Abstract
Cell-free virus preparations from persistently infected monoblastoid cells (HU937) become progressively less infectious during long-term passage. This effect is specific for cell lines derived from U937 and is not observed in persistently infected T-cell lines. Reduced infectivity is correlated with accumulation of unusual, high-molecular-weight, extrachromosomal forms of the human immunodeficiency virus type 1 (HIV-1) DNA. These DNA molecules contain multiple copies of the viral genome, and their structures are highly variable. Of 17 subclones of the HU937 cell line, 15 unique restriction fragment patterns were observed for the HIV-1 viral DNA. Structural analysis of these viral DNA species indicated that they were formed by sequential rounds of long terminal repeat-mediated integration of one circular DNA form into preexisting monomeric or multimeric structures. These viral DNA structures are termed nested self-integrates. Once formed, self-integrates prove to be stable and can be maintained for several months in culture. The unusual structures of HIV-1 DNA in persistently infected monoblastoid cells attest to an alternative to the accepted retrovirus life cycle. The self-integrated viral DNA species reported here may explain some aspects of the mechanism controlling establishment and maintenance of persistent HIV-1 infection in cells of the monocyte/macrophage lineage.
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Selected References
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- Alizon M., Sonigo P., Barré-Sinoussi F., Chermann J. C., Tiollais P., Montagnier L., Wain-Hobson S. Molecular cloning of lymphadenopathy-associated virus. Nature. 1984 Dec 20;312(5996):757–760. doi: 10.1038/312757a0. [DOI] [PubMed] [Google Scholar]
- Armstrong J. A., Horne R. Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet. 1984 Aug 18;2(8399):370–372. doi: 10.1016/s0140-6736(84)90540-3. [DOI] [PubMed] [Google Scholar]
- Asjö B., Ivhed I., Gidlund M., Fuerstenberg S., Fenyö E. M., Nilsson K., Wigzell H. Susceptibility to infection by the human immunodeficiency virus (HIV) correlates with T4 expression in a parental monocytoid cell line and its subclones. Virology. 1987 Apr;157(2):359–365. doi: 10.1016/0042-6822(87)90278-9. [DOI] [PubMed] [Google Scholar]
- Chayt K. J., Harper M. E., Marselle L. M., Lewin E. B., Rose R. M., Oleske J. M., Epstein L. G., Wong-Staal F., Gallo R. C. Detection of HTLV-III RNA in lungs of patients with AIDS and pulmonary involvement. JAMA. 1986 Nov 7;256(17):2356–2359. [PubMed] [Google Scholar]
- Clapham P. R., Weiss R. A., Dalgleish A. G., Exley M., Whitby D., Hogg N. Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: receptor modulation and differentiation induced by phorbol ester. Virology. 1987 May;158(1):44–51. doi: 10.1016/0042-6822(87)90236-4. [DOI] [PubMed] [Google Scholar]
- Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
- Dhar R., McClements W. L., Enquist L. W., Vande Woude G. F. Nucleotide sequences of integrated Moloney sarcoma provirus long terminal repeats and their host and viral junctions. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3937–3941. doi: 10.1073/pnas.77.7.3937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gabuzda D. H., Ho D. D., de la Monte S. M., Hirsch M. S., Rota T. R., Sobel R. A. Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS. Ann Neurol. 1986 Sep;20(3):289–295. doi: 10.1002/ana.410200304. [DOI] [PubMed] [Google Scholar]
- Gendelman H. E., Orenstein J. M., Martin M. A., Ferrua C., Mitra R., Phipps T., Wahl L. A., Lane H. C., Fauci A. S., Burke D. S. Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med. 1988 Apr 1;167(4):1428–1441. doi: 10.1084/jem.167.4.1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goedert J. J., Biggar R. J., Melbye M., Mann D. L., Wilson S., Gail M. H., Grossman R. J., DiGioia R. A., Sanchez W. C., Weiss S. H. Effect of T4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus. JAMA. 1987 Jan 16;257(3):331–334. [PubMed] [Google Scholar]
- Griffin B. E., Björck E., Bjursell G., Lindahl T. Sequence complexity of circular Epstein-Bar virus DNA in transformed cells. J Virol. 1981 Oct;40(1):11–19. doi: 10.1128/jvi.40.1.11-19.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haas J. G., Riethmüller G., Ziegler-Heitbrock H. W. Monocyte phenotype and function in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related disorders. Scand J Immunol. 1987 Oct;26(4):371–379. doi: 10.1111/j.1365-3083.1987.tb02269.x. [DOI] [PubMed] [Google Scholar]
- Hirt B. Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol. 1967 Jun 14;26(2):365–369. doi: 10.1016/0022-2836(67)90307-5. [DOI] [PubMed] [Google Scholar]
- Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
- Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
- Lang W., Anderson R. E., Perkins H., Grant R. M., Lyman D., Winkelstein W., Jr, Royce R., Levy J. A. Clinical, immunologic, and serologic findings in men at risk for acquired immunodeficiency syndrome. The San Francisco Men's Health Study. JAMA. 1987 Jan 16;257(3):326–330. [PubMed] [Google Scholar]
- Lifson J. D., Reyes G. R., McGrath M. S., Stein B. S., Engleman E. G. AIDS retrovirus induced cytopathology: giant cell formation and involvement of CD4 antigen. Science. 1986 May 30;232(4754):1123–1127. doi: 10.1126/science.3010463. [DOI] [PubMed] [Google Scholar]
- Lifson J., Coutré S., Huang E., Engleman E. Role of envelope glycoprotein carbohydrate in human immunodeficiency virus (HIV) infectivity and virus-induced cell fusion. J Exp Med. 1986 Dec 1;164(6):2101–2106. doi: 10.1084/jem.164.6.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luciw P. A., Potter S. J., Steimer K., Dina D., Levy J. A. Molecular cloning of AIDS-associated retrovirus. Nature. 1984 Dec 20;312(5996):760–763. doi: 10.1038/312760a0. [DOI] [PubMed] [Google Scholar]
- Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
- McDougal J. S., Kennedy M. S., Sligh J. M., Cort S. P., Mawle A., Nicholson J. K. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science. 1986 Jan 24;231(4736):382–385. doi: 10.1126/science.3001934. [DOI] [PubMed] [Google Scholar]
- Muñoz A., Carey V., Saah A. J., Phair J. P., Kingsley L. A., Fahey J. L., Ginzburg H. M., Polk B. F. Predictors of decline in CD4 lymphocytes in a cohort of homosexual men infected with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1988;1(4):396–404. [PubMed] [Google Scholar]
- 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]
- Pallesen G., Gerstoft J., Mathiesen L. Stages in LAV/HTLV-III lymphadenitis. I. Histological and immunohistological classification. Scand J Immunol. 1987 Jan;25(1):83–91. doi: 10.1111/j.1365-3083.1987.tb01049.x. [DOI] [PubMed] [Google Scholar]
- Pauza C. D., Galindo J., Richman D. D. Human immunodeficiency virus infection of monoblastoid cells: cellular differentiation determines the pattern of virus replication. J Virol. 1988 Oct;62(10):3558–3564. doi: 10.1128/jvi.62.10.3558-3564.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pauza C. D. HIV persistence in monocytes leads to pathogenesis and AIDS. Cell Immunol. 1988 Apr 1;112(2):414–424. doi: 10.1016/0008-8749(88)90310-3. [DOI] [PubMed] [Google Scholar]
- Pauza C. D., Price T. M. Human immunodeficiency virus infection of T cells and monocytes proceeds via receptor-mediated endocytosis. J Cell Biol. 1988 Sep;107(3):959–968. doi: 10.1083/jcb.107.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Plata F., Autran B., Martins L. P., Wain-Hobson S., Raphaël M., Mayaud C., Denis M., Guillon J. M., Debré P. AIDS virus-specific cytotoxic T lymphocytes in lung disorders. Nature. 1987 Jul 23;328(6128):348–351. doi: 10.1038/328348a0. [DOI] [PubMed] [Google Scholar]
- Richter A., Ozer H. L., DesGroseillers L., Jolicoeur P. An X-linked gene affecting mouse cell DNA synthesis also affects production of unintegrated linear and supercoiled DNA of murine leukemia virus. Mol Cell Biol. 1984 Jan;4(1):151–159. doi: 10.1128/mcb.4.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanchez-Pescador R., Power M. D., Barr P. J., Steimer K. S., Stempien M. M., Brown-Shimer S. L., Gee W. W., Renard A., Randolph A., Levy J. A. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science. 1985 Feb 1;227(4686):484–492. doi: 10.1126/science.2578227. [DOI] [PubMed] [Google Scholar]
- Shoemaker C., Goff S., Gilboa E., Paskind M., Mitra S. W., Baltimore D. Structure of a cloned circular Moloney murine leukemia virus DNA molecule containing an inverted segment: implications for retrovirus integration. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3932–3936. doi: 10.1073/pnas.77.7.3932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takeuchi Y., Nagumo T., Hoshino H. Low fidelity of cell-free DNA synthesis by reverse transcriptase of human immunodeficiency virus. J Virol. 1988 Oct;62(10):3900–3902. doi: 10.1128/jvi.62.10.3900-3902.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urdal D. L., Call S. M., Jackson J. L., Dower S. K. Affinity purification and chemical analysis of the interleukin-1 receptor. J Biol Chem. 1988 Feb 25;263(6):2870–2877. [PubMed] [Google Scholar]
- Van Beveren C., Rands E., Chattopadhyay S. K., Lowy D. R., Verma I. M. Long terminal repeat of murine retroviral DNAs: sequence analysis, host-proviral junctions, and preintegration site. J Virol. 1982 Feb;41(2):542–556. doi: 10.1128/jvi.41.2.542-556.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss A., Hollander H., Stobo J. Acquired immunodeficiency syndrome: epidemiology, virology, and immunology. Annu Rev Med. 1985;36:545–562. doi: 10.1146/annurev.me.36.020185.002553. [DOI] [PubMed] [Google Scholar]
- Wiley C. A., Schrier R. D., Nelson J. A., Lampert P. W., Oldstone M. B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7089–7093. doi: 10.1073/pnas.83.18.7089. [DOI] [PMC free article] [PubMed] [Google Scholar]