1887

Journal of General Virology header logo

Volume 89, Issue 6

Recombination increases human immunodeficiency virus fitness, but not necessarily diversity Free

Abstract

Recombination can facilitate the accumulation of mutations and accelerate the emergence of resistance to current antiretroviral therapies for human immunodeficiency virus (HIV) infection. Yet, since recombination can also dissociate favourable combinations of mutations, the benefit of recombination to HIV remains in question. The confounding effects of mutation, multiple infections of cells, random genetic drift and fitness selection that underlie HIV evolution render the influence of recombination difficult to unravel. We developed computer simulations that mimic the genomic diversification of HIV within an infected individual and elucidate the influence of recombination. We find, interestingly, that when the effective population size of HIV is small, recombination increases both the diversity and the mean fitness of the viral population. When the effective population size is large, recombination increases viral fitness but decreases diversity. In effect, recombination enhances (lowers) the likelihood of the existence of multi-drug resistant strains of HIV in infected individuals prior to the onset of therapy when the effective population size is small (large). Our simulations are consistent with several recent experimental observations, including the evolution of HIV diversity and divergence . The intriguing dependencies on the effective population size appear due to the subtle interplay of drift, selection and epistasis, which we discuss in the light of modern population genetics theories. Current estimates of the effective population size of HIV have large discrepancies. Our simulations present an avenue for accurate determination of the effective population size of HIV and facilitate establishment of the benefit of recombination to HIV.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83668-0
2008-06-01
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/6/1467.html?itemId=/content/journal/jgv/10.1099/vir.0.83668-0&mimeType=html&fmt=ahah

References

  1. Achaz G., Palmer S., Kearney M., Maldarelli F., Mellors J. W., Coffin J. M., Wakeley J. 2004; A robust measure of HIV-1 population turnover within chronically infected individuals. Mol Biol Evol 21:1902–1912 [CrossRef]
     [Google Scholar]
  2. Althaus C. L., Bonhoeffer S. 2005; Stochastic interplay between mutation and recombination during the acquisition of drug resistance mutations in human immunodeficiency virus type 1. J Virol 79:13572–13578 [CrossRef]
     [Google Scholar]
  3. Barouch D. H., Kunstman J., Kuroda M. J., Schmitz J. E., Santra S., Peyerl F. W., Krivulka G. R., Beaudry K., Lifton M. A. other authors 2002; Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335–339 [CrossRef]
     [Google Scholar]
  4. Blackard J. T., Cohen D. E., Mayer K. H. 2002; Human immunodeficiency virus superinfection and recombination: current state of knowledge and potential clinical consequences. Clin Infect Dis 34:1108–1114 [CrossRef]
     [Google Scholar]
  5. Bocharov G., Ford N. J., Edwards J., Breinig T., Wain-Hobson S., Meyerhans A. 2005; A genetic-algorithm approach to simulating human immunodeficiency virus evolution reveals the strong impact of multiply infected cells and recombination. J Gen Virol 86:3109–3118 [CrossRef]
     [Google Scholar]
  6. Bonhoeffer S., Chappey C., Parkin N. T., Whitcomb J. M., Petropoulos C. J. 2004; Evidence for positive epistasis in HIV-1. Science 306:1547–1550 [CrossRef]
     [Google Scholar]
  7. Bretscher M. T., Althaus C. L., Muller V., Bonhoeffer S. 2004; Recombination in HIV and the evolution of drug resistance: for better or for worse?. Bioessays 26:180–188 [CrossRef]
     [Google Scholar]
  8. Brown A. J. L. 1997; Analysis of HIV-1 env gene sequences reveals evidence for a low effective number in the viral population. Proc Natl Acad Sci U S A 94:1862–1865 [CrossRef]
     [Google Scholar]
  9. Charpentier C., Nora T., Tenaillon O., Clavel F., Hance A. J. 2006; Extensive recombination among human immunodeficiency virus type 1 quasispecies makes an important contribution to viral diversity in individual patients. J Virol 80:2472–2482 [CrossRef]
     [Google Scholar]
  10. Chen J., Dang Q., Unutmaz D., Pathak V. K., Maldarelli F., Powell D., Hu W.-S. 2005; Mechanisms of nonrandom human immunodeficiency virus type 1 infection and double infection: preference in virus entry is important but is not the sole factor. J Virol 79:4140–4149 [CrossRef]
     [Google Scholar]
  11. Christiansen F. B., Otto S. P., Bergman A., Feldman M. W. 1998; Waiting with and without recombination: the time to production of a double mutant. Theor Popul Biol 53:199–215 [CrossRef]
     [Google Scholar]
  12. Clavel F., Hance A. J. 2004; Medical progress: HIV drug resistance. N Engl J Med 350:1023–1035 [CrossRef]
     [Google Scholar]
  13. Dang Q., Chen J., Unutmaz D., Coffin J. M., Pathak V. K., Powell D., KewalRamani V. N., Maldarelli F., Hu W.-S. 2004; Nonrandom HIV-1 infection and double infection via direct and cell-mediated pathways. Proc Natl Acad Sci U S A 101:632–637 [CrossRef]
     [Google Scholar]
  14. Dimitrov D. S., Martin M. A. 1995; CD4+ cell turnover. Nature 375:194–195 [CrossRef]
     [Google Scholar]
  15. Dimitrov D. S., Willey R. L., Sato H., Chang L. J., Blumenthal R., Martin M. A. 1993; Quantitation of human immunodeficiency virus type 1 infection kinetics. J Virol 67:2182–2190
     [Google Scholar]
  16. Dixit N. M., Markowitz M., Ho D. D., Perelson A. S. 2004; Estimates of intracellular delay and average drug efficacy from viral load data of HIV-infected individuals under antiretroviral therapy. Antivir Ther 9:237–246
     [Google Scholar]
  17. Eshel I., Feldman M. W. 1970; On the evolutionary effect of recombination. Theor Popul Biol 1:88–100 [CrossRef]
     [Google Scholar]
  18. Ewens W. J. 2004 Mathematical Population Genetics New York: Springer;
     [Google Scholar]
  19. Fraser C. 2005; HIV recombination: what is the impact on antiretroviral therapy?. J R Soc Interface 2:489–503 [CrossRef]
     [Google Scholar]
  20. Frost S. D. W., Nijhuis M., Schuurman R., Boucher C. A. B., Brown A. J. L. 2000; Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. J Virol 74:6262–6268 [CrossRef]
     [Google Scholar]
  21. Frost S. D. W., Dumaurier M. J., Wain-Hobson S., Brown A. J. L. 2001; Genetic drift and within-host metapopulation dynamics of HIV-1 infection. Proc Natl Acad Sci U S A 98:6975–6980 [CrossRef]
     [Google Scholar]
  22. Haase A. T., Henry K., Zupancic M., Sedgewick G., Faust R. A., Melroe H., Cavert W., Gebhard K., Staskus K. other authors 1996; Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274:985–989 [CrossRef]
     [Google Scholar]
  23. Hartl D. L., Clark A. G. 2007 Principles of Population Genetics Sunderland, MA: Sinauer Associates;
     [Google Scholar]
  24. Herbeck J. T., Nickle D. C., Learn G. H., Gottlieb G. S., Curlin M. E., Heath L., Mullins J. I. 2006; Human immunodeficiency virus type 1 env evolves toward ancestral states upon transmission to a new host. J Virol 80:1637–1644 [CrossRef]
     [Google Scholar]
  25. Hill W. G., Robertson A. 1966; Effect of linkage on limits to artificial selection. Genet Res 8:269–294 [CrossRef]
     [Google Scholar]
  26. Hockett R. D., Kilby J. M., Derdeyn C. A., Saag M. S., Sillers M., Squires K., Chiz S., Nowak M. A., Shaw G. M., Bucy R. P. 1999; Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. J Exp Med 189:1545–1554 [CrossRef]
     [Google Scholar]
  27. Jetzt A. E., Yu H., Klarmann G. J., Ron Y., Preston B. D., Dougherty J. P. 2000; High rate of recombination throughout the human immunodeficiency virus type 1 genome. J Virol 74:1234–1240 [CrossRef]
     [Google Scholar]
  28. Jung A., Maier R., Vartanian J. P., Bocharov G., Jung V., Fischer U., Meese E., Wain-Hobson S., Meyerhans A. 2002; Multiply infected spleen cells in HIV patients. Nature 418:144 [CrossRef]
     [Google Scholar]
  29. Kellam P., Larder B. A. 1995; Retroviral recombination can lead to linkage of reverse-transcriptase mutations that confer increased zidovudine resistance. J Virol 69:669–674
     [Google Scholar]
  30. Kils-Hutten L., Cheynier R., Wain-Hobson S., Meyerhans A. 2001; Phylogenetic reconstruction of intrapatient evolution of human immunodeficiency virus type 1: predominance of drift and purifying selection. J Gen Virol 82:1621–1627
     [Google Scholar]
  31. Kimura M. 1980; A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16:111–120 [CrossRef]
     [Google Scholar]
  32. Kouyos R. D., Althaus C. L., Bonhoeffer S. 2006a; Stochastic or deterministic: what is the effective population size of HIV-1?. Trends Microbiol 14:507–511 [CrossRef]
     [Google Scholar]
  33. Kouyos R. D., Otto S. P., Bonhoeffer S. 2006b; Effect of varying epistasis on the evolution of recombination. Genetics 173:589–597 [CrossRef]
     [Google Scholar]
  34. Kouyos R. D., Silander O. K., Bonhoeffer S. 2007; Epistasis between deleterious mutations and the evolution of recombination. Trends Ecol Evol 22:308–315 [CrossRef]
     [Google Scholar]
  35. Lech W. J., Wang G., Yang Y. L., Chee Y., Dorman K., McCrae D., Lazzeroni L. C., Erickson J. W., Sinsheimer J. S., Kaplan A. H. 1996; In vivo sequence diversity of the protease of human immunodeficiency virus type 1: presence of protease inhibitor-resistant variants in untreated subjects. J Virol 70:2038–2043
     [Google Scholar]
  36. Levy D. N., Aldrovandi G. M., Kutsch O., Shaw G. M. 2004; Dynamics of HIV-1 recombination in its natural target cells. Proc Natl Acad Sci U S A 101:4204–4209 [CrossRef]
     [Google Scholar]
  37. Mansky L. M., Temin H. M. 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
     [Google Scholar]
  38. Markham R. B., Wang W. C., Weisstein A. E., Wang Z., Munoz A., Templeton A., Margolick J., Vlahov D., Quinn T. other authors 1998; Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline. Proc Natl Acad Sci U S A 95:12568–12573 [CrossRef]
     [Google Scholar]
  39. Markowitz M., Louie M., Hurley A., Sun E., Di Mascio M. 2003; A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo. J Virol 77:5037–5038 [CrossRef]
     [Google Scholar]
  40. Moutouh L., Corbeil J., Richman D. D. 1996; Recombination leads to the rapid emergence of HIV-1 dually resistant mutants under selective drug pressure. Proc Natl Acad Sci U S A 93:6106–6111 [CrossRef]
     [Google Scholar]
  41. Nijhuis M., Boucher C. A. B., Schipper P., Leitner T., Schuurman R., Albert J. 1998; Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy. Proc Natl Acad Sci U S A 95:14441–14446 [CrossRef]
     [Google Scholar]
  42. Otto S. P., Barton N. H. 2001; Selection for recombination in small populations. Evolution 55:1921–1931 [CrossRef]
     [Google Scholar]
  43. Otto S. P., Lenormand T. 2002; Resolving the paradox of sex and recombination. Nat Rev Genet 3:252–261 [CrossRef]
     [Google Scholar]
  44. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. 1996; HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586 [CrossRef]
     [Google Scholar]
  45. Piatak M., Saag M. S., Yang L. C., Clark S. J., Kappes J. C., Luk K. C., Hahn B. H., Shaw G. M., Lifson J. D. 1993; High-levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259:1749–1754 [CrossRef]
     [Google Scholar]
  46. Rhodes T., Wargo H., Hu W.-S. 2003; High rates of human immunodeficiency virus type 1 recombination: near-random segregation of markers one kilobase apart in one round of viral replication. J Virol 77:11193–11200 [CrossRef]
     [Google Scholar]
  47. Ribeiro R. M., Bonhoeffer S. 2000; Production of resistant HIV mutants during antiretroviral therapy. Proc Natl Acad Sci U S A 97:7681–7686 [CrossRef]
     [Google Scholar]
  48. Rice W. R. 2002; Experimental tests of the adaptive significance of sexual recombination. Nat Rev Genet 3:241–251 [CrossRef]
     [Google Scholar]
  49. Rodrigo A. G., Shpaer E. G., Delwart E. L., Iversen A. K. N., Gallo M. V., Brojatsch J., Hirsch M. S., Walker B. D., Mullins J. I. 1999; Coalescent estimates of HIV-1 generation time in vivo . Proc Natl Acad Sci U S A 96:2187–2191 [CrossRef]
     [Google Scholar]
  50. Rouzine I. M., Coffin J. M. 1999; Linkage disequilibrium test implies a large effective population number for HIV in vivo . Proc Natl Acad Sci U S A 96:10758–10763 [CrossRef]
     [Google Scholar]
  51. Rouzine I. M., Coffin J. M. 2005; Evolution of human immunodeficiency virus under selection and weak recombination. Genetics 170:7–18 [CrossRef]
     [Google Scholar]
  52. Rouzine I. M., Rodrigo A., Coffin J. M. 2001; Transition between stochastic evolution and deterministic evolution in the presence of selection: general theory and application to virology. Microbiol Mol Biol Rev 65:151–185 [CrossRef]
     [Google Scholar]
  53. Seo T.-K., Thorne J. L., Hasegawa M., Kishino H. 2002; Estimation of effective population size of HIV-1 within a host: a pseudomaximum-likelihood approach. Genetics 160:1283–1293
     [Google Scholar]
  54. Shankarappa R., Margolick J. B., Gange S. J., Rodrigo A. G., Upchurch D., Farzadegan H., Gupta P., Rinaldo C. R., Learn G. H. other authors 1999; Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol 73:10489–10502
     [Google Scholar]
  55. Shriner D., Rodrigo A. G., Nickle D. C., Mullins J. I. 2004a; Pervasive genomic recombination of HIV-1 in vivo. Genetics 167:1573–1583 [CrossRef]
     [Google Scholar]
  56. Shriner D., Shankarappa R., Jensen M. A., Nickle D. C., Mittler J. E., Margolick J. B., Mullins J. I. 2004b; Influence of random genetic drift on human immunodeficiency virus type I env evolution during chronic infection. Genetics 166:1155–1164 [CrossRef]
     [Google Scholar]
  57. Simon V., Ho D. D., Karim Q. A. 2006; HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 368:489–504 [CrossRef]
     [Google Scholar]
  58. Suryavanshi G. W., Dixit N. M. 2007; Emergence of recombinant forms of HIV: dynamics and scaling. PLoS Comput Biol 3:e205 [CrossRef]
     [Google Scholar]
  59. Thomson M. M., Perez-Alvarez L., Najera R. 2002; Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy. Lancet Infect Dis 2:461–471 [CrossRef]
     [Google Scholar]
  60. Williamson S., Perry S. M., Bustamante C. D., Orive M. E., Stearns M. N., Kelly J. K. 2005; A statistical characterization of consistent patterns of human immunodeficiency virus evolution within infected patients. Mol Biol Evol 22:456–468
     [Google Scholar]
  61. Yuste E., Moya A., Lopez-Galindez C. 2002; Frequency-dependent selection in human immunodeficiency virus type 1. J Gen Virol 83:103–106
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83668-0
Loading
Recombination increases human immunodeficiency virus fitness, but not necessarily diversity
J. Gen. Virol. 89, 1467 (2008); https://doi.org/10.1099/vir.0.83668-0
/content/journal/jgv/10.1099/vir.0.83668-0
/content/journal/jgv/10.1099/vir.0.83668-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error