Abstract
Retinoic acid (RA) exerts potent suppressive and upregulatory effects on human immunodeficiency virus (HIV) expression in mononuclear phagocytes, strikingly similar to the effects of the cytokine transforming growth factor beta (TGF-beta). RA significantly inhibited phorbol ester-mediated, but not tumor necrosis factor alpha-mediated, induction of HIV transcription in the chronically infected promonocytic U1 cell line. RA and TGF-beta also completely suppressed the induction of virus production in U1 cells by interleukin 6 alone or in combination with glucocorticoids, which predominantly upregulate virus expression at the posttranscriptional level. Despite the close parallel to TGF-beta-induced effects, no evidence was obtained that RA mediated its effect by inducing secretion of active TGF-beta 1, -beta 2, or -beta 3. As with chronically infected U1 cells, similar inhibitory effects were also observed in primary monocyte-derived macrophages previously infected with HIV and then exposed to either RA or TGF-beta. In contrast, stimulation of monocyte-derived macrophages or U937 cells (the parental cell line of U1) with either RA or TGF-beta prior to in vitro infection resulted in the enhancement of virus production. Given the already successful use of retinoids in the treatment of several malignancies and the present demonstration of their capability of blocking the induction of HIV expression in infected mononuclear phagocytes, it would be of interest to pursue the potential role of this class of compounds in the development of strategies aimed at the pharmacologic regulation of HIV expression.
Full text
PDF![2689](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab8d/48727/064d0ebcff09/pnas01081-0190.png)
![2690](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab8d/48727/5e4abc591af5/pnas01081-0191.png)
![2691](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab8d/48727/4579d751ec8c/pnas01081-0192.png)
![2692](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab8d/48727/4d1b9274615c/pnas01081-0193.png)
![2693](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab8d/48727/268c1d783901/pnas01081-0194.png)
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- Bonhomme L., Fredj G., Averous S., Szekely A. M., Ecstein E., Trumbic B., Meyer P., Lang J. M., Misset J. L., Jasmin C. Topical treatment of epidemic Kaposi's sarcoma with all-trans-retinoic acid. Ann Oncol. 1991 Mar;2(3):234–235. doi: 10.1093/oxfordjournals.annonc.a057916. [DOI] [PubMed] [Google Scholar]
- Chantry D., Turner M., Abney E., Feldmann M. Modulation of cytokine production by transforming growth factor-beta. J Immunol. 1989 Jun 15;142(12):4295–4300. [PubMed] [Google Scholar]
- Choi Y., Fuchs E. TGF-beta and retinoic acid: regulators of growth and modifiers of differentiation in human epidermal cells. Cell Regul. 1990 Oct;1(11):791–809. doi: 10.1091/mbc.1.11.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Benedetti F., Falk L., Ruscetti F. W., Colburn N. H., Faltynek C. R., Oppenheim J. J. Synergistic inhibition of phorbol ester-induced transformation of JB6 cells by transforming growth factor-beta and retinoic acid. Cancer Res. 1991 Feb 15;51(4):1158–1164. [PubMed] [Google Scholar]
- Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Falk L. A., De Benedetti F., Lohrey N., Birchenall-Roberts M. C., Ellingsworth L. W., Faltynek C. R., Ruscetti F. W. Induction of transforming growth factor-beta 1 (TGF-beta 1), receptor expression and TGF-beta 1 protein production in retinoic acid-treated HL-60 cells: possible TGF-beta 1-mediated autocrine inhibition. Blood. 1991 Mar 15;77(6):1248–1255. [PubMed] [Google Scholar]
- Fernie B. F., Poli G., Fauci A. S. Alpha interferon suppresses virion but not soluble human immunodeficiency virus antigen production in chronically infected T-lymphocytic cells. J Virol. 1991 Jul;65(7):3968–3971. doi: 10.1128/jvi.65.7.3968-3971.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Flynn P. J., Miller W. J., Weisdorf D. J., Arthur D. C., Brunning R., Branda R. F. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood. 1983 Dec;62(6):1211–1217. [PubMed] [Google Scholar]
- Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988 Feb 15;140(4):1117–1122. [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]
- Glick A. B., Flanders K. C., Danielpour D., Yuspa S. H., Sporn M. B. Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis. Cell Regul. 1989 Nov;1(1):87–97. doi: 10.1091/mbc.1.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
- Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kekow J., Wachsman W., McCutchan J. A., Cronin M., Carson D. A., Lotz M. Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8321–8325. doi: 10.1073/pnas.87.21.8321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kekow J., Wachsman W., McCutchan J. A., Gross W. L., Zachariah M., Carson D. A., Lotz M. Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J Clin Invest. 1991 Mar;87(3):1010–1016. doi: 10.1172/JCI115059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keller J. R., Mantel C., Sing G. K., Ellingsworth L. R., Ruscetti S. K., Ruscetti F. W. Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines. J Exp Med. 1988 Aug 1;168(2):737–750. doi: 10.1084/jem.168.2.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keller J. R., Sing G. K., Ellingsworth L. R., Ruscetti F. W. Transforming growth factor beta: possible roles in the regulation of normal and leukemic hematopoietic cell growth. J Cell Biochem. 1989 Feb;39(2):175–184. doi: 10.1002/jcb.240390209. [DOI] [PubMed] [Google Scholar]
- Kitano K., Baldwin G. C., Raines M. A., Golde D. W. Differentiating agents facilitate infection of myeloid leukemia cell lines by monocytotropic HIV-1 strains. Blood. 1990 Nov 15;76(10):1980–1988. [PubMed] [Google Scholar]
- Koyanagi Y., O'Brien W. A., Zhao J. Q., Golde D. W., Gasson J. C., Chen I. S. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988 Sep 23;241(4873):1673–1675. doi: 10.1126/science.241.4873.1673. [DOI] [PubMed] [Google Scholar]
- Kraemer K. H., DiGiovanna J. J., Moshell A. N., Tarone R. E., Peck G. L. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988 Jun 23;318(25):1633–1637. doi: 10.1056/NEJM198806233182501. [DOI] [PubMed] [Google Scholar]
- Lazdins J. K., Klimkait T., Woods-Cook K., Walker M., Alteri E., Cox D., Cerletti N., Shipman R., Bilbe G., McMaster G. In vitro effect of transforming growth factor-beta on progression of HIV-1 infection in primary mononuclear phagocytes. J Immunol. 1991 Aug 15;147(4):1201–1207. [PubMed] [Google Scholar]
- Linial M., Gunderson N., Groudine M. Enhanced transcription of c-myc in bursal lymphoma cells requires continuous protein synthesis. Science. 1985 Dec 6;230(4730):1126–1132. doi: 10.1126/science.2999973. [DOI] [PubMed] [Google Scholar]
- Lo Coco F., Avvisati G., Diverio D., Petti M. C., Alcalay M., Pandolfi P. P., Zangrilli D., Biondi A., Rambaldi A., Moleti M. L. Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia. Blood. 1991 Apr 15;77(8):1657–1659. [PubMed] [Google Scholar]
- Lotem J., Sachs L. Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells. Blood. 1990 Oct 1;76(7):1315–1322. [PubMed] [Google Scholar]
- Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
- Michael N. L., Morrow P., Mosca J., Vahey M., Burke D. S., Redfield R. R. Induction of human immunodeficiency virus type 1 expression in chronically infected cells is associated primarily with a shift in RNA splicing patterns. J Virol. 1991 Mar;65(3):1291–1303. doi: 10.1128/jvi.65.3.1291-1303.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakashima H., Harada S., Yamamoto N. Effect of retinoic acid on the replication of human immunodeficiency virus in HTLV-I-positive MT-4 cells. Med Microbiol Immunol. 1987;176(4):189–198. doi: 10.1007/BF00196686. [DOI] [PubMed] [Google Scholar]
- Pautrat G., Suzan M., Salaun D., Corbeau P., Allasia C., Morel G., Filippi P. Human immunodeficiency virus type 1 infection of U937 cells promotes cell differentiation and a new pathway of viral assembly. Virology. 1990 Dec;179(2):749–758. doi: 10.1016/0042-6822(90)90142-e. [DOI] [PubMed] [Google Scholar]
- Peterson P. K., Gekker G., Chao C. C., Schut R., Molitor T. W., Balfour H. H., Jr Cocaine potentiates HIV-1 replication in human peripheral blood mononuclear cell cocultures. Involvement of transforming growth factor-beta. J Immunol. 1991 Jan 1;146(1):81–84. [PubMed] [Google Scholar]
- Petkovich M., Brand N. J., Krust A., Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. doi: 10.1038/330444a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Poli G., Kinter A. L., Justement J. S., Bressler P., Kehrl J. H., Fauci A. S. Transforming growth factor beta suppresses human immunodeficiency virus expression and replication in infected cells of the monocyte/macrophage lineage. J Exp Med. 1991 Mar 1;173(3):589–597. doi: 10.1084/jem.173.3.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Roberts A. B., Anzano M. A., Lamb L. C., Smith J. M., Sporn M. B. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5339–5343. doi: 10.1073/pnas.78.9.5339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenberg Z. F., Fauci A. S. The immunopathogenesis of HIV infection. Adv Immunol. 1989;47:377–431. doi: 10.1016/s0065-2776(08)60665-3. [DOI] [PubMed] [Google Scholar]
- Sporn M. B., Roberts A. B. Interactions of retinoids and transforming growth factor-beta in regulation of cell differentiation and proliferation. Mol Endocrinol. 1991 Jan;5(1):3–7. doi: 10.1210/mend-5-1-3. [DOI] [PubMed] [Google Scholar]
- Sporn M. B., Roberts A. B. Role of retinoids in differentiation and carcinogenesis. Cancer Res. 1983 Jul;43(7):3034–3040. [PubMed] [Google Scholar]
- Suzan M., Salaun D., Neuveut C., Spire B., Hirsch I., Le Bouteiller P., Querat G., Sire J. Induction of NF-KB during monocyte differentiation by HIV type 1 infection. J Immunol. 1991 Jan 1;146(1):377–383. [PubMed] [Google Scholar]
- Tsunawaki S., Sporn M., Ding A., Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988 Jul 21;334(6179):260–262. doi: 10.1038/334260a0. [DOI] [PubMed] [Google Scholar]
- Valette A., Botanch C. Transforming growth factor beta (TGF-beta) potentiates the inhibitory effect of retinoic acid on human breast carcinoma (MCF-7) cell proliferation. Growth Factors. 1990;2(4):283–287. doi: 10.3109/08977199009167023. [DOI] [PubMed] [Google Scholar]
- Wahl S. M., Allen J. B., McCartney-Francis N., Morganti-Kossmann M. C., Kossmann T., Ellingsworth L., Mai U. E., Mergenhagen S. E., Orenstein J. M. Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J Exp Med. 1991 Apr 1;173(4):981–991. doi: 10.1084/jem.173.4.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wahl S. M., McCartney-Francis N., Mergenhagen S. E. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989 Aug;10(8):258–261. doi: 10.1016/0167-5699(89)90136-9. [DOI] [PubMed] [Google Scholar]
- Wakefield L. M., Winokur T. S., Hollands R. S., Christopherson K., Levinson A. D., Sporn M. B. Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest. 1990 Dec;86(6):1976–1984. doi: 10.1172/JCI114932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warrell R. P., Jr, Frankel S. R., Miller W. H., Jr, Scheinberg D. A., Itri L. M., Hittelman W. N., Vyas R., Andreeff M., Tafuri A., Jakubowski A. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385–1393. doi: 10.1056/NEJM199105163242002. [DOI] [PubMed] [Google Scholar]