Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency (original) (raw)

Abstract

The vpr gene product of human immunodeficiency virus (HIV) and simian immunodeficiency virus is a virion-associated regulatory protein that has been shown using vpr mutant viruses to increase virus replication, particularly in monocytes/macrophages. We have previously shown that vpr can directly inhibit cell proliferation and induce cell differentiation, events linked to the control of HIV replication, and also that the replication of a vpr mutant but not that of wild-type HIV type 1 (HIV-1) was compatible with cellular proliferation (D. N. Levy, L. S. Fernandes, W. V. Williams, and D. B. Weiner, Cell 72:541-550, 1993). Here we show that purified recombinant Vpr protein, in concentrations of < 100 pg/ml to 100 ng/ml, increases wild-type HIV-1 replication in newly infected transformed cell lines via a long-lasting increase in cellular permissiveness to HIV replication. The activity of extracellular Vpr protein could be completely inhibited by anti-Vpr antibodies. Extracellular Vpr also induced efficient HIV-1 replication in newly infected resting peripheral blood mononuclear cells. Extracellular Vpr transcomplemented a vpr mutant virus which was deficient in replication in promonocytic cells, restoring full replication competence. In addition, extracellular Vpr reactivated HIV-1 expression in five latently infected cell lines of T-cell, B-cell, and promonocytic origin which normally express very low levels of HIV RNA and protein, indicating an activation of translational or pretranslational events in the virus life cycle. Together, these results describe a novel pathway governing HIV replication and a potential target for the development of anti-HIV therapeutics.

Full Text

The Full Text of this article is available as a PDF (824.1 KB).

Selected References

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

  1. Balotta C., Lusso P., Crowley R., Gallo R. C., Franchini G. Antisense phosphorothioate oligodeoxynucleotides targeted to the vpr gene inhibit human immunodeficiency virus type 1 replication in primary human macrophages. J Virol. 1993 Jul;67(7):4409–4414. doi: 10.1128/jvi.67.7.4409-4414.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  3. Bukrinsky M. I., Stanwick T. L., Dempsey M. P., Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science. 1991 Oct 18;254(5030):423–427. doi: 10.1126/science.1925601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Butera S. T., Perez V. L., Wu B. Y., Nabel G. J., Folks T. M. Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection. J Virol. 1991 Sep;65(9):4645–4653. doi: 10.1128/jvi.65.9.4645-4653.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cann A. J., Zack J. A., Go A. S., Arrigo S. J., Koyanagi Y., Green P. L., Koyanagi Y., Pang S., Chen I. S. Human immunodeficiency virus type 1 T-cell tropism is determined by events prior to provirus formation. J Virol. 1990 Oct;64(10):4735–4742. doi: 10.1128/jvi.64.10.4735-4742.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen E. A., Dehni G., Sodroski J. G., Haseltine W. A. Human immunodeficiency virus vpr product is a virion-associated regulatory protein. J Virol. 1990 Jun;64(6):3097–3099. doi: 10.1128/jvi.64.6.3097-3099.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen E. A., Terwilliger E. F., Jalinoos Y., Proulx J., Sodroski J. G., Haseltine W. A. Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr. 1990;3(1):11–18. [PubMed] [Google Scholar]
  8. Dahl K. E., Burrage T., Jones F., Miller G. Persistent nonproductive infection of Epstein-Barr virus-transformed human B lymphocytes by human immunodeficiency virus type 1. J Virol. 1990 Apr;64(4):1771–1783. doi: 10.1128/jvi.64.4.1771-1783.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dahl K., Martin K., Miller G. Differences among human immunodeficiency virus strains in their capacities to induce cytolysis or persistent infection of a lymphoblastoid cell line immortalized by Epstein-Barr virus. J Virol. 1987 May;61(5):1602–1608. doi: 10.1128/jvi.61.5.1602-1608.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Edgington S. M. Molecular crosstalk. Will virology and growth-factor research aid cytokine drug discovery? Biotechnology (N Y) 1993 Apr;11(4):465-7, 470. doi: 10.1038/nbt0493-465. [DOI] [PubMed] [Google Scholar]
  11. Embretson J., Zupancic M., Beneke J., Till M., Wolinsky S., Ribas J. L., Burke A., Haase A. T. Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):357–361. doi: 10.1073/pnas.90.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  13. Felber B. K., Pavlakis G. N. Molecular biology of HIV-1: positive and negative regulatory elements important for virus expression. AIDS. 1993;7 (Suppl 1):S51–S62. [PubMed] [Google Scholar]
  14. Folks T. M., Clouse K. A., Justement J., Rabson A., Duh E., Kehrl J. H., Fauci A. S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2365–2368. doi: 10.1073/pnas.86.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  16. Frankel A. D., Pabo C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988 Dec 23;55(6):1189–1193. doi: 10.1016/0092-8674(88)90263-2. [DOI] [PubMed] [Google Scholar]
  17. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  18. Garcia-Blanco M. A., Cullen B. R. Molecular basis of latency in pathogenic human viruses. Science. 1991 Nov 8;254(5033):815–820. doi: 10.1126/science.1658933. [DOI] [PubMed] [Google Scholar]
  19. Garrett E. D., Tiley L. S., Cullen B. R. Rev activates expression of the human immunodeficiency virus type 1 vif and vpr gene products. J Virol. 1991 Mar;65(3):1653–1657. doi: 10.1128/jvi.65.3.1653-1657.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  21. Gentz R., Chen C. H., Rosen C. A. Bioassay for trans-activation using purified human immunodeficiency virus tat-encoded protein: trans-activation requires mRNA synthesis. Proc Natl Acad Sci U S A. 1989 Feb;86(3):821–824. doi: 10.1073/pnas.86.3.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Harris R. A., Everett R. D., Zhu X. X., Silverstein S., Preston C. M. Herpes simplex virus type 1 immediate-early protein Vmw110 reactivates latent herpes simplex virus type 2 in an in vitro latency system. J Virol. 1989 Aug;63(8):3513–3515. doi: 10.1128/jvi.63.8.3513-3515.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hattori N., Michaels F., Fargnoli K., Marcon L., Gallo R. C., Franchini G. The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8080–8084. doi: 10.1073/pnas.87.20.8080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ho D. D., Rota T. R., Hirsch M. S. Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest. 1986 May;77(5):1712–1715. doi: 10.1172/JCI112491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hsu D. H., de Waal Malefyt R., Fiorentino D. F., Dang M. N., Vieira P., de Vries J., Spits H., Mosmann T. R., Moore K. W. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 1990 Nov 9;250(4982):830–832. doi: 10.1126/science.2173142. [DOI] [PubMed] [Google Scholar]
  26. Kappes J. C., Conway J. A., Lee S. W., Shaw G. M., Hahn B. H. Human immunodeficiency virus type 2 vpx protein augments viral infectivity. Virology. 1991 Sep;184(1):197–209. doi: 10.1016/0042-6822(91)90836-z. [DOI] [PubMed] [Google Scholar]
  27. Lang S. M., Weeger M., Stahl-Hennig C., Coulibaly C., Hunsmann G., Müller J., Müller-Hermelink H., Fuchs D., Wachter H., Daniel M. M. Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus. J Virol. 1993 Feb;67(2):902–912. doi: 10.1128/jvi.67.2.902-912.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levy D. N., Fernandes L. S., Williams W. V., Weiner D. B. Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell. 1993 Feb 26;72(4):541–550. doi: 10.1016/0092-8674(93)90073-y. [DOI] [PubMed] [Google Scholar]
  29. Levy D. N., Refaeli Y., MacGregor R. R., Weiner D. B. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10873–10877. doi: 10.1073/pnas.91.23.10873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Levy J. A., Hoffman A. D., Kramer S. M., Landis J. A., Shimabukuro J. M., Oshiro L. S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science. 1984 Aug 24;225(4664):840–842. doi: 10.1126/science.6206563. [DOI] [PubMed] [Google Scholar]
  31. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Levy J. A., Shimabukuro J., McHugh T., Casavant C., Stites D., Oshiro L. AIDS-associated retroviruses (ARV) can productively infect other cells besides human T helper cells. Virology. 1985 Dec;147(2):441–448. doi: 10.1016/0042-6822(85)90146-1. [DOI] [PubMed] [Google Scholar]
  33. Lewis P., Hensel M., Emerman M. Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992 Aug;11(8):3053–3058. doi: 10.1002/j.1460-2075.1992.tb05376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Li G., Simm M., Potash M. J., Volsky D. J. Human immunodeficiency virus type 1 DNA synthesis, integration, and efficient viral replication in growth-arrested T cells. J Virol. 1993 Jul;67(7):3969–3977. doi: 10.1128/jvi.67.7.3969-3977.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lindholm P. F., Reid R. L., Brady J. N. Extracellular Tax1 protein stimulates tumor necrosis factor-beta and immunoglobulin kappa light chain expression in lymphoid cells. J Virol. 1992 Mar;66(3):1294–1302. doi: 10.1128/jvi.66.3.1294-1302.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lu Y. L., Spearman P., Ratner L. Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol. 1993 Nov;67(11):6542–6550. doi: 10.1128/jvi.67.11.6542-6550.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Marcuzzi A., Weinberger J., Weinberger O. K. Transcellular activation of the human immunodeficiency virus type 1 long terminal repeat in cocultured lymphocytes. J Virol. 1992 Jul;66(7):4228–4232. doi: 10.1128/jvi.66.7.4228-4232.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. McAllister R. M., Isaacs H., Rongey R., Peer M., Au W., Soukup S. W., Gardner M. B. Establishment of a human medulloblastoma cell line. Int J Cancer. 1977 Aug 15;20(2):206–212. doi: 10.1002/ijc.2910200207. [DOI] [PubMed] [Google Scholar]
  39. Merrill J. E., Chen I. S. HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 1991 Jul;5(10):2391–2397. doi: 10.1096/fasebj.5.10.2065887. [DOI] [PubMed] [Google Scholar]
  40. Mikovits J. A., Lohrey N. C., Schulof R., Courtless J., Ruscetti F. W. Activation of infectious virus from latent human immunodeficiency virus infection of monocytes in vivo. J Clin Invest. 1992 Oct;90(4):1486–1491. doi: 10.1172/JCI116016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Myers G., MacInnes K., Korber B. The emergence of simian/human immunodeficiency viruses. AIDS Res Hum Retroviruses. 1992 Mar;8(3):373–386. doi: 10.1089/aid.1992.8.373. [DOI] [PubMed] [Google Scholar]
  42. Nicholson J. K., Cross G. D., Callaway C. S., McDougal J. S. In vitro infection of human monocytes with human T lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). J Immunol. 1986 Jul 1;137(1):323–329. [PubMed] [Google Scholar]
  43. Ogawa K., Shibata R., Kiyomasu T., Higuchi I., Kishida Y., Ishimoto A., Adachi A. Mutational analysis of the human immunodeficiency virus vpr open reading frame. J Virol. 1989 Sep;63(9):4110–4114. doi: 10.1128/jvi.63.9.4110-4114.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pantaleo G., Graziosi C., Butini L., Pizzo P. A., Schnittman S. M., Kotler D. P., Fauci A. S. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9838–9842. doi: 10.1073/pnas.88.21.9838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  46. Paxton W., Connor R. I., Landau N. R. Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. J Virol. 1993 Dec;67(12):7229–7237. doi: 10.1128/jvi.67.12.7229-7237.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Perez V. L., Rowe T., Justement J. S., Butera S. T., June C. H., Folks T. M. An HIV-1-infected T cell clone defective in IL-2 production and Ca2+ mobilization after CD3 stimulation. J Immunol. 1991 Nov 1;147(9):3145–3148. [PubMed] [Google Scholar]
  48. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Poli G., Fauci A. S. The effect of cytokines and pharmacologic agents on chronic HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):191–197. doi: 10.1089/aid.1992.8.191. [DOI] [PubMed] [Google Scholar]
  50. Pomerantz R. J., Trono D., Feinberg M. B., Baltimore D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell. 1990 Jun 29;61(7):1271–1276. doi: 10.1016/0092-8674(90)90691-7. [DOI] [PubMed] [Google Scholar]
  51. Popovic M., Read-Connole E., Gallo R. C. T4 positive human neoplastic cell lines susceptible to and permissive for HTLV-III. Lancet. 1984 Dec 22;2(8417-8418):1472–1473. doi: 10.1016/s0140-6736(84)91666-0. [DOI] [PubMed] [Google Scholar]
  52. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  53. Schrier R. D., McCutchan J. A., Venable J. C., Nelson J. A., Wiley C. A. T-cell-induced expression of human immunodeficiency virus in macrophages. J Virol. 1990 Jul;64(7):3280–3288. doi: 10.1128/jvi.64.7.3280-3288.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schrier R. D., McCutchan J. A., Wiley C. A. Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages. J Virol. 1993 Oct;67(10):5713–5720. doi: 10.1128/jvi.67.10.5713-5720.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Shibata R., Adachi A., Sakai H., Ishimoto A., Miura T., Hayami M. Mutational analysis of simian immunodeficiency virus from African green monkeys and human immunodeficiency virus type 2. J Med Primatol. 1990;19(3-4):217–225. [PubMed] [Google Scholar]
  56. Shibata R., Miura T., Hayami M., Ogawa K., Sakai H., Kiyomasu T., Ishimoto A., Adachi A. Mutational analysis of the human immunodeficiency virus type 2 (HIV-2) genome in relation to HIV-1 and simian immunodeficiency virus SIV (AGM). J Virol. 1990 Feb;64(2):742–747. doi: 10.1128/jvi.64.2.742-747.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Smith S. D., Shatsky M., Cohen P. S., Warnke R., Link M. P., Glader B. E. Monoclonal antibody and enzymatic profiles of human malignant T-lymphoid cells and derived cell lines. Cancer Res. 1984 Dec;44(12 Pt 1):5657–5660. [PubMed] [Google Scholar]
  58. Stanley S. K., Bressler P. B., Poli G., Fauci A. S. Heat shock induction of HIV production from chronically infected promonocytic and T cell lines. J Immunol. 1990 Aug 15;145(4):1120–1126. [PubMed] [Google Scholar]
  59. Stevenson M., Stanwick T. L., Dempsey M. P., Lamonica C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. doi: 10.1002/j.1460-2075.1990.tb08274.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Stratton M. R., Darling J., Pilkington G. J., Lantos P. L., Reeves B. R., Cooper C. S. Characterization of the human cell line TE671. Carcinogenesis. 1989 May;10(5):899–905. doi: 10.1093/carcin/10.5.899. [DOI] [PubMed] [Google Scholar]
  61. Tristem M., Marshall C., Karpas A., Hill F. Evolution of the primate lentiviruses: evidence from vpx and vpr. EMBO J. 1992 Sep;11(9):3405–3412. doi: 10.1002/j.1460-2075.1992.tb05419.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tristem M., Marshall C., Karpas A., Petrik J., Hill F. Origin of vpx in lentiviruses. Nature. 1990 Sep 27;347(6291):341–342. doi: 10.1038/347341b0. [DOI] [PubMed] [Google Scholar]
  63. Viscidi R. P., Mayur K., Lederman H. M., Frankel A. D. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science. 1989 Dec 22;246(4937):1606–1608. doi: 10.1126/science.2556795. [DOI] [PubMed] [Google Scholar]
  64. Wong-Staal F., Chanda P. K., Ghrayeb J. Human immunodeficiency virus: the eighth gene. AIDS Res Hum Retroviruses. 1987 Spring;3(1):33–39. doi: 10.1089/aid.1987.3.33. [DOI] [PubMed] [Google Scholar]
  65. Yu X. F., Matsuda M., Essex M., Lee T. H. Open reading frame vpr of simian immunodeficiency virus encodes a virion-associated protein. J Virol. 1990 Nov;64(11):5688–5693. doi: 10.1128/jvi.64.11.5688-5693.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Yuan X., Matsuda Z., Matsuda M., Essex M., Lee T. H. Human immunodeficiency virus vpr gene encodes a virion-associated protein. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1265–1271. doi: 10.1089/aid.1990.6.1265. [DOI] [PubMed] [Google Scholar]
  67. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]
  68. Zack J. A., Haislip A. M., Krogstad P., Chen I. S. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J Virol. 1992 Mar;66(3):1717–1725. doi: 10.1128/jvi.66.3.1717-1725.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Zhu X. X., Chen J. X., Young C. S., Silverstein S. Reactivation of latent herpes simplex virus by adenovirus recombinants encoding mutant IE-0 gene products. J Virol. 1990 Sep;64(9):4489–4498. doi: 10.1128/jvi.64.9.4489-4498.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]