1887

Abstract

We have attempted to relate genetic recombination involving human immunodeficiency virus type 1 (HIV-1) to multiple drug resistance by using PEG to fuse subclones of U937 cells that carried HIV-1 recombinants resistant to either 3′-azido-3′-deoxythymidine (AZT) or the (-) enantiomer of 2′,3′-dideoxy-3′-thiacytidine (3TC). The parental viruses employed contained well-defined mutations in the gene. Fused cells were cocultured with the MT4 lymphocyte cell line for virus amplification to yield progeny that, in some cases, possessed different patterns of drug resistance from parental viruses. Mutational analyses were performed by PCR to substantiate these observations, which were also confirmed by direct sequencing of single strands of DNA segments, obtained from plaque-purified viruses. These studies indicate that viral recombination had occurred, and establish a theoretical basis on which to conclude that the acquisition of multiple drug resistance on the part of HIV-1 may be related to its ability to promote cell fusion.

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1995-10-01
2024-04-19
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References

  1. Boucher C. A. B., Lange J. M. A., Miedema F. F., Weverling G. J., Koot M., Mulder J. W., Goudsmit J., Kellam P., Larder B. A., Tersmette M. 1992; HIV-1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment. AIDS 6:1259–1264
    [Google Scholar]
  2. Boucher C. A. B., Cammack N., Schipper P., Schuurman R., Rouse P., Wainberg M. A., Cameron J. M. 1993; High level resistance to (–) enantiometric 2′-deoxy-3′-thiacytidine (3TC) in vitro is due to one amino acid substitution in the catalytic site of HIV-1 reverse transcriptase. Antimicrobial Agents and Chemotherapy 37:2231–2234
    [Google Scholar]
  3. Boulerice F., Li X., Lvovich A., Wainberg M. A. 1991; Recovery of infectious human immunodeficiency virus type 1 after fusion of defectively infected clones of U-937 cells. Journal of Virology 65:5589–5592
    [Google Scholar]
  4. Bour S., Boulerice F., Wainberg M. A. 1991; Inhibition of gpl60 and CD4 maturation in U937 cells after both defective and productive infections by human immunodeficiency virus type 1. Journal of Virology 65:6387–6396
    [Google Scholar]
  5. Eron J. J., Chow Y.-K., Caliendo A. M., Videler J., Devore K. M., Cooley T. P., Liebman H. A., Kaplan J. C., Hirsch M. S., D’Aquila R. T. 1993; pol Mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo. Antimicrobial Agents and Chemotherapy 37:1480–1487
    [Google Scholar]
  6. Gao Q., Gu Z., Parniak M. A., Li X., Wainberg M. A. 1992; In vitro selection of variants of human immunodeficiency virus type 1 resistant to 3′-azido-3′-deoxythymidine and 2′, 3′-dideoxyinosine. Journal of Virology 66:12–19
    [Google Scholar]
  7. Groenink M., Andeweg A. C., Foucher R. A., Broersen S., van der Jagt R. C., Schuitemaker H., de Groede R. E., Bosch M. L., Huisman H. G., Tersmette M. 1992; 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. Journal of Virology 66:6175–6180
    [Google Scholar]
  8. Gu Z., Gao Q., Li X., Parniak M. A., Wainberg M. A. 1992; Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2′, 3′-dideoxy-inosine and 2′, 3′-dideoxycytidine. Journal of Virology 66:7128–7135
    [Google Scholar]
  9. Gu Z., Gao Q., Fang H., Salomon H., Parniak M. A., Goldberg E., Cameron J., Wainberg M. A. 1994; Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2′, 3′-dide-oxycytidine and 2′, 3′-dideoxy-3′-thiacytidine. Antimicrobial Agents and Chemotherapy 38:275–281
    [Google Scholar]
  10. Kellam P., Larder B. A. 1995; Retroviral recombination can lead to linkage of reverse transcriptase mutations that confer increased zidovudine resistance. Journal of Virology 69:669–674
    [Google Scholar]
  11. Kellam P., Boucher C. A. B., Tijnagel J. M. G. H., Larder B. A. 1994; Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance. Journal of Virology 75:341–351
    [Google Scholar]
  12. Larder B. A., Kemp S. D. 1989; Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 246:1155–1158
    [Google Scholar]
  13. Larder B. A., Darby G., Richman D. D. 1989; HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734
    [Google Scholar]
  14. Larder B. A., Coates K. E., Kemp S. D. 1991; Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. Journal of Virology 65:5232–5236
    [Google Scholar]
  15. Lifson J. D., Feinberg M. B., Reyes G. R., Rabin L., Banapour B., Chakrabarti S., Moss B., Wong-Staal F., Steimer K. S., Engleman E. G. 1986; Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature 323:725–728
    [Google Scholar]
  16. McInnes A., Rennick D. M. 1988; Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. Journal of Experimental Medicine 167:598–611
    [Google Scholar]
  17. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. 1993; HIV infection is active and progressive in lymphoid tissue during the clinical latent stage of disease. Nature 362:725–728
    [Google Scholar]
  18. Rooke R., Tremblay M., Soudeyns H., Destephano L., Yao X.-J., Fanning M., Montaner J. S. G., O’Shaughnessy M., Gelmon K., Tsoukas C., Ruedy J., Wainberg M. A. 1989; Isolation of drug-resistant variants of HIV-1 from patients on longterm zidovudine (AZT) therapy. AIDS 3:411–115
    [Google Scholar]
  19. Roy S., Wainberg M. A. 1988; Role of the mononuclear phagocyte system in the development of acquired immunodeficiency syndrome (AIDS). Journal of Leukocyte Biology 43:91–97
    [Google Scholar]
  20. Sodroski J., Goh W. C., Rosen C., Campbell K., Haseltine W. A. 1986; Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature 322:470–474
    [Google Scholar]
  21. Srinivasan A., York D., Jannoun-Nasr R., Kalyanaraman S., Swan D., Benson J., Bohan C., Luciw P. A., Schnoll S., Robinson R. A., Desai S. M., Devare S. G. 1989; Generation of hybrid human immunodeficiency virus by homologous recombination. Proceedings of the National Academy of Sciences, USA 86:6388–6392
    [Google Scholar]
  22. St Clair M. H., Martin J. L., Tudor-Williams G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. 1991; Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 153:1557–1559
    [Google Scholar]
  23. Tersmette M., de Goede R. E. Y., Bert J. M. A., Winkel I. N., Gruters R. A., Cuypers H. T., Huisman H. G., Miedema F. 1988; Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Journal of Virology 62:2026–2032
    [Google Scholar]
  24. Tisdale M., Kemp S. D., Parry N. R., Larder B. A. 1993; Rapid in vitro selection of human immunodeficiency virus type 1 resistance to 3′-thiacytidine inhibitors due to a mutation in the YMDD motif of reverse transcriptase. Proceedings of the National Academy of Sciences, USA 90:5653–5656
    [Google Scholar]
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