Chemokine receptors and HIV

Journal of Leukocyte Biology

Volumn 62, Issue 1, 1997, Pages 20-29

  Broder, Christopher C ^a,c   Collman, Ronald G ^b  

^a UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center   (United States)

Author keywords

Chemokines; Fusion; Receptors

Indexed keywords

CD4 ANTIGEN; CELL SURFACE RECEPTOR; CHEMOKINE RECEPTOR; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MONOCYTE CHEMOTACTIC PROTEIN; RANTES;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANIMAL CELL; ARTICLE; CONTROLLED STUDY; GENETIC POLYMORPHISM; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFECTION RESISTANCE; MACROPHAGE; MEMBRANE FUSION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; SIMIAN IMMUNODEFICIENCY VIRUS; VIRUS ENVELOPE; VIRUS INFECTION; VIRUS ISOLATION;

ANIMALIA; FELIDAE; FELINE IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; SIMIAE; SIMIAN IMMUNODEFICIENCY VIRUS;

EID: 0030862523     PISSN: 07415400     EISSN: None     Source Type: Journal    
DOI: 10.1002/jlb.62.1.20     Document Type: Article

References (84)

1. D'Souza, M. P., Harden, V. A. (1996) Chemokines and HIV-1 second receptors. Confluence of two fields generates optimism in AIDS research. Nat. Med. 2, 1293-1300.
2. Premack, B. A., Schall, T. J. (1996) Chemokine receptors: Gateways to inflamation and infection. Nat. Med. 2, 1174-1178.
3. Broder, C. C., Dimitrov, D. S. (1996) HIV and the 7-transmembrane domain receptors. Pathobiol. 64, 171-179.
4. Fauci, A. S. (1996) Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529-534.
5. Moore, J. P., Trkola, A., Dragic, T. (1997) Co-receptors for HIV-1 entry. Curr. Op. Immunol. In press.
6. Moore, J., Jameson, B., Weiss, R., Sattentau, Q. (1993) The HIV-cell fusion reaction. In Virol Fusion Mechanisms (J. Bentz, ed.), Boca Raton, FL: CRC Press, 233-289.
7. Connor, R. I., Ho, D. D. (1994) Transmission and pathogenesis of human immunodeficiency virus type 1. AIDS Res. Hum. Retroviruses 10, 321-323.
8. Miedema, F., Meyaard, L., Koot, M., Klein, M. R., Roos, M. T. L., Groenink, M., Fouchier, R. A. M., Van't Wout, A. B., Tersmette, M., Schellekens, P. T. A., Schuitemaker, H. (1994) Changing virus-host interactions in the course of HIV-1 infection. Immunol. Rev. 140. 35-72.
9. Collman, R., Balliet, J. W., Gregory, S. A., Friedman, H., Kolson, D. L., Nathanson, N., Srinivasan, A. (1992) An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J. Virol. 66, 7517-7521.
10. Planelles, V., Chen, I. S. Y. (1993) The biological and molecular basis for cell tropism in HIV. In Human Retroviruses (B. R. Cullen, ed.), New York: Oxford University Press, 17-48.
11. + T-cell lines vs. primary macrophages. froc. Natl. Acad. Sci. USA 92, 9004-9008.
12. Feng, Y., Broder, C. C., Kennedy, P. E., Berger, E. A. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872-877.
13. Bleui, C. C., Farzan, M., Choe, H., Parolin, C., Clark-Lewis, I., Sodroski, J., Springer, T. A. (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTER/fusin and blocks HIV-1 entry. Nature 382, 829-833.
14. Oberlin, E., Amara, A., Bachelerie, F., Bessia, C., Virelizier, J.-L., Arenzana-Seisdedos, F., Schwartz, O., Heard, J.-M., Clark-Lewis, I., Legler, D. F., Loetscher, M., Baggiolini, M., Moser, B. (1996) The CXC chemokine SDF-1 is the ligand for LESTER/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833-835.
15. Adams, D. H., Lloyd, A. R. (1997) Chemokines: leucocyte recruitment and activation cytokines. Lancet 349, 490-495.
16. + T cells. Science 270, 1811-1815.
17. Paxton, W. A., Martin, S. R., Tse, D., O'Brien, T. R., Skurnick, J., Van-Devanter, N. L., Padian, N., Braun, J. F., Kotler, D. P., Wolinsky, S. M., Koup, R. A. (1996) Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nature Med. 2, 412-417.
18. Samson, M., Labbe, O., Mollereau, C., Vassart, G., Parmentier, M. (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35, 3362-3367.
19. Combadiere, C., Ahuja, S. K., Tiffany, H. L., Murphy, P. M. (1996) Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J. Leukoc. Biol. 60, 147-152.
20. Alkhatib, G., Combadiere, C., Broder, C. C., Feng, Y., Kennedy, P. E., Murphy, P. M., Berger, E. A. (1996) CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955-1958.
21. + cells is mediated by the chemokine receptor CC-CKR5. Nature 381, 667-673.
22. Deng, H., Liu R., Ellmeier, W., Choe, S., Unutmaz, D., Burkhart, M., Marzio, P. D., Marmon, S., Sutton, R. E., Hill, C. M., Davis, C. B., Peiper, S. C., Schall, T. J., Littman, D. R., Landau, N. R. (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661-666.
23. Doranz, B. J., Rucker, J., Yi, Y., Smyth, R. J., Samson, M., Peiper, S. C., Parmentier, M., Collman, R. G., Doms, R. W. (1996) A dual-tropic primary HIV-1 isolate that uses fusin and the b-chemokine receptors CKR-5. CKR-3, and CKR-2b as fusion cofactors. Cell 85, 1149-1158.
24. Choe, H., Farzan, M., Sun, Y. Sullivan, N., Rollins, B., Ponath, P. D., Wu, L., Mackay, C. R., LaRosa, G., Newman, W., Gerard, N., Gerard, C., Sodroski, J. (1996) The ß-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135-1148.
25. Murphy, P. R. (1994) The molecular biology of leukocyte chemoattractant receptors. Annu. Rev. Immunol. 12, 593-633.
26. Combadiere, C., Ahuja, S. K., Murphy, P. M. (1995) Cloning and functional expression of a human eosinophil CC chemokine receptor. J. Biol. Chem. 270, 16491-16494.
27. Lu, Z. H., Wang, Z. X., Horuk, R., Hesselgesser, J., Lou, Y. C., Handley, T. J., Peiper, S. C. (1995) The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain. Biol. Chem. 270, 26239-26245.
28. Horuk, R., Chitnis, C. E., Darbonne, W. C., Colby, T. J., Rybick, A., Hadley, T. J., Miller, L. H. (1993) A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science 261, 1182-1184.
29. Blumenthal, R., Dimitrov, D. S. (1996) Membrane fusion. In Handbook of Physiology. Section on Cell Physiology (J. F. Hoffman, J. C. Jarmeson, eds.), New York: Oxford University Press.
30. Atchison, R. E., Gosling, J., Monteclaro, F. S., Franci, C., Digilio, L., Charo, I. F., Goldsmith, M. A. (1996) Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines. Science 274, 1924-1926.
31. Lu, Z.-H., Berson, J. F., Chen, Y.-H., Turner, J. D., Zhang, T.-Y., Sharron, M., Jenks, M. H., Wang, Z.-X., Kim, J., Rucker, J., Hoxie, J. A., Peiper, S. C., Doms, R. W. (1997) Evolution of HIV-1 co-receptor usage through interactions with distinct CCR5 and CXCR4 domains. Proc. Natl. Acad. Sci. USA. In press.
32. Golding, H., Dimitrov, D. S., Manischewitz, J., Broder, C. C., Robinson, J., Fabian, S., Littman, D. R., Lapham, C. K. (1995) Phorbol ester-induced down modulation of tailess CD4 receptors requires prior binding of gp120 and suggests a role for accessory molecules. J. Virol. 69, 6140-6148.
33. Lapham, C. K., Ouyang, J., Chandrasekhar, B., Nguyen, N. Y., Dimitrov, D. S., Golding, H. (1996) Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science 274, 602-605.
34. Endres, M. J., Clapham, P. R., Marsh, M., Ahuja, M., Turner, J. D., McKnight, A., Thomas, J. F., Stoebenau-Haggarty, B., Choe, S., Vance, P. J., Wells, T. N. C., Power, C. A., Sutterwala, S. S., Doms, R. W., Landau, N. R., Hoxie, J. A. (1996) CD4-mdependent infection by H1V-2 is mediated bv fusin/CXCR4. Cell 87, 745-756.
35. Trkola, A., Dragic, T., Arthos, J., Binley, J. M., Olson, W. C., Allaway, G. P., Chen-Mayer, C., Robinson, J., Maddon, P. J., Moore, J. P. (1996) CD4-dependent antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384, 184-187.
36. Wu, L., Gerard, N. P., Wyatt, R., Choe, H., Parolin, C., Ruffing, N., Borsetti, A., Cardoso, A. A., Desjardin, E., Newman, W., Gerard, C., Sodroski, J. (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384, 179-183.
37. Gudermann, T., Nurnberg, B., Schultz, G. (1995) Receptors and G proteins as primary components of transmembrane signal transduction. J. Mol. Med. 73, 51-63.
38. Rucker, J., Samson, M., Doranz, B. J., Libert, F., Berson, J. F., Broder, C. C., Vassart, G., Doms, R. W., Parmentier, M. (1996) Regions in β-chemokine receptors CCR-5 and CCR-2b that determine HIV-I cofactor specificity. Cell 87, 437-446.
39. Malaykh, A. M. S., Reitz, J., Louie. A., Hall, L., Lori, F. (1995) Multiple determinants of growth of human immunodeficiency virus type 1 in monocyte-macrophages. Virology 206, 646-650.
40. Kim, F. M., Kolson, D. L., Balliet, J. W., Srinivasan, A., Collman, R. G. (1995) V3-independent determinants of macrophage tropism in a primary human immunodeficiency virus type 1 isolate. J. Virol. 69, 1755-1761.
41. Valentin, A., Albert, J., Fenyö, E. M., Asjö, B. (1994) Dual tropism for macrophages and lymphocytes is a common feature of primary human immunodeficiency virus type 1 and 2 isolates. J. Virol. 68, 6684-6689.
42. Simmons, G., Wilkinson, D., Reeves, J. D., Dittmar, M. T., Beddows, S., Weber, J., Carnegie, G., Desselberger, U., Gray, P. W., Weiss, R. A., Clapham, P. R. (1996) Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J. Virol. 70, 8355-8360.
43. Zhang, L., Huang, Y., Cao, Y., Ho, D. D. (1996) HIV-1 subtype and second-receptor use. Nature 383, 768.
44. Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S., Landau, N. R. (1997) Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J. Exp. Med. 185, 621-628.
45. Dittmar, M. T., McKnight, A., Simmons, G., Clapham, P. R., Weiss, R. A., Simmonds, P. (1997) HIV-1 tropism and co-receptor use. Nature 385, 495-496.
46. McKnight, A., Wilkinson, D., Simmons, G., Talbot, S., Picard, L., Ahuja, M., Marsh, M., Hoxie, J. A., Clapham, P. R. (1997) Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR-4) is both cell type and virus strain dependent. J. Virol. 71, 1692-1696.
47. Marcon, L., Choe, H., Martin, K. A., Farzan, M., Ponath, P. D., Wu, L., Newman, W., Gerard, N., Gerard, C., Sodroski, J. (1997) Utilization of C-C chemokine receptor 5 by the envelope glycoproteins of a pathogenic simian immunodeficiency virus, SIVmac239. J. Virol. 71, 2522-2527.
48. Chen, Z., Zhou, P., Ho, D. D., Landau, N. R., Marx, P. A. (1997) Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J. Virol. 71, 2705-2714.
49. Edinger, A. L., Amedee, A., Miller, K., Doranz, B. J., Endres, M., Sharron, M., Samson, M., Lu, Z.-H., Clements, J. E., Murphey-Corb, M., Peiper, S. C., Parmentier, M., Broder, C. C., Doms, R. W. (1997) Differential utilization of CCR-5 by macrophage and T-cell tropic SIV strains. Proc. Natl. Acad. Sci. USA 94, 4005-4010.
50. Mori, K., Ringler, D. J., Desrosiers, R. C. (1993) Restricted replication of simian immunodeficiency virus strain 239 in macrophages is determined bv env but is not due to restricted entry. J. Virol. 67, 2807-2814.
51. Willett, B. J., Hosie, M. J., Neil, J. C., Turner, J. D., Hoxie, J. A. (1997) Common mechanism of infection by lentiviruses. Nature 385, 587.
52. Samson, M., Liberi, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C.-M., Saragosti, S., LapoumEroulie, C., Cogniaux, J., Forceille, C., Muyldermans, G., Verhofstede, C., Burtonboy, G., Georges, M., Imai, T., Rana, S., Yi, Y., Smyth, R. J., Collman, R. G., Doms, R. W., Vassart, G., Parmentier, M. (1996) Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene. Nature 381, 722-725.
53. Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuki, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., Landau, N. R. (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367-377.
54. Rana, S., Besson, G., Cook, D. G., Rucker, J., Smyth, R. J., Yi. Y., Turner, J. D., Guo, H.-H., Du, J.-G., Peiper, S. C., Lavi, E., Samson, M., Libert, F., Liesnard, C., Vassart, G., Doms, R. W., Parmentier, M., Collman, R. G. (1997) Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the Dccr5 mutation. J. Virol. 71, 3219-3227.
55. + T-cell-derived factor(s), but not b-chemokines RANTES. MIP-1α and MIP-1β, suppress HIV-1 replication in monocyte/macrophages. Proc. Natl. Acad. Sci. USA 93, 15341-15345.
56. Schmidtmayerova, H., Sherry, B., Bukrinsky, M. (1996) Chemokines and HIV replication. Nature 382, 767.
57. Cheng-Mayer, C., Liu, R., Landau, N. R., Stomatatos, L. (1997) Macrophage tropism of human immunodeficiency virus type 1 and utilization of the CC-CKR5 co-receptor. J. Virol. 71, 1657-1661.
58. + T lymphocytes from two multiply exposed unifected individuals resist infection with primary non-syncytium-inducing isolates of human immunodeficiency virus type-1. J. Virol. 70, 8758-8764.
59. Granelli-Piperno, A., Moser, B., Pope, M., Chen, D., Wei, Y., Isdell, F., O'Doherty, U., Paxton, W., Koup, R., Mojsov, S., Bhardwaj, N., Clark-Lewis I., Baggiolini, M., Steinman, R. M. (1996) Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J. Exp. Med. 184, 2433-2438.
60. He, J., Chen, Y., Farzan, M., Choe, H., Ohagen, A., Gartner, S., Busciglio, J., Yang, X., Hofmann, W., Newman, W., Mackay, C. R., Sodroski, J., Gabuzda, D. (1997) CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature 385, 645-649.
61. Combadiere, C., Ahuja, S. K., Damme, J. V., Tiffany, H. I., Gao, J.-L., Murphy, P. M. (1995) Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2b. J. Biol. Chem. 270, 29671-29675.
62. Loetscher, M., Geiser, T., O'Reilly, T., Zwahlen, R., Baggiolini, M., Moser, B. (1994) Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J. Biol. Chem. 269, 232-237.
63. Dean, M., Carrington, M., Winkler, C., Huttley, G. A., Smith, M. W., Allikmets, R., Goedert, J. J., Buchbinder, S. P., Vittinghoff, E., Gomperts, E., Donfield, S., Vlahov, D., Kaslow, R., Saah, A., Rinaldo, C., Detels, K., O'Brien, S. J. (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856-1862.
64. Huang, Y., Paxton, W. A., Wolinsky, S. M., Neumann, A. U., Zhang, L., He, T., Kang, S., Ceradini, D., Jin, Z., Yazdanbakhsh, K., Kunstman, K., Erickson, D., Dragon, E., Landau, N. R., Phair, J., Ho, D. D., Koup, R. A. (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med. 2, 1240-1243.
65. Michael, N. L., Chang, G., Louie, L. G., Mascola, J. R., Dondero, D., Birx, D. L., Sheppard, H. W. (1997) The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nature Med. 3, 338-340.
66. Biti, R., French, R., Young, J., Bennetts, B., Stewart, G., Liang, T. (1997) HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nature Med. 3, 252-253.
67. Klein, M. R., Miedema, F. (1995) Long-term survivors of HIV-1 infection. Trends Microbiol. 3, 386-391.
68. Gillespie, F. P., Doros, L., Vitale, J., Blackwell, C., Gosselin, J., Snyder, B. W., Wadsworth, S. C. (1993) Tissue-specific expression of human CD4 in transgenic mice. Mol. Cell Biol. 13, 2952-2958.
69. Killeen, N., Sawada, S., Littman, D. R. (1993) Regulated expression of human CD4 rescues helper T-cell development in mice lacking expression of endogenous CD4. Eur. Mol. Biol. Org. J. 12, 1547-1553.
70. Hanna, Z., Simard, C., Laperriere, A., Jolicoeur, P. (1994) Specific expression of the human CD4 gene in mature CD4(+) CD8(-) and immature CD4(+) CD8(+) T cells and in macrophages of transgenic mice. Mol. Cell Biol. 14, 1084-1094.
71. Snyder, B. W., Vitale, J., Milos, P., Gosselin, J., Gillespie, F., Ebert, K., Hague, B. F., Kindt, T. J., Wadsworth, S., Leibowitz, P. (1995) Developmental and tissue-specific expression of human CD4 in transgenic rabbits. J. Mol. Reprod. Dev. 40, 419-428.
72. Dunn, C. S., Mehtali, M., Houdebine, L. M., Gut, J.-P., Kirn, A., Aubertin, A.-M. (1995) Human immunodeficiency virus type 1 infection of human CD4-transgenic rabbits. J. Gen. Virol. 76, 1327-1336.
73. Trono, D. (1994) Molecular biology of HIV. Clin. Lab. Med. 14, 203-220.
74. Cho, S., Kindt, T. J., Zhao, T.-M., Sawasdikosol, S., Hague, B. F. (1995) Replication of HIV type 1 in rabbit cell lines is not limited by deficiencies in tat, rev, or long terminal repeat function. AIDS Res. Hum. Retroviruses 11, 1487-1493.
75. Arenzana-Seisdedos, F., Virelizier, J. I., Rousset, D., Clark-Lewis, I., Loetscher, P., Moser, B., Baggiolini, M. (1996) HIV blocked by chemokine antagonist. Nature 383, 400.
76. Capon, D. J., Chamow, S. M., Mordenti, J., Marsters, S. A., Gregory, I., Mitsuya, H., Byrn, R. A., Lucas, C., Wurm, F. M., Groopman, J. E. (1989) Designing CD4 immunoadhesins for AIDS therapy. Nature 337, 525-531.
77. Wild, C. T., Shugars, D. C., Greenwell, T. K., McDanal, C. B., Matthews, T. J. (1994) Peptides corresponding to a predictive α-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc. Natl. Acad. Sci. USA 91, 9770-9774.
78. Strader, C. D., Fong, T. M., Tota, M. R., Underwood, D., Dixon, R. A. (1994) Structure and function of G protein-coupled receptors. Annu. Rev. Biochem. 63, 101-132.
79. Dimitrov, D. S. (1996) Fusin-a place for HIV-1 and T4 cells to meet. Nature Med. 2, 640-641.
80. Nussbaum, O., Broder, C. C., Berger, E. A. (1994) Fusogenic mechanisms of enveloped-virus glycoproteins analyzed by a novel recombinant vaccinia virus-based assay quantitating cell fusion-dependent reporter gene activation. J. Virol. 68, 5411-5422.
81. Broder, C. C., Earl, P. L. (1996) Design and construction of vaccinia virus-recombinants. In Expression and Detection of Recombinant Genes (R. S. Tuan, ed.), Humana Press, 173-197.
82. Broder, C. C., Dimitrov, D. S., Blumenthal, R., Berger, E. A. (1993) The block to HIV-1 envelope glycoprotein-mediated membrane fusion in animal cells expressing human CD4 can be overcome by a human cell component(s). Virol. 193, 483-491.
83. Alkhatib, G., Broder, C. C., Berger, E. A. (1996) Cell type-specific accessory factors determine human immunodeficiency virus type-1 tropism for T-cell lines vs. primary macrophages. J. Virol. 70, 6487-6494.
84. Alexander, W. A., Moss, B., Fuerst, T. R. (1992) Regulated expression of foreign genes in vaccinia virus under the control of bacteriophage T7 RNA polymerase and the Escherichia coli lac repressor. J. Virol. 66, 2934-2942.