkhout B., Verhoef K., van Wamel J. L.& Back N. K. . 1999Genetic instability of live, attenuated human immunodeficiency virus type 1 vaccine strains. J. Virol. 73, 1138–1145. Crossref, PubMed, ISI, Google ScholarBerkhout B., Das A. T.& Beerens N. . 2001HIV-1 RNA editing, hypermutation and error-prone reverse transcription. Science 292, 7. (doi:10.1126/science.292.5514.7a). Crossref, PubMed, Google ScholarBoden D., Pusch O., Lee F., Tucker L.& Ramratnam B. . 2003Human immunodeficiency virus type 1 escape from RNA interference. J. Virol. 77, 11531–11535. (doi:10.1128/JVI.77.21.11531-11535.2003). Crossref, PubMed, ISI, Google ScholarBreaker R. R. . 2004Natural and engineered nucleic acids as tools to explore biology. Nature 432, 838–845. (doi:10.1038/nature03195). Crossref, PubMed, ISI, Google ScholarChakrabarti L. A., Metzner K. J., Ivanovic T., Cheng H., Louis-Virelizier J., Connor R. I.& Cheng-Mayer C. . 2003A truncated form of Nef selected during pathogenic reversion of simian immunodeficiency virus SIVmac239Deltanef increases viral replication. J. Virol. 77, 1245–1256. (doi:10.1128/JVI.77.2.1245-1256.2003). Crossref, PubMed, ISI, Google ScholarCoffin J. M. . 1995HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267, 483–489. (doi:10.1126/science.7824947). Crossref, PubMed, ISI, Google ScholarDas A. T., Klaver B., Klasens B. I. F., van Wamel J. L. B.& Berkhout B. . 1997A conserved hairpin motif in the R-U5 region of the human immunodeficiency virus type 1 RNA genome is essential for replication. J. Virol. 71, 2346–2356. Crossref, PubMed, ISI, Google ScholarDas A. T., van Dam A. P., Klaver B.& Berkhout B. . 1998Improved envelope function selected by long-term cultivation of a translation-impaired HIV-1 mutant. Virology 244, 552–562. Crossref, PubMed, ISI, Google ScholarDas A. T., Klaver B.& Berkhout B. . 1999aA hairpin structure in the R region of the human immunodeficiency virus type 1 RNA genome is instrumental in polyadenylation site selection. J. Virol. 73, 81–91. Crossref, PubMed, ISI, Google ScholarDas A. T., Land A., Braakman I., Klaver B.& Berkhout B. . 1999bHIV-1 evolves into a non-syncytium-inducing virus upon prolonged culture in vitro. Virology 263, 55–69. (doi:10.1006/viro.1999.9898). Crossref, PubMed, ISI, Google ScholarDas A. T., Brummelkamp T. R., Westerhout E. M., Vink M., Madiredjo M., Bernards R.& Berkhout B. . 2004aHuman immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J. Virol. 78, 2601–2605. (doi:10.1128/JVI.78.5.2601-2605.2004). Crossref, PubMed, ISI, Google ScholarDas A. T., Zhou X., Vink M., Klaver B., Verhoef K., Marzio G.& Berkhout B. . 2004bViral evolution as a tool to improve the tetracycline-regulated gene expression system. J. Biol. Chem. 279, 18776–18782. (doi:10.1074/jbc.M313895200). Crossref, PubMed, ISI, Google ScholarDas A. T., Harwig A., Vrolijk M. M.& Berkhout B. . 2007The TAR hairpin of human immunodeficiency virus type-1 can be deleted when not required for Tat-mediated activation of transcription. J. Virol. 81, 7742–7748. (doi:10.1128/JVI.00392-07). Crossref, PubMed, ISI, Google ScholarDomingo E.& Wain-Hobson S. . 2009The 30th anniversary of quasispecies. Meeting on ‘Quasispecies: past, present and future.’. EMBO Rep. 10, 444–448. (doi:10.1038/embor.2009.61). Crossref, PubMed, ISI, Google ScholarDoria-Rose N. A.& Vogt V. M. . 1998In vivo selection of Rous sarcoma virus mutants with randomized sequences in the packaging signal. J. Virol. 72, 8073–8082. Crossref, PubMed, ISI, Google ScholarGossen M.& Bujard H. . 2001Tetracyclines in the control of gene expression in eukaryotes. Tetracyclines in biology, chemistry and medicine (eds, Nelson M., Hillen W.& Greenwald R. A. ), pp. 139–157. Basel, Switzerland: Birkhäuser Verlag. Google ScholarHaasnoot J., Westerhout E. M.& Berkhout B. . 2007RNA interference against viruses: strike and counterstrike. Nat. Biotechnol. 25, 1435–1443. (doi:10.1038/nbt1369). Crossref, PubMed, ISI, Google ScholarHache G., Shindo K., Albin J. S.& Harris R. S. . 2008Evolution of HIV-1 isolates that use a novel Vif-independent mechanism to resist restriction by human APOBEC3G. Curr. Biol. 18, 819–824. (doi:10.1016/j.cub.2008.04.073). Crossref, PubMed, ISI, Google ScholarHache G., Abbink T. E., Berkhout B.& Harris R. S. . 2009Optimal translation initiation enables Vif-deficient human immunodeficiency virus type 1 to escape restriction by APOBEC3G. J. Virol. 83, 5956–5960. (doi:10.1128/JVI.00045-09). Crossref, PubMed, ISI, Google ScholarHofmann-Lehmann R., Vlasak J., Williams A. L., Chenine A. L., McClure H. M., Anderson D. C., O'Neil S.& Ruprecht R. M. . 2003Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 17, 157–166. (doi:10.1097/00002030-200301240-00004). Crossref, PubMed, ISI, Google ScholarHuthoff H.& Berkhout B. . 2001Two alternating structures for the HIV-1 leader RNA. RNA 7, 143–157. (doi:10.1017/S1355838201001881). Crossref, PubMed, ISI, Google ScholarJohnson R. P.& Desrosiers R. C. . 1998Protective immunity induced by live attenuated simian immunodeficiency virus. Curr. Opin. Immunol. 10, 436–443. (doi:10.1016/S0952-7915(98)80118-0). Crossref, PubMed, ISI, Google ScholarKeulen W., Boucher C.& Berkhout B. . 1996Nucleotide substitution patterns can predict the requirements for drug-resistance of HIV-1 proteins. Antiviral Res. 31, 45–57. (doi:10.1016/0166-3542(96)00944-8). Crossref, PubMed, ISI, Google ScholarKeulen W., Back N. K. T., van Wijk A., Boucher C. A. B.& Berkhout B. . 1997Initial appearance of the 184Ile variant in lamivudine-treated patients is caused by the mutational bias of the human immunodeficiency virus type 1 reverse transcriptase. J. Virol. 71, 3346–3350. Crossref, PubMed, ISI, Google ScholarKlaver B.& Berkhout B. . 1994Evolution of a disrupted TAR RNA hairpin structure in the HIV-1 virus. EMBO J. 13, 2650–2659. Crossref, PubMed, ISI, Google ScholarKlovins J., Tsareva N. A., de Smit M. H., Berzins V.& van Duin J. . 1997Rapid evolution of translational control mechanisms in RNA genomes. J. Mol. Biol. 265, 372–384. (doi:10.1006/jmbi.1996.0745). Crossref, PubMed, ISI, Google ScholarKoff W. C., 2006HIV vaccine design: insights from live attenuated SIV vaccines. Nat. Immunol. 7, 19–23. (doi:10.1038/ni1296). Crossref, PubMed, ISI, Google ScholarLacey S. F.& Larder B. A. . 1994Mutagenic study of codons 74 and 215 of the human immunodeficiency virus type 1 reverse transcriptase, which are significant in nucleoside analog resistance. J. Virol. 5, 3421–3424. Crossref, Google ScholarLee S. K., 2005Lentiviral delivery of short hairpin RNAs protects CD4 T cells from multiple clades and primary isolates of HIV. Blood 106, 818–826. (doi:10.1182/blood-2004-10-3959). Crossref, PubMed, ISI, Google ScholarLeonard J. N., Shah P. S., Burnett J. C.& Schaffer D. V. . 2008HIV evades RNA interference directed at TAR by an indirect compensatory mechanism. Cell Host Microbe 4, 484–494. (doi:10.1016/j.chom.2008.09.008). Crossref, PubMed, ISI, Google ScholarLicis N., Balklava Z.& van Duin J. . 2000Forced retroevolution of an RNA bacteriophage. Virology 271, 298–306. (doi:10.1006/viro.2000.0327). Crossref, PubMed, ISI, Google ScholarMarzio G., Verhoef K., Vink M.& Berkhout B. . 2001In vitro evolution of a highly replicating, doxycycline-dependent HIV for applications in vaccine studies. Proc. Natl Acad. Sci. USA 98, 6342–6347. (doi:10.1073/pnas.111031498). Crossref, PubMed, ISI, Google ScholarMarzio G., Vink M., Verhoef K., de Ronde A.& Berkhout B. . 2002Efficient human immunodeficiency virus replication requires a fine-tuned level of transcription. J. Virol. 76, 3084–3088. (doi:10.1128/JVI.76.6.3084-3088.2002). Crossref, PubMed, ISI, Google ScholarMills J., Desrosiers R., Rud E.& Almond N. . 2000Live attenuated HIV vaccines: proposal for further research and development. AIDS Res. Hum. Retroviruses 16, 1453–1461. (doi:10.1089/088922200750005976). Crossref, PubMed, ISI, Google ScholarMorris S., Johnson M., Stavnezer E.& Leis J. . 2002Replication of avian sarcoma virus in vivo requires an interaction between the viral RNA and the TpsiC loop of the tRNA(Trp) primer. J. Virol. 76, 7571–7577. (doi:10.1128/JVI.76.15.7571-7577.2002). Crossref, PubMed, ISI, Google ScholarMunoz J. L., Parks W. P., Wolinsky S. M., Korber B. T.& Hutto C. . 1993HIV-1 reverse transcriptase. A diversity generator and quasispecies regulator. Ann. NY Acad. Sci. 693, 65–70. (doi:10.1111/j.1749-6632.1993.tb26257.x). Crossref, PubMed, ISI, Google ScholarObbard D. J., Gordon K. H., Buck A. H.& Jiggins F. M. . 2009The evolution of RNAi as a defence against viruses and transposable elements. Phil. Trans. R. Soc. B 364, 99–115. (doi:10.1098/rstb.2008.0168). Link, ISI, Google ScholarOlsthoorn R. C. L.& van Duin J. . 1996Evolutionary reconstruction of a hairpin deleted from the genome of an RNA virus. Proc. Natl Acad. Sci. USA 93, 12 256–12 261. (doi:10.1073/pnas.93.22.12256). Crossref, ISI, Google ScholarOoms M., Huthoff H., Russell R., Liang C.& Berkhout B. . 2004A riboswitch regulates RNA dimerization and packaging in human immunodeficiency virus type 1 virions. J. Virol. 78, 10 814–10 819. (doi:10.1128/JVI.78.19.10814-10819.2004). Crossref, ISI, Google ScholarRieger A.& Nassal M. . 1995Distinct requirements for primary sequence in the 5′- and 3′-part of a bulge in the hepatitis B virus RNA encapsidation signal revealed by a combination in vivo selection/in vitro amplification system. Nucleic Acids Res. 23, 3909–3915. (doi:10.1093/nar/23.19.3909). Crossref, PubMed, ISI, Google ScholarSun X., Zhang G.& Simon A. E. . 2005Short internal sequences involved in replication and virion accumulation in a subviral RNA of turnip crinkle virus. J. Virol. 79, 512–524. (doi:10.1128/JVI.79.1.512-524.2005). Crossref, PubMed, ISI, Google Scholarter Brake O., Konstantinova P., Ceylan M.& Berkhout B. . 2006Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol. Ther. 14, 883–892. (doi:10.1016/j.ymthe.2006.07.007). Crossref, PubMed, ISI, Google Scholarter Brake O., 't Hooft K., Liu Y. P., Centlivre M., von Eije K. J.& Berkhout B. . 2008aLentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition. Mol. Ther. 16, 557–564. (doi:10.1038/sj.mt.6300382). Crossref, PubMed, ISI, Google Scholarter Brake O., von Eije K. J.& Berkhout B. . 2008bProbing the sequence space available for HIV-1 evolution. AIDS 22, 1875–1877. (doi:10.1097/QAD.0b013e328309efe3). Crossref, PubMed, ISI, Google ScholarVerhoef K.& Berkhout B. . 1999A second-site mutation that restores replication of a Tat-defective human immunodeficiency virus. J. Virol. 73, 2781–2789. Crossref, PubMed, ISI, Google ScholarVerhoef K., Marzio G., Hillen W., Bujard H.& Berkhout B. . 2001Strict control of human immunodeficiency virus type 1 replication by a genetic switch: Tet for Tat. J. Virol. 75, 979–987. (doi:10.1128/JVI.75.2.979-987.2001). Crossref, PubMed, ISI, Google Scholarvon Eije K. J.& Berkhout B. . 2009RNA-interference-based gene therapy approaches to HIV type-1 treatment: tackling the hurdles from bench to bedside. Antivir. Chem. Chemother. 19, 221–233. Crossref, PubMed, Google Scholarvon Eije K. J., ter Brake O.& Berkhout B. . 2008Human immunodeficiency virus type 1 escape is restricted when conserved genome sequences are targeted by RNA interference. J. Virol. 82, 2895–2903. (doi:10.1128/JVI.02035-07). Crossref, PubMed, ISI, Google Scholarvon Eije K. J., ter Brake O.& Berkhout B. . 2009Stringent testing identifies highly potent and escape-proof anti-HIV short hairpin RNAs. J. Gene Med. 11, 459–467. (doi:10.1002/jgm.1329). Crossref, PubMed, ISI, Google ScholarVrolijk M. M., Ooms M., Harwig A., Das A. T.& Berkhout B. . 2008Destabilization of the TAR hairpin affects the structure and function of the HIV-1 leader RNA. Nucleic Acids Res. 36, 4352–4363. (doi:10.1093/nar/gkn364). Crossref, PubMed, ISI, Google ScholarVrolijk M. M., Harwig A., Berkhout B.& Das A. T. . 2009Destabilization of the TAR hairpin leads to extension of the polyA hairpin and inhibition of HIV-1 polyadenylation. Retrovirology 6, 13. (doi:10.1186/1742-4690-6-13). Crossref, PubMed, ISI, Google ScholarWesterhout E. M., Ooms M., Vink M., Das A. T.& Berkhout B. . 2005HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res. 33, 796–804. (doi:10.1093/nar/gki220). Crossref, PubMed, ISI, Google ScholarWhatmore A. M., Cook N., Hall G. A., Sharpe S., Rud E. W.& Cranage M. P. . 1995Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence. J. Virol. 69, 5117–5123. Crossref, PubMed, ISI, Google ScholarWhitney J. B.& Ruprecht R. M. . 2004Live attenuated HIV vaccines: pitfalls and prospects. Curr. Opin. Infect. Dis. 17, 17–26. (doi:10.1097/00001432-200402000-00004). Crossref, PubMed, ISI, Google ScholarYoon M.& Spear P. G. . 2004Random mutagenesis of the gene encoding a viral ligand for multiple cell entry receptors to obtain viral mutants altered for receptor usage. Proc. Natl Acad. Sci. USA 101, 17 252–17 257. (doi:10.1073/pnas.0407892101). Crossref, ISI, Google ScholarZhang J.& Simon A. E. . 2005Importance of sequence and structural elements within a viral replication repressor. Virology 333, 301–315. Crossref, PubMed, ISI, Google ScholarZhou X., Vink M., Berkhout B.& Das A. T. . 2006aModification of the Tet-On regulatory system prevents the conditional-live HIV-1 variant from losing doxycycline-control. Retrovirology 3, 82. (doi:10.1186/1742-4690-3-82). Crossref, PubMed, ISI, Google ScholarZhou X., Vink M., Klaver B., Berkhout B.& Das A. T. . 2006bOptimization of the Tet-On system for regulated gene expression through viral evolution. Gene Ther. 13, 1382–1390. (doi:10.1038/sj.gt.3302780). Crossref, PubMed, ISI, Google ScholarZhou X., Vink M., Klaver B., Verhoef K., Marzio G., Das A. T.& Berkhout B. . 2006cThe genetic stability of a conditional-live HIV-1 variant can be improved by mutations in the Tet-On regulatory system that restrain evolution. J. Biol. Chem. 281, 17084–17091. (doi:10.1074/jbc.M513400200). Crossref, PubMed, ISI, Google ScholarZhou X., Symons J., Hoppes R., Krueger C., Berens C., Hillen W., Berkhout B.& Das A. T. . 2007Improved single-chain transactivators of the Tet-On gene expression system. BMC Biotechnol. 7, 6. (doi:10.1186/1472-6750-7-6). Crossref, PubMed, ISI, Google Scholar


