Skip to main content
Genetics logoLink to Genetics
. 2004 Aug;167(4):1573–1583. doi: 10.1534/genetics.103.023382

Pervasive genomic recombination of HIV-1 in vivo.

Daniel Shriner 1, Allen G Rodrigo 1, David C Nickle 1, James I Mullins 1
PMCID: PMC1470992  PMID: 15342499

Abstract

Recombinants of preexisting human immunodeficiency virus type 1 (HIV-1) strains are now circulating globally. To increase our understanding of the importance of these recombinants, we assessed recombination within an individual infected from a single source by studying the linkage patterns of the auxiliary genes of HIV-1 subtype B. Maximum-likelihood phylogenetic techniques revealed evidence for recombination from topological incongruence among adjacent genes. Coalescent methods were then used to estimate the in vivo recombination rate. The estimated mean rate of 1.38 x 10(-4) recombination events/adjacent sites/generation is approximately 5.5-fold greater than the reported point mutation rate of 2.5 x 10(-5)/site/generation. Recombination was found to be frequent enough to mask evidence for purifying selection by Tajima's D test. Thus, recombination is a major evolutionary force affecting genetic variation within an HIV-1-infected individual, of the same order of magnitude as point mutational change.

Full Text

The Full Text of this article is available as a PDF (160.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Awadalla Philip. The evolutionary genomics of pathogen recombination. Nat Rev Genet. 2003 Jan;4(1):50–60. doi: 10.1038/nrg964. [DOI] [PubMed] [Google Scholar]
  2. Carr J. K., Salminen M. O., Koch C., Gotte D., Artenstein A. W., Hegerich P. A., St Louis D., Burke D. S., McCutchan F. E. Full-length sequence and mosaic structure of a human immunodeficiency virus type 1 isolate from Thailand. J Virol. 1996 Sep;70(9):5935–5943. doi: 10.1128/jvi.70.9.5935-5943.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cullen B. R. HIV-1 auxiliary proteins: making connections in a dying cell. Cell. 1998 May 29;93(5):685–692. doi: 10.1016/s0092-8674(00)81431-2. [DOI] [PubMed] [Google Scholar]
  4. DeStefano J. J., Mallaber L. M., Rodriguez-Rodriguez L., Fay P. J., Bambara R. A. Requirements for strand transfer between internal regions of heteropolymer templates by human immunodeficiency virus reverse transcriptase. J Virol. 1992 Nov;66(11):6370–6378. doi: 10.1128/jvi.66.11.6370-6378.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Delassus S., Cheynier R., Wain-Hobson S. Evolution of human immunodeficiency virus type 1 nef and long terminal repeat sequences over 4 years in vivo and in vitro. J Virol. 1991 Jan;65(1):225–231. doi: 10.1128/jvi.65.1.225-231.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Diaz R. S., Sabino E. C., Mayer A., Mosley J. W., Busch M. P. Dual human immunodeficiency virus type 1 infection and recombination in a dually exposed transfusion recipient. The Transfusion Safety Study Group. J Virol. 1995 Jun;69(6):3273–3281. doi: 10.1128/jvi.69.6.3273-3281.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ewens W. J. A note on the sampling theory for infinite alleles and infinite sites models. Theor Popul Biol. 1974 Oct;6(2):143–148. doi: 10.1016/0040-5809(74)90020-3. [DOI] [PubMed] [Google Scholar]
  8. Frost S. D., Dumaurier M. J., Wain-Hobson S., Brown A. J. Genetic drift and within-host metapopulation dynamics of HIV-1 infection. Proc Natl Acad Sci U S A. 2001 May 29;98(12):6975–6980. doi: 10.1073/pnas.131056998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fu Y. X. New statistical tests of neutrality for DNA samples from a population. Genetics. 1996 May;143(1):557–570. doi: 10.1093/genetics/143.1.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gao F., Robertson D. L., Morrison S. G., Hui H., Craig S., Decker J., Fultz P. N., Girard M., Shaw G. M., Hahn B. H. The heterosexual human immunodeficiency virus type 1 epidemic in Thailand is caused by an intersubtype (A/E) recombinant of African origin. J Virol. 1996 Oct;70(10):7013–7029. doi: 10.1128/jvi.70.10.7013-7029.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gao F., Yue L., Robertson D. L., Hill S. C., Hui H., Biggar R. J., Neequaye A. E., Whelan T. M., Ho D. D., Shaw G. M. Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology. J Virol. 1994 Nov;68(11):7433–7447. doi: 10.1128/jvi.68.11.7433-7447.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gao F., Yue L., White A. T., Pappas P. G., Barchue J., Hanson A. P., Greene B. M., Sharp P. M., Shaw G. M., Hahn B. H. Human infection by genetically diverse SIVSM-related HIV-2 in west Africa. Nature. 1992 Aug 6;358(6386):495–499. doi: 10.1038/358495a0. [DOI] [PubMed] [Google Scholar]
  13. Gratton S., Cheynier R., Dumaurier M. J., Oksenhendler E., Wain-Hobson S. Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14566–14571. doi: 10.1073/pnas.97.26.14566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Groenink M., Andeweg A. C., Fouchier R. A., Broersen S., van der Jagt R. C., Schuitemaker H., de Goede R. E., Bosch M. L., Huisman H. G., Tersmette M. Phenotype-associated env gene variation among eight related human immunodeficiency virus type 1 clones: evidence for in vivo recombination and determinants of cytotropism outside the V3 domain. J Virol. 1992 Oct;66(10):6175–6180. doi: 10.1128/jvi.66.10.6175-6180.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Howell R. M., Fitzgibbon J. E., Noe M., Ren Z. J., Gocke D. J., Schwartzer T. A., Dubin D. T. In vivo sequence variation of the human immunodeficiency virus type 1 env gene: evidence for recombination among variants found in a single individual. AIDS Res Hum Retroviruses. 1991 Nov;7(11):869–876. doi: 10.1089/aid.1991.7.869. [DOI] [PubMed] [Google Scholar]
  16. Hu W. S., Temin H. M. Genetic consequences of packaging two RNA genomes in one retroviral particle: pseudodiploidy and high rate of genetic recombination. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1556–1560. doi: 10.1073/pnas.87.4.1556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hu W. S., Temin H. M. Retroviral recombination and reverse transcription. Science. 1990 Nov 30;250(4985):1227–1233. doi: 10.1126/science.1700865. [DOI] [PubMed] [Google Scholar]
  18. Hudson R. R., Kaplan N. L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics. 1985 Sep;111(1):147–164. doi: 10.1093/genetics/111.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hudson R. R. Two-locus sampling distributions and their application. Genetics. 2001 Dec;159(4):1805–1817. doi: 10.1093/genetics/159.4.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hudson Richard R. Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics. 2002 Feb;18(2):337–338. doi: 10.1093/bioinformatics/18.2.337. [DOI] [PubMed] [Google Scholar]
  21. Jetzt A. E., Yu H., Klarmann G. J., Ron Y., Preston B. D., Dougherty J. P. High rate of recombination throughout the human immunodeficiency virus type 1 genome. J Virol. 2000 Feb;74(3):1234–1240. doi: 10.1128/jvi.74.3.1234-1240.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jung Andreas, Maier Reinhard, Vartanian Jean-Pierre, Bocharov Gennady, Jung Volker, Fischer Ulrike, Meese Eckart, Wain-Hobson Simon, Meyerhans Andreas. Recombination: Multiply infected spleen cells in HIV patients. Nature. 2002 Jul 11;418(6894):144–144. doi: 10.1038/418144a. [DOI] [PubMed] [Google Scholar]
  23. Kirpensteijn Jolle, Timmermans-Sprang Elpetra P. M., van Garderen Evert, Rutteman Gerard R., Lantinga-van Leeuwen Irma S., Mol Jan A. Growth hormone gene expression in canine normal growth plates and spontaneous osteosarcoma. Mol Cell Endocrinol. 2002 Nov 29;197(1-2):179–185. doi: 10.1016/s0303-7207(02)00269-1. [DOI] [PubMed] [Google Scholar]
  24. Kishino H., Hasegawa M. Evaluation of the maximum likelihood estimate of the evolutionary tree topologies from DNA sequence data, and the branching order in hominoidea. J Mol Evol. 1989 Aug;29(2):170–179. doi: 10.1007/BF02100115. [DOI] [PubMed] [Google Scholar]
  25. Kuhner M. K., Yamato J., Felsenstein J. Maximum likelihood estimation of recombination rates from population data. Genetics. 2000 Nov;156(3):1393–1401. doi: 10.1093/genetics/156.3.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Leitner T., Escanilla D., Marquina S., Wahlberg J., Broström C., Hansson H. B., Uhlén M., Albert J. Biological and molecular characterization of subtype D, G, and A/D recombinant HIV-1 transmissions in Sweden. Virology. 1995 May 10;209(1):136–146. doi: 10.1006/viro.1995.1237. [DOI] [PubMed] [Google Scholar]
  27. Liu S. L., Schacker T., Musey L., Shriner D., McElrath M. J., Corey L., Mullins J. I. Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses. J Virol. 1997 Jun;71(6):4284–4295. doi: 10.1128/jvi.71.6.4284-4295.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liu Shan-Lu, Mittler John E., Nickle David C., Mulvania Thera M., Shriner Daniel, Rodrigo Allen G., Kosloff Barry, He Xi, Corey Lawrence, Mullins James I. Selection for human immunodeficiency virus type 1 recombinants in a patient with rapid progression to AIDS. J Virol. 2002 Nov;76(21):10674–10684. doi: 10.1128/JVI.76.21.10674-10684.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Luo G. X., Taylor J. Template switching by reverse transcriptase during DNA synthesis. J Virol. 1990 Sep;64(9):4321–4328. doi: 10.1128/jvi.64.9.4321-4328.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mansky L. M. Forward mutation rate of human immunodeficiency virus type 1 in a T lymphoid cell line. AIDS Res Hum Retroviruses. 1996 Mar 1;12(4):307–314. doi: 10.1089/aid.1996.12.307. [DOI] [PubMed] [Google Scholar]
  31. Martins L. P., Chenciner N., Asjö B., Meyerhans A., Wain-Hobson S. Independent fluctuation of human immunodeficiency virus type 1 rev and gp41 quasispecies in vivo. J Virol. 1991 Aug;65(8):4502–4507. doi: 10.1128/jvi.65.8.4502-4507.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Maynard Smith J., Smith N. H. Detecting recombination from gene trees. Mol Biol Evol. 1998 May;15(5):590–599. doi: 10.1093/oxfordjournals.molbev.a025960. [DOI] [PubMed] [Google Scholar]
  33. McVean Gil, Awadalla Philip, Fearnhead Paul. A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics. 2002 Mar;160(3):1231–1241. doi: 10.1093/genetics/160.3.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meyerhans A., Cheynier R., Albert J., Seth M., Kwok S., Sninsky J., Morfeldt-Månson L., Asjö B., Wain-Hobson S. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell. 1989 Sep 8;58(5):901–910. doi: 10.1016/0092-8674(89)90942-2. [DOI] [PubMed] [Google Scholar]
  35. Meyerhans A., Vartanian J. P., Wain-Hobson S. DNA recombination during PCR. Nucleic Acids Res. 1990 Apr 11;18(7):1687–1691. doi: 10.1093/nar/18.7.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Michael N. L., Chang G., d'Arcy L. A., Ehrenberg P. K., Mariani R., Busch M. P., Birx D. L., Schwartz D. H. Defective accessory genes in a human immunodeficiency virus type 1-infected long-term survivor lacking recoverable virus. J Virol. 1995 Jul;69(7):4228–4236. doi: 10.1128/jvi.69.7.4228-4236.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Morris A., Marsden M., Halcrow K., Hughes E. S., Brettle R. P., Bell J. E., Simmonds P. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. J Virol. 1999 Oct;73(10):8720–8731. doi: 10.1128/jvi.73.10.8720-8731.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Onafuwa Adewunmi, An Wenfeng, Robson Nicole D., Telesnitsky Alice. Human immunodeficiency virus type 1 genetic recombination is more frequent than that of Moloney murine leukemia virus despite similar template switching rates. J Virol. 2003 Apr;77(8):4577–4587. doi: 10.1128/JVI.77.8.4577-4587.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Peliska J. A., Benkovic S. J. Mechanism of DNA strand transfer reactions catalyzed by HIV-1 reverse transcriptase. Science. 1992 Nov 13;258(5085):1112–1118. doi: 10.1126/science.1279806. [DOI] [PubMed] [Google Scholar]
  40. Rambaut A., Grassly N. C. Seq-Gen: an application for the Monte Carlo simulation of DNA sequence evolution along phylogenetic trees. Comput Appl Biosci. 1997 Jun;13(3):235–238. doi: 10.1093/bioinformatics/13.3.235. [DOI] [PubMed] [Google Scholar]
  41. Robertson D. L., Hahn B. H., Sharp P. M. Recombination in AIDS viruses. J Mol Evol. 1995 Mar;40(3):249–259. doi: 10.1007/BF00163230. [DOI] [PubMed] [Google Scholar]
  42. Robertson D. L., Sharp P. M., McCutchan F. E., Hahn B. H. Recombination in HIV-1. Nature. 1995 Mar 9;374(6518):124–126. doi: 10.1038/374124b0. [DOI] [PubMed] [Google Scholar]
  43. Rodrigo A. G., Goracke P. C., Rowhanian K., Mullins J. I. Quantitation of target molecules from polymerase chain reaction-based limiting dilution assays. AIDS Res Hum Retroviruses. 1997 Jun 10;13(9):737–742. doi: 10.1089/aid.1997.13.737. [DOI] [PubMed] [Google Scholar]
  44. Rozas J., Rozas R. DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics. 1999 Feb;15(2):174–175. doi: 10.1093/bioinformatics/15.2.174. [DOI] [PubMed] [Google Scholar]
  45. Sabino E. C., Shpaer E. G., Morgado M. G., Korber B. T., Diaz R. S., Bongertz V., Cavalcante S., Galvão-Castro B., Mullins J. I., Mayer A. Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil. J Virol. 1994 Oct;68(10):6340–6346. doi: 10.1128/jvi.68.10.6340-6346.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Salminen M. O., Carr J. K., Robertson D. L., Hegerich P., Gotte D., Koch C., Sanders-Buell E., Gao F., Sharp P. M., Hahn B. H. Evolution and probable transmission of intersubtype recombinant human immunodeficiency virus type 1 in a Zambian couple. J Virol. 1997 Apr;71(4):2647–2655. doi: 10.1128/jvi.71.4.2647-2655.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schierup M. H., Hein J. Consequences of recombination on traditional phylogenetic analysis. Genetics. 2000 Oct;156(2):879–891. doi: 10.1093/genetics/156.2.879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Shankarappa R., Margolick J. B., Gange S. J., Rodrigo A. G., Upchurch D., Farzadegan H., Gupta P., Rinaldo C. R., Learn G. H., He X. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol. 1999 Dec;73(12):10489–10502. doi: 10.1128/jvi.73.12.10489-10502.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stuhlmann H., Berg P. Homologous recombination of copackaged retrovirus RNAs during reverse transcription. J Virol. 1992 Apr;66(4):2378–2388. doi: 10.1128/jvi.66.4.2378-2388.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics. 1989 Nov;123(3):585–595. doi: 10.1093/genetics/123.3.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tanese N., Telesnitsky A., Goff S. P. Abortive reverse transcription by mutants of Moloney murine leukemia virus deficient in the reverse transcriptase-associated RNase H function. J Virol. 1991 Aug;65(8):4387–4397. doi: 10.1128/jvi.65.8.4387-4397.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Telesnitsky A., Blain S. W., Goff S. P. Defects in Moloney murine leukemia virus replication caused by a reverse transcriptase mutation modeled on the structure of Escherichia coli RNase H. J Virol. 1992 Feb;66(2):615–622. doi: 10.1128/jvi.66.2.615-622.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wakeley John, Takahashi Tsuyoshi. Gene genealogies when the sample size exceeds the effective size of the population. Mol Biol Evol. 2003 Feb;20(2):208–213. doi: 10.1093/molbev/msg024. [DOI] [PubMed] [Google Scholar]
  54. Watterson G. A. On the number of segregating sites in genetical models without recombination. Theor Popul Biol. 1975 Apr;7(2):256–276. doi: 10.1016/0040-5809(75)90020-9. [DOI] [PubMed] [Google Scholar]
  55. Worobey M. A novel approach to detecting and measuring recombination: new insights into evolution in viruses, bacteria, and mitochondria. Mol Biol Evol. 2001 Aug;18(8):1425–1434. doi: 10.1093/oxfordjournals.molbev.a003928. [DOI] [PubMed] [Google Scholar]
  56. Yang Y. L., Wang G., Dorman K., Kaplan A. H. Long polymerase chain reaction amplification of heterogeneous HIV type 1 templates produces recombination at a relatively high frequency. AIDS Res Hum Retroviruses. 1996 Mar 1;12(4):303–306. doi: 10.1089/aid.1996.12.303. [DOI] [PubMed] [Google Scholar]
  57. Yang Z. Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods. J Mol Evol. 1994 Sep;39(3):306–314. doi: 10.1007/BF00160154. [DOI] [PubMed] [Google Scholar]
  58. Yang Z., Nielsen R., Goldman N., Pedersen A. M. Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics. 2000 May;155(1):431–449. doi: 10.1093/genetics/155.1.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Zhang J., Tang L. Y., Li T., Ma Y., Sapp C. M. Most retroviral recombinations occur during minus-strand DNA synthesis. J Virol. 2000 Mar;74(5):2313–2322. doi: 10.1128/jvi.74.5.2313-2322.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Zhang L., Huang Y., Yuan H., Tuttleton S., Ho D. D. Genetic characterization of vif, vpr, and vpu sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology. 1997 Feb 17;228(2):340–349. doi: 10.1006/viro.1996.8378. [DOI] [PubMed] [Google Scholar]
  61. Zhu T., Wang N., Carr A., Wolinsky S., Ho D. D. Evidence for coinfection by multiple strains of human immunodeficiency virus type 1 subtype B in an acute seroconvertor. J Virol. 1995 Feb;69(2):1324–1327. doi: 10.1128/jvi.69.2.1324-1327.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zhuang Jianling, Jetzt Amanda E., Sun Guoli, Yu Hong, Klarmann George, Ron Yacov, Preston Bradley D., Dougherty Joseph P. Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots. J Virol. 2002 Nov;76(22):11273–11282. doi: 10.1128/JVI.76.22.11273-11282.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES