1887

Abstract

The initiation of drug therapy results in a reduction in the human immunodeficiency virus type 1 (HIV-1) population, which represents a potential genetic bottleneck. The effect of this drug-induced genetic bottleneck on the population dynamics of the envelope (Env) regions has been addressed in several studies. However, it is difficult to investigate the effect on the gene of the genetic bottleneck induced not only by entry inhibitors but also by non-entry inhibitors, particularly . Therefore, this study used an selection system using unique bulk primary isolates established in the laboratory to observe the effects of the antiretroviral drug-induced bottleneck on the integrase and genes. Env diversity was decreased significantly in one primary isolate [KP-1, harbouring both CXCR4 (X4)- and CCR5 (R5)-tropic variants] when passaged in the presence or absence of raltegravir (RAL) during selection. Furthermore, the RAL-selected KP-1 variant had a completely different Env sequence from that in the passage control (particularly evident in the gp120, V1/V2 and V4-loop regions), and a different number of potential -glycosylation sites. A similar pattern was also observed in other primary isolates when using different classes of drugs. This is the first study to explore the influence of anti-HIV drugs on bottlenecks in bulk primary HIV isolates with highly diverse Env sequences using selection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.047167-0
2013-05-01
2019-12-08
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/5/933.html?itemId=/content/journal/jgv/10.1099/vir.0.047167-0&mimeType=html&fmt=ahah

References

  1. Anastassopoulou C. G. , Ketas T. J. , Klasse P. J. , Moore J. P. . ( 2009; ). Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. . Proc Natl Acad Sci U S A 106:, 5318–5323. [CrossRef] [PubMed]
    [Google Scholar]
  2. Berro R. , Sanders R. W. , Lu M. , Klasse P. J. , Moore J. P. . ( 2009; ). Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry. . PLoS Pathog 5:, e1000548. [CrossRef] [PubMed]
    [Google Scholar]
  3. 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] [PubMed]
    [Google Scholar]
  4. Delwart E. L. , Pan H. , Neumann A. , Markowitz M. . ( 1998; ). Rapid, transient changes at the env locus of plasma human immunodeficiency virus type 1 populations during the emergence of protease inhibitor resistance. . J Virol 72:, 2416–2421.[PubMed]
    [Google Scholar]
  5. Eigen M. . ( 1993; ). The origin of genetic information: viruses as models. . Gene 135:, 37–47. [CrossRef] [PubMed]
    [Google Scholar]
  6. Gulick R. M. , Lalezari J. , Goodrich J. , Clumeck N. , DeJesus E. , Horban A. , Nadler J. , Clotet B. , Karlsson A. . & other authors ( 2008; ). Maraviroc for previously treated patients with R5 HIV-1 infection. . N Engl J Med 359:, 1429–1441. [CrossRef] [PubMed]
    [Google Scholar]
  7. Hatada M. , Yoshimura K. , Harada S. , Kawanami Y. , Shibata J. , Matsushita S. . ( 2010; ). Human immunodeficiency virus type 1 evasion of a neutralizing anti-V3 antibody involves acquisition of a potential glycosylation site in V2. . J Gen Virol 91:, 1335–1345. [CrossRef] [PubMed]
    [Google Scholar]
  8. Hombrouck A. , Voet A. , Van Remoortel B. , Desadeleer C. , De Maeyer M. , Debyser Z. , Witvrouw M. . ( 2008; ). Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137. . Antimicrob Agents Chemother 52:, 2069–2078. [CrossRef] [PubMed]
    [Google Scholar]
  9. Ibáñez A. , Clotet B. , Martínez M. A. . ( 2000; ). Human immunodeficiency virus type 1 population bottleneck during indinavir therapy causes a genetic drift in the env quasispecies. . J Gen Virol 81:, 85–95.[PubMed]
    [Google Scholar]
  10. Jacobson J. M. , Thompson M. A. , Lalezari J. P. , Saag M. S. , Zingman B. S. , D’Ambrosio P. , Stambler N. , Rotshteyn Y. , Marozsan A. J. . & other authors ( 2010; ). Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. . J Infect Dis 201:, 1481–1487. [CrossRef] [PubMed]
    [Google Scholar]
  11. Kitrinos K. M. , Nelson J. A. , Resch W. , Swanstrom R. . ( 2005; ). Effect of a protease inhibitor-induced genetic bottleneck on human immunodeficiency virus type 1 env gene populations. . J Virol 79:, 10627–10637. [CrossRef] [PubMed]
    [Google Scholar]
  12. Kobayashi M. , Nakahara K. , Seki T. , Miki S. , Kawauchi S. , Suyama A. , Wakasa-Morimoto C. , Kodama M. , Endoh T. , Oosugi E. . ( 2008; ). Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. . Antiviral Res 80:, 213–222. [CrossRef] [PubMed]
    [Google Scholar]
  13. Maeda Y. , Yusa K. , Harada S. . ( 2008; ). Altered sensitivity of an R5X4 HIV-1 strain 89.6 to coreceptor inhibitors by a single amino acid substitution in the V3 region of gp120. . Antiviral Res 77:, 128–135. [CrossRef] [PubMed]
    [Google Scholar]
  14. McNicholas P. , Wei Y. , Whitcomb J. , Greaves W. , Black T. A. , Tremblay C. L. , Strizki J. M. . ( 2010; ). Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial. . J Infect Dis 201:, 1470–1480. [CrossRef] [PubMed]
    [Google Scholar]
  15. Nájera R. , Delgado E. , Pérez-Alvarez L. , Thomson M. M. . ( 2002; ). Genetic recombination and its role in the development of the HIV-1 pandemic. . AIDS 16: (Suppl. 4), S3–S16.[PubMed] [CrossRef]
    [Google Scholar]
  16. Nettles R. , Schurmann D. , Zhu L. , Stonier M. , Huang S. P. , Chien C. , Krystal M. , Wind-Rotolo M. , Bertz R. , Grasela D. . ( 2011; ). Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class oral HIV attachment inhibitor. . In 18th Conference on Retroviruses and Opportunistic Infections, abstract 49. Boston, MA.
  17. Nijhuis M. , Boucher C. A. , 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] [PubMed]
    [Google Scholar]
  18. Nora T. , Charpentier C. , Tenaillon O. , Hoede C. , Clavel F. , Hance A. J. . ( 2007; ). Contribution of recombination to the evolution of human immunodeficiency viruses expressing resistance to antiretroviral treatment. . J Virol 81:, 7620–7628. [CrossRef] [PubMed]
    [Google Scholar]
  19. Rhee S.-Y. , Liu T. F. , Kiuchi M. , Zioni R. , Gifford R. J. , Holmes S. P. , Shafer R. W. . ( 2008; ). Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. . Retrovirology 5:, 74. [CrossRef] [PubMed]
    [Google Scholar]
  20. Sheehy N. , Desselberger U. , Whitwell H. , Ball J. K. . ( 1996; ). Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy. . J Gen Virol 77:, 1071–1081. [CrossRef] [PubMed]
    [Google Scholar]
  21. Shibata J. , Yoshimura K. , Honda A. , Koito A. , Murakami T. , Matsushita S. . ( 2007; ). Impact of V2 mutations on escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary human immunodeficiency virus type 1 isolate. . J Virol 81:, 3757–3768. [CrossRef] [PubMed]
    [Google Scholar]
  22. Sing T. , Low A. J. , Beerenwinkel N. , Sander O. , Cheung P. K. , Domingues F. S. , Büch J. , Däumer M. , Kaiser R. . & other authors ( 2007; ). Predicting HIV coreceptor usage on the basis of genetic and clinical covariates. . Antivir Ther 12:, 1097–1106.[PubMed]
    [Google Scholar]
  23. Steigbigel R. T. , Cooper D. A. , Kumar P. N. , Eron J. E. , Schechter M. , Markowitz M. , Loutfy M. R. , Lennox J. L. , Gatell J. M. . & other authors ( 2008; ). Raltegravir with optimized background therapy for resistant HIV-1 infection. . N Engl J Med 359:, 339–354. [CrossRef] [PubMed]
    [Google Scholar]
  24. Stupple P. A. , Batchelor D. V. , Corless M. , Dorr P. K. , Ellis D. , Fenwick D. R. , Galan S. R. , Jones R. M. , Mason H. J. . & other authors ( 2011; ). An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propylacetamide (PF-232798). . J Med Chem 54:, 67–77. [CrossRef] [PubMed]
    [Google Scholar]
  25. Tamura K. , Dudley J. , Nei M. , Kumar S. . ( 2007; ). mega4: Molecular Evolutionary Genetics Analysis (mega) software version 4.0. . Mol Biol Evol 24:, 1596–1599. [CrossRef] [PubMed]
    [Google Scholar]
  26. Tilton J. C. , Wilen C. B. , Didigu C. A. , Sinha R. , Harrison J. E. , Agrawal-Gamse C. , Henning E. A. , Bushman F. D. , Martin J. N. . & other authors ( 2010; ). A maraviroc-resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drug-bound CCR5. . J Virol 84:, 10863–10876. [CrossRef] [PubMed]
    [Google Scholar]
  27. Toma J. , Weinheimer S. P. , Stawiski E. , Whitcomb J. M. , Lewis S. T. , Petropoulos C. J. , Huang W. . ( 2011; ). Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab. . J Virol 85:, 3872–3880. [CrossRef] [PubMed]
    [Google Scholar]
  28. Vignuzzi M. , Stone J. K. , Arnold J. J. , Cameron C. E. , Andino R. . ( 2006; ). Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. . Nature 439:, 344–348. [CrossRef] [PubMed]
    [Google Scholar]
  29. Yoshimura K. , Shibata J. , Kimura T. , Honda A. , Maeda Y. , Koito A. , Murakami T. , Mitsuya H. , Matsushita S. . ( 2006; ). Resistance profile of a neutralizing anti-HIV monoclonal antibody, KD-247, that shows favourable synergism with anti-CCR5 inhibitors. . AIDS 20:, 2065–2073. [CrossRef] [PubMed]
    [Google Scholar]
  30. Yoshimura K. , Harada S. , Hatada M. , Matsushita S. . ( 2009; ). Mutations in V4 and C4 regions of the HIV-1 CRF08-BC envelope induced by the in vitro selection of Maraviroc Confer cross-resistance to other CCR5 inhibitors. . In 16th Conference on Retroviruses and Opportunistic Infections, p. 640. Montreal, Canada:.
  31. Yoshimura K. , Harada S. , Matsushita S. . ( 2010a; ). Two step escape pathway of the HIV-1 subtype C primary isolate induced by the in vitro selection of Maraviroc. In 17th Conference on Retroviruses and Opportunistic Infections, abstract 535. San Francisco, CA:.
  32. Yoshimura K. , Harada S. , Shibata J. , Hatada M. , Yamada Y. , Ochiai C. , Tamamura H. , Matsushita S. . ( 2010b; ). Enhanced exposure of human immunodeficiency virus type 1 primary isolate neutralization epitopes through binding of CD4 mimetic compounds. . J Virol 84:, 7558–7568. [CrossRef] [PubMed]
    [Google Scholar]
  33. Yusa K. , Maeda Y. , Fujioka A. , Monde K. , Harada S. . ( 2005; ). Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 loop library. . J Biol Chem 280:, 30083–30090. [CrossRef] [PubMed]
    [Google Scholar]
  34. Zhang Y. M. , Dawson S. C. , Landsman D. , Lane H. C. , Salzman N. P. . ( 1994; ). Persistence of four related human immunodeficiency virus subtypes during the course of zidovudine therapy: relationship between virion RNA and proviral DNA. . J Virol 68:, 425–432.[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.047167-0
Loading
/content/journal/jgv/10.1099/vir.0.047167-0
Loading

Data & Media loading...

Supplements

Supplementary Figures 

PDF

Most Cited This Month

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