J. Virol., 06 1996, 3536-3544, Vol 70, No. 6
Copyright © 1996, American Society for Microbiology

Spontaneous mutations in the human immunodeficiency virus type 1 gag gene that affect viral replication in the presence of cyclosporins

C Aberham, S Weber and W Phares
Sandoz Forschungsinstitut, Vienna, Austria.

Human immunodeficiency virus type 1 mutants that are resistant to inhibition by cyclosporins arise spontaneously in vitro during propagation in a HeLa-CD4+ cell line in the presence of a nonimmunosuppressive analog of cyclosporin A. Interestingly, the phenotype of all of the mutants examined is drug resistant and drug dependent, with both cyclosporin A and its analog. Four independently isolated mutants have been analyzed genetically by construction of recombinant proviruses in the NL4-3 parental strain background and subsequent testing of the chimeric viruses in HeLa cells. The cyclosporin-resistant, cyclosporin-dependent phenotype consistently transfers with a 1.3-kb fragment of gag, within which the four mutants share one of two possible single amino acid exchanges in a proline-rich stretch in the capsid domain of Pr55gag. These mutants provide the first evidence that mutations in human immunodeficiency virus type 1 gag confer resistance to cyclosporins; however, replication is conditional on the presence of the drug. In the T-cell line CEM, replication of the recombinant mutant viruses is also cyclosporin dependent. The drug-dependent replication in HeLa cells is stringent, and in the absence of cyclosporin only revertant viruses with the parental phenotype grow out of cultures infected with cyclosporin- dependent virus. In at least one isolate examined, the revertant phenotype appears to be due to suppressor mutations near the proline- rich region.

This article has been cited by other articles:

• Ptak, R. G., Gallay, P. A., Jochmans, D., Halestrap, A. P., Ruegg, U. T., Pallansch, L. A., Bobardt, M. D., de Bethune, M.-P., Neyts, J., De Clercq, E., Dumont, J.-M., Scalfaro, P., Besseghir, K., Wenger, R. M., Rosenwirth, B. (2008). Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent. Antimicrob. Agents Chemother. 52: 1302-1317 [Abstract] [Full Text]  
• Schneidewind, A., Brockman, M. A., Yang, R., Adam, R. I., Li, B., Le Gall, S., Rinaldo, C. R., Craggs, S. L., Allgaier, R. L., Power, K. A., Kuntzen, T., Tung, C.-S., LaBute, M. X., Mueller, S. M., Harrer, T., McMichael, A. J., Goulder, P. J. R., Aiken, C., Brander, C., Kelleher, A. D., Allen, T. M. (2007). Escape from the Dominant HLA-B27-Restricted Cytotoxic T-Lymphocyte Response in Gag Is Associated with a Dramatic Reduction in Human Immunodeficiency Virus Type 1 Replication. J. Virol. 81: 12382-12393 [Abstract] [Full Text]  
• Song, C., Aiken, C. (2007). Analysis of Human Cell Heterokaryons Demonstrates that Target Cell Restriction of Cyclosporine-Resistant Human Immunodeficiency Virus Type 1 Mutants Is Genetically Dominant. J. Virol. 81: 11946-11956 [Abstract] [Full Text]  
• Robida, J. M., Nelson, H. B., Liu, Z., Tang, H. (2007). Characterization of Hepatitis C Virus Subgenomic Replicon Resistance to Cyclosporine In Vitro. J. Virol. 81: 5829-5840 [Abstract] [Full Text]  
• Yang, R., Aiken, C. (2007). A Mutation in Alpha Helix 3 of CA Renders Human Immunodeficiency Virus Type 1 Cyclosporin A Resistant and Dependent: Rescue by a Second-Site Substitution in a Distal Region of CA. J. Virol. 81: 3749-3756 [Abstract] [Full Text]  
• Geller, R., Vignuzzi, M., Andino, R., Frydman, J. (2007). Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev. 21: 195-205 [Abstract] [Full Text]  
• Adamson, C. S., Ablan, S. D., Boeras, I., Goila-Gaur, R., Soheilian, F., Nagashima, K., Li, F., Salzwedel, K., Sakalian, M., Wild, C. T., Freed, E. O. (2006). In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat). J. Virol. 80: 10957-10971 [Abstract] [Full Text]  
• Saini, M., Potash, M. J. (2006). Novel Activities of Cyclophilin A and Cyclosporin A during HIV-1 Infection of Primary Lymphocytes and Macrophages. J. Immunol. 177: 443-449 [Abstract] [Full Text]  
• Sokolskaja, E., Berthoux, L., Luban, J. (2006). Cyclophilin A and TRIM5{alpha} Independently Regulate Human Immunodeficiency Virus Type 1 Infectivity in Human Cells. J. Virol. 80: 2855-2862 [Abstract] [Full Text]  
• Chatterji, U., Bobardt, M. D., Stanfield, R., Ptak, R. G., Pallansch, L. A., Ward, P. A., Jones, M. J., Stoddart, C. A., Scalfaro, P., Dumont, J.-M., Besseghir, K., Rosenwirth, B., Gallay, P. A. (2005). Naturally Occurring Capsid Substitutions Render HIV-1 Cyclophilin A Independent in Human Cells and TRIM-cyclophilin-resistant in Owl Monkey Cells. J. Biol. Chem. 280: 40293-40300 [Abstract] [Full Text]  
• Hatziioannou, T., Perez-Caballero, D., Cowan, S., Bieniasz, P. D. (2005). Cyclophilin Interactions with Incoming Human Immunodeficiency Virus Type 1 Capsids with Opposing Effects on Infectivity in Human Cells. J. Virol. 79: 176-183 [Abstract] [Full Text]  
• Sokolskaja, E., Sayah, D. M., Luban, J. (2004). Target Cell Cyclophilin A Modulates Human Immunodeficiency Virus Type 1 Infectivity. J. Virol. 78: 12800-12808 [Abstract] [Full Text]  
• Berthoux, L., Sebastian, S., Sokolskaja, E., Luban, J. (2004). Lv1 Inhibition of Human Immunodeficiency Virus Type 1 Is Counteracted by Factors That Stimulate Synthesis or Nuclear Translocation of Viral cDNA. J. Virol. 78: 11739-11750 [Abstract] [Full Text]  
• Hatziioannou, T., Cowan, S., von Schwedler, U. K., Sundquist, W. I., Bieniasz, P. D. (2004). Species-Specific Tropism Determinants in the Human Immunodeficiency Virus Type 1 Capsid. J. Virol. 78: 6005-6012 [Abstract] [Full Text]  
• Ganser-Pornillos, B. K., von Schwedler, U. K., Stray, K. M., Aiken, C., Sundquist, W. I. (2004). Assembly Properties of the Human Immunodeficiency Virus Type 1 CA Protein. J. Virol. 78: 2545-2552 [Abstract] [Full Text]  
• Bosco, D. A., Eisenmesser, E. Z., Pochapsky, S., Sundquist, W. I., Kern, D. (2002). Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc. Natl. Acad. Sci. USA 99: 5247-5252 [Abstract] [Full Text]  
• Fujita, M., Yoshida, A., Miyaura, M., Sakurai, A., Akari, H., Koyama, A. H., Adachi, A. (2001). Cyclophilin A-Independent Replication of a Human Immunodeficiency Virus Type 1 Isolate Carrying a Small Portion of the Simian Immunodeficiency Virus SIVMAC gag Capsid Region. J. Virol. 75: 10527-10531 [Abstract] [Full Text]  
• Srivastava, M., Cartas, M., Rizvi, T. A., Singh, S. P., Serio, D., Kalyanaraman, V. S., Pollard, H. B., Srinivasan, A. (1999). HIV-1 Gag shares a signature motif with annexin (Anx7), which is required for virus replication. Proc. Natl. Acad. Sci. USA 96: 2704-2709 [Abstract] [Full Text]  
• Sherry, B., Zybarth, G., Alfano, M., Dubrovsky, L., Mitchell, R., Rich, D., Ulrich, P., Bucala, R., Cerami, A., Bukrinsky, M. (1998). Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes. Proc. Natl. Acad. Sci. USA 95: 1758-1763 [Abstract] [Full Text]  
• Ackerson, B., Rey, O., Canon, J., Krogstad, P. (1998). Cells with High Cyclophilin A Content Support Replication of Human Immunodeficiency Virus Type 1 Gag Mutants with Decreased Ability To Incorporate Cyclophilin A. J. Virol. 72: 303-308 [Abstract] [Full Text]  
• Dolinski, K., Muir, S., Cardenas, M., Heitman, J. (1997). All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in cerevisiae. Proc. Natl. Acad. Sci. USA 94: 13093-13098 [Abstract] [Full Text]  
• Dolinski, K., Scholz, C., Muir, R. S., Rospert, S., Schmid, F. X., Cardenas, M. E., Heitman, J. (1997). Functions of FKBP12 and Mitochondrial Cyclophilin Active Site Residues In Vitro and In Vivo in Saccharomyces cerevisiae. Mol. Biol. Cell 8: 2267-2280 [Abstract] [Full Text]  
• Bukovsky, A. A., Weimann, A., Accola, M. A., Gottlinger, H. G. (1997). Transfer of the HIV-1 cyclophilin-binding site to simian immunodeficiency virus from Macaca mulatta can confer both cyclosporin sensitivity and cyclosporin dependence. Proc. Natl. Acad. Sci. USA 94: 10943-10948 [Abstract] [Full Text]  
• Bosco, D. A., Eisenmesser, E. Z., Pochapsky, S., Sundquist, W. I., Kern, D. (2002). Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc. Natl. Acad. Sci. USA 99: 5247-5252 [Abstract] [Full Text]