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. 1995 Mar;69(3):1645–1651. doi: 10.1128/jvi.69.3.1645-1651.1995

Differential effects of human cytomegalovirus on integrated and unintegrated human immunodeficiency virus sequences.

V Koval 1, F M Jault 1, P G Pal 1, T N Moreno 1, C Aiken 1, D Trono 1, S A Spector 1, D H Spector 1
PMCID: PMC188762  PMID: 7853500

Abstract

Human cytomegalovirus (HCMV) has been implicated as a potential cofactor in human immunodeficiency virus type 1 (HIV-1)-related disease. Previously, we reported that HCMV inhibits HIV-1 RNA and protein synthesis in cells productively infected with both viruses but, in transient assays, activates an HIV-1 long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) construct introduced into the cell by transfection (V. Koval, C. Clark, M. Vaishnav, S. A. Spector, and D. H. Spector, J. Virol. 65:6969-6978, 1991). We show here that HCMV can also activate an infectious proviral HIV-1 genome transiently transfected into a cell. To ascertain whether integration of the HIV-1 provirus plays a role in these differential effects, we generated monoclonal and polyclonal cell lines that each contain a single integrated copy of an HIV-1 LTR-CAT construct and compared the regulatory effects of HCMV and HIV-1 infection in these cells with those occurring in the same type of cell transiently transfected with the HIV-1 LTR-CAT construct. We find that HCMV activates the transfected HIV-1 promoter 230-fold but activates the integrated promoter only 2.8- to 54-fold. In contrast, HIV-1 stimulates the integrated HIV-1 promoter 2,700- to 6,000-fold but stimulates the transfected promoter only 80-fold. Thus, the relative response of the HIV-1 promoter to HCMV and HIV-1 regulatory proteins depends upon whether it is integrated. To determine if HIV-1 gene products are necessary for the HCMV-mediated repression, we constructed cell lines containing two different stably integrated HIV-1 proviruses: one is tat- and nef-minus and transcriptionally inactive, while the other is env- and nef-minus but actively expresses the other HIV-1 gene products. Upon infection with HCMV, HIV-1 antigen production was stimulated from the inactive HIV-1 genome but inhibited from the active genome. We propose that HCMV has two separate effects on HIV-1 replication during a coinfection. One is a slight stimulatory effect which would be undetectable during an active HIV-1 infection, while the other is a net inhibitory effect that is mediated by an interaction between HCMV and HIV-1 gene products.

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Selected References

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  1. Adachi A., Gendelman H. E., Koenig S., Folks T., Willey R., Rabson A., Martin M. A. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986 Aug;59(2):284–291. doi: 10.1128/jvi.59.2.284-291.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adams C. C., Workman J. L. Nucleosome displacement in transcription. Cell. 1993 Feb 12;72(3):305–308. doi: 10.1016/0092-8674(93)90109-4. [DOI] [PubMed] [Google Scholar]
  3. Bonetti A., Weber R., Vogt M. W., Wunderli W., Siegenthaler W., Lüthy R. Co-infection with human immunodeficiency virus-type 1 (HIV-1) and cytomegalovirus in two intravenous drug users. Ann Intern Med. 1989 Aug 15;111(4):293–296. doi: 10.7326/0003-4819-111-4-293. [DOI] [PubMed] [Google Scholar]
  4. Bozzette S. A., Arcia J., Bartok A. E., McGlynn L. M., McCutchan J. A., Richman D. D., Spector S. A. Impact of Pneumocystis carinii and cytomegalovirus on the course and outcome of atypical pneumonia in advanced human immunodeficiency virus disease. J Infect Dis. 1992 Jan;165(1):93–98. doi: 10.1093/infdis/165.1.93. [DOI] [PubMed] [Google Scholar]
  5. Chattopadhyay S. K., Oliff A. I., Linemeyer D. L., Lander M. R., Lowy D. R. Genomes of murine leukemia viruses isolated from wild mice. J Virol. 1981 Sep;39(3):777–791. doi: 10.1128/jvi.39.3.777-791.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Feinberg M. B., Baltimore D., Frankel A. D. The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation. Proc Natl Acad Sci U S A. 1991 May 1;88(9):4045–4049. doi: 10.1073/pnas.88.9.4045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Felsenfeld G. Chromatin as an essential part of the transcriptional mechanism. Nature. 1992 Jan 16;355(6357):219–224. doi: 10.1038/355219a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Ho W. Z., Harouse J. M., Rando R. F., Gönczöl E., Srinivasan A., Plotkin S. A. Reciprocal enhancement of gene expression and viral replication between human cytomegalovirus and human immunodeficiency virus type 1. J Gen Virol. 1990 Jan;71(Pt 1):97–103. doi: 10.1099/0022-1317-71-1-97. [DOI] [PubMed] [Google Scholar]
  10. Jault F. M., Spector S. A., Spector D. H. The effects of cytomegalovirus on human immunodeficiency virus replication in brain-derived cells correlate with permissiveness of the cells for each virus. J Virol. 1994 Feb;68(2):959–973. doi: 10.1128/jvi.68.2.959-973.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jeang K. T., Berkhout B., Dropulic B. Effects of integration and replication on transcription of the HIV-1 long terminal repeat. J Biol Chem. 1993 Nov 25;268(33):24940–24949. [PubMed] [Google Scholar]
  12. Koval V., Clark C., Vaishnav M., Spector S. A., Spector D. H. Human cytomegalovirus inhibits human immunodeficiency virus replication in cells productively infected by both viruses. J Virol. 1991 Dec;65(12):6969–6978. doi: 10.1128/jvi.65.12.6969-6978.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laird P. W., Zijderveld A., Linders K., Rudnicki M. A., Jaenisch R., Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991 Aug 11;19(15):4293–4293. doi: 10.1093/nar/19.15.4293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lathey J. L., Spector D. H., Spector S. A. Human cytomegalovirus-mediated enhancement of human immunodeficiency virus type-1 production in monocyte-derived macrophages. Virology. 1994 Feb 15;199(1):98–104. doi: 10.1006/viro.1994.1101. [DOI] [PubMed] [Google Scholar]
  15. Peterlin B. M., Luciw P. A., Barr P. J., Walker M. D. Elevated levels of mRNA can account for the trans-activation of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9734–9738. doi: 10.1073/pnas.83.24.9734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rabkin C. S., Hatzakis A., Griffiths P. D., Pillay D., Ragni M. V., Hilgartner M. W., Goedert J. J. Cytomegalovirus infection and risk of AIDS in human immunodeficiency virus-infected hemophilia patients. National Cancer Institute Multicenter Hemophilia Cohort Study Group. J Infect Dis. 1993 Nov;168(5):1260–1263. doi: 10.1093/infdis/168.5.1260. [DOI] [PubMed] [Google Scholar]
  17. Ratner L., Fisher A., Jagodzinski L. L., Mitsuya H., Liou R. S., Gallo R. C., Wong-Staal F. Complete nucleotide sequences of functional clones of the AIDS virus. AIDS Res Hum Retroviruses. 1987 Spring;3(1):57–69. doi: 10.1089/aid.1987.3.57. [DOI] [PubMed] [Google Scholar]
  18. Skolnik P. R., Kosloff B. R., Hirsch M. S. Bidirectional interactions between human immunodeficiency virus type 1 and cytomegalovirus. J Infect Dis. 1988 Mar;157(3):508–514. doi: 10.1093/infdis/157.3.508. [DOI] [PubMed] [Google Scholar]
  19. Staprans S. I., Rabert D. K., Spector D. H. Identification of sequence requirements and trans-acting functions necessary for regulated expression of a human cytomegalovirus early gene. J Virol. 1988 Sep;62(9):3463–3473. doi: 10.1128/jvi.62.9.3463-3473.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Trono D., Feinberg M. B., Baltimore D. HIV-1 Gag mutants can dominantly interfere with the replication of the wild-type virus. Cell. 1989 Oct 6;59(1):113–120. doi: 10.1016/0092-8674(89)90874-x. [DOI] [PubMed] [Google Scholar]
  21. Wade E. J., Spector D. H. The human cytomegalovirus origin of DNA replication (oriLyt) is the critical cis-acting sequence regulating replication-dependent late induction of the viral 1.2-kilobase RNA promoter. J Virol. 1994 Oct;68(10):6567–6577. doi: 10.1128/jvi.68.10.6567-6577.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Webster A. Cytomegalovirus as a possible cofactor in HIV disease progression. J Acquir Immune Defic Syndr. 1991;4 (Suppl 1):S47–S52. [PubMed] [Google Scholar]
  23. Webster A., Lee C. A., Cook D. G., Grundy J. E., Emery V. C., Kernoff P. B., Griffiths P. D. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet. 1989 Jul 8;2(8654):63–66. doi: 10.1016/s0140-6736(89)90312-7. [DOI] [PubMed] [Google Scholar]

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