This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Martinez-Picado, J.
Right arrow Articles by D'Aquila, R. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Martinez-Picado, J.
Right arrow Articles by D'Aquila, R. T.

 Previous Article  |  Next Article 

Journal of Virology, May 1999, p. 3744-3752, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Replicative Fitness of Protease Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1

Javier Martinez-Picado,1,2 Anu V. Savara,1 Lorraine Sutton,1 and Richard T. D'Aquila1,*

Infectious Disease Unit and AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,1 and Fundació irsiCaixa, Badalona, Spain2

Received 10 August 1998/Accepted 19 January 1999

The relative replicative fitness of human immunodeficiency virus type 1 (HIV-1) mutants selected by different protease inhibitors (PIs) in vivo was determined. Each mutant was compared to wild type (WT), NL4-3, in the absence of drugs by several methods, including clonal genotyping of cultures infected with two competing viral variants, kinetics of viral antigen production, and viral infectivity/virion particle ratios. A nelfinavir-selected protease D30N substitution substantially decreased replicative capacity relative to WT, while a saquinavir-selected L90M substitution moderately decreased fitness. The D30N mutant virus was also outcompeted by the L90M mutant in the absence of drugs. A major natural polymorphism of the HIV-1 protease, L63P, compensated well for the impairment of fitness caused by L90M but only slightly improved the fitness of D30N. Multiply substituted indinavir-selected mutants M46I/L63P/V82T/I84V and L10R/M46I/L63P/V82T/I84V were just as fit as WT. These results indicate that the mutations which are usually initially selected by nelfinavir and saquinavir, D30N and L90M, respectively, impair fitness. However, additional mutations may improve the replicative capacity of these and other drug-resistant mutants. Hypotheses based on the greater fitness impairment of the nelfinavir-selected D30N mutant are suggested to explain observations that prolonged responses to delayed salvage regimens, including alternate PIs, may be relatively common after nelfinavir failure.

* Corresponding author. Mailing address: Infectious Disease Unit and AIDS Research Center, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129. Phone: (617) 726-5776. Fax: (617) 726-5411. E-mail: daquila{at}helix.mgh.harvard.edu.

Journal of Virology, May 1999, p. 3744-3752, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Parry, C. M., Kohli, A., Boinett, C. J., Towers, G. J., McCormick, A. L., Pillay, D. (2009). Gag Determinants of Fitness and Drug Susceptibility in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1. J. Virol. 83: 9094-9101 [Abstract] [Full Text]  
  • Bracciale, L., Colafigli, M., Zazzi, M., Corsi, P., Meraviglia, P., Micheli, V., Maserati, R., Gianotti, N., Penco, G., Setti, M., Di Giambenedetto, S., Butini, L., Vivarelli, A., Trezzi, M., De Luca, A. (2009). Prevalence of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy: evolution over 12 years and predictors. J Antimicrob Chemother 64: 607-615 [Abstract] [Full Text]  
  • Adamson, C. S., Waki, K., Ablan, S. D., Salzwedel, K., Freed, E. O. (2009). Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457). J. Virol. 83: 4884-4894 [Abstract] [Full Text]  
  • Miura, T., Brockman, M. A., Brumme, Z. L., Brumme, C. J., Pereyra, F., Trocha, A., Block, B. L., Schneidewind, A., Allen, T. M., Heckerman, D., Walker, B. D. (2009). HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1. J. Virol. 83: 140-149 [Abstract] [Full Text]  
  • Margerison, E. S., Maguire, M., Pillay, D., Cane, P., Elston, R. C. (2008). The HIV-1 protease substitution K55R: a protease-inhibitor-associated substitution involved in restoring viral replication. J Antimicrob Chemother 61: 786-791 [Abstract] [Full Text]  
  • Dykes, C., Demeter, L. M. (2007). Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness. Clin. Microbiol. Rev. 20: 550-578 [Abstract] [Full Text]  
  • Taiwo, B. O., Murphy, R. (2007). Transmitted Resistance: An Overview and Its Potential Relevance to the Management of HIV-Infected Persons in Resource-Limited Settings. J Int Assoc Physicians AIDS Care (Chic Ill) 6: 188-197 [Abstract]  
  • Parera, M., Fernandez, G., Clotet, B., Martinez, M. A. (2007). HIV-1 Protease Catalytic Efficiency Effects Caused by Random Single Amino Acid Substitutions. Mol Biol Evol 24: 382-387 [Abstract] [Full Text]  
  • Dykes, C., Wang, J., Jin, X., Planelles, V., An, D. S., Tallo, A., Huang, Y., Wu, H., Demeter, L. M. (2006). Evaluation of a multiple-cycle, recombinant virus, growth competition assay that uses flow cytometry to measure replication efficiency of human immunodeficiency virus type 1 in cell culture.. J. Clin. Microbiol. 44: 1930-1943 [Abstract] [Full Text]  
  • Brann, T. W., Dewar, R. L., Jiang, M.-K., Shah, A., Nagashima, K., Metcalf, J. A., Falloon, J., Lane, H. C., Imamichi, T. (2006). Functional Correlation between a Novel Amino Acid Insertion at Codon 19 in the Protease of Human Immunodeficiency Virus Type 1 and Polymorphism in the p1/p6 Gag Cleavage Site in Drug Resistance and Replication Fitness.. J. Virol. 80: 6136-6145 [Abstract] [Full Text]  
  • Gonzalez, L. M. F., Aguiar, R. S., Afonso, A., Brindeiro, P. A., Arruda, M. B., Soares, M. A., Brindeiro, R. M., Tanuri, A. (2006). Biological characterization of human immunodeficiency virus type 1 subtype C protease carrying indinavir drug-resistance mutations.. J. Gen. Virol. 87: 1303-1309 [Abstract] [Full Text]  
  • Wu, H., Huang, Y., Dykes, C., Liu, D., Ma, J., Perelson, A. S., Demeter, L. M. (2006). Modeling and Estimation of Replication Fitness of Human Immunodeficiency Virus Type 1 In Vitro Experiments by Using a Growth Competition Assay. J. Virol. 80: 2380-2389 [Abstract] [Full Text]  
  • Weinheimer, S., Discotto, L., Friborg, J., Yang, H., Colonno, R. (2005). Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones. Antimicrob. Agents Chemother. 49: 3816-3824 [Abstract] [Full Text]  
  • Resch, W., Parkin, N., Watkins, T., Harris, J., Swanstrom, R. (2005). Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir. J. Virol. 79: 10638-10649 [Abstract] [Full Text]  
  • Arien, K. K., Abraha, A., Quinones-Mateu, M. E., Kestens, L., Vanham, G., Arts, E. J. (2005). The Replicative Fitness of Primary Human Immunodeficiency Virus Type 1 (HIV-1) Group M, HIV-1 Group O, and HIV-2 Isolates. J. Virol. 79: 8979-8990 [Abstract] [Full Text]  
  • Springer, K. L., Chou, S., Li, S., Giller, R. H., Quinones, R., Shira, J. E., Weinberg, A. (2005). How Evolution of Mutations Conferring Drug Resistance Affects Viral Dynamics and Clinical Outcomes of Cytomegalovirus-Infected Hematopoietic Cell Transplant Recipients. J. Clin. Microbiol. 43: 208-213 [Abstract] [Full Text]  
  • Lu, J., Sista, P., Giguel, F., Greenberg, M., Kuritzkes, D. R. (2004). Relative Replicative Fitness of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide (T-20). J. Virol. 78: 4628-4637 [Abstract] [Full Text]  
  • Charpentier, C., Dwyer, D. E., Mammano, F., Lecossier, D., Clavel, F., Hance, A. J. (2004). Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors. J. Virol. 78: 4234-4247 [Abstract] [Full Text]  
  • Draenert, R., Le Gall, S., Pfafferott, K. J., Leslie, A. J., Chetty, P., Brander, C., Holmes, E. C., Chang, S.-C., Feeney, M. E., Addo, M. M., Ruiz, L., Ramduth, D., Jeena, P., Altfeld, M., Thomas, S., Tang, Y., Verrill, C. L., Dixon, C., Prado, J. G., Kiepiela, P., Martinez-Picado, J., Walker, B. D., Goulder, P. J.R. (2004). Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection. JEM 199: 905-915 [Abstract] [Full Text]  
  • Clavel, F., Hance, A. J. (2004). HIV Drug Resistance. NEJM 350: 1023-1035 [Full Text]  
  • Leigh Brown, A. J., Frost, S. D. W., Good, B., Daar, E. S., Simon, V., Markowitz, M., Collier, A. C., Connick, E., Conway, B., Margolick, J. B., Routy, J.-P., Corbeil, J., Hellmann, N. S., Richman, D. D., Little, S. J. (2004). Genetic Basis of Hypersusceptibility to Protease Inhibitors and Low Replicative Capacity of Human Immunodeficiency Virus Type 1 Strains in Primary Infection. J. Virol. 78: 2242-2246 [Abstract] [Full Text]  
  • Collins, J. A., Thompson, M. G., Paintsil, E., Ricketts, M., Gedzior, J., Alexander, L. (2004). Competitive Fitness of Nevirapine-Resistant Human Immunodeficiency Virus Type 1 Mutants. J. Virol. 78: 603-611 [Abstract] [Full Text]  
  • Trkola, A., Kuster, H., Leemann, C., Ruprecht, C., Joos, B., Telenti, A., Hirschel, B., Weber, R., Bonhoeffer, S., Gunthard, H. F. (2003). Human Immunodeficiency Virus Type 1 Fitness Is a Determining Factor in Viral Rebound and Set Point in Chronic Infection. J. Virol. 77: 13146-13155 [Abstract] [Full Text]  
  • Goodenow, M. M., Rose, S. L., Tuttle, D. L., Sleasman, J. W. (2003). HIV-1 fitness and macrophages. J. Leukoc. Biol. 74: 657-666 [Abstract] [Full Text]  
  • Perrin, V., Mammano, F. (2003). Parameters Driving the Selection of Nelfinavir-Resistant Human Immunodeficiency Virus Type 1 Variants. J. Virol. 77: 10172-10175 [Abstract] [Full Text]  
  • Weber, J., Rangel, H. R., Chakraborty, B., Tadele, M., Martinez, M. A., Martinez-Picado, J., Marotta, M. L., Mirza, M., Ruiz, L., Clotet, B., Wrin, T., Petropoulos, C. J., Quinones-Mateu, M. E. (2003). A novel TaqMan real-time PCR assay to estimate ex vivo human immunodeficiency virus type 1 fitness in the era of multi-target (pol and env) antiretroviral therapy. J. Gen. Virol. 84: 2217-2228 [Abstract] [Full Text]  
  • Frenkel, L. M., Wang, Y., Learn, G. H., McKernan, J. L., Ellis, G. M., Mohan, K. M., Holte, S. E., De Vange, S. M., Pawluk, D. M., Melvin, A. J., Lewis, P. F., Heath, L. M., Beck, I. A., Mahalanabis, M., Naugler, W. E., Tobin, N. H., Mullins, J. I. (2003). Multiple Viral Genetic Analyses Detect Low-Level Human Immunodeficiency Virus Type 1 Replication during Effective Highly Active Antiretroviral Therapy. J. Virol. 77: 5721-5730 [Abstract] [Full Text]  
  • Wu, T. D., Schiffer, C. A., Gonzales, M. J., Taylor, J., Kantor, R., Chou, S., Israelski, D., Zolopa, A. R., Fessel, W. J., Shafer, R. W. (2003). Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments. J. Virol. 77: 4836-4847 [Abstract] [Full Text]  
  • Watkins, T., Resch, W., Irlbeck, D., Swanstrom, R. (2003). Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors. Antimicrob. Agents Chemother. 47: 759-769 [Abstract] [Full Text]  
  • Huang, W., Gamarnik, A., Limoli, K., Petropoulos, C. J., Whitcomb, J. M. (2002). Amino Acid Substitutions at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Susceptibility to Delavirdine and Impair Virus Replication. J. Virol. 77: 1512-1523 [Abstract] [Full Text]  
  • Matsuoka-Aizawa, S., Sato, H., Hachiya, A., Tsuchiya, K., Takebe, Y., Gatanaga, H., Kimura, S., Oka, S. (2002). Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication. J. Virol. 77: 318-327 [Abstract] [Full Text]  
  • Barbour, J. D., Wrin, T., Grant, R. M., Martin, J. N., Segal, M. R., Petropoulos, C. J., Deeks, S. G. (2002). Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults. J. Virol. 76: 11104-11112 [Abstract] [Full Text]  
  • Cuevas, J. M., Elena, S. F., Moya, A. (2002). Molecular Basis of Adaptive Convergence in Experimental Populations of RNA Viruses. Genetics 162: 533-542 [Abstract] [Full Text]  
  • Resch, W., Ziermann, R., Parkin, N., Gamarnik, A., Swanstrom, R. (2002). Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly. J. Virol. 76: 8659-8666 [Abstract] [Full Text]  
  • Walmsley, S., Loutfy, M. (2002). Can Structured Treatment Interruptions (STIs) Be Used as a Strategy to Decrease Total Drug Requirements and Toxicity in HIV Infection?. J Int Assoc Physicians AIDS Care (Chic Ill) 1: 95-103 [Abstract]  
  • Kijak, G. H., Simon, V., Balfe, P., Vanderhoeven, J., Pampuro, S. E., Zala, C., Ochoa, C., Cahn, P., Markowitz, M., Salomon, H. (2002). Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure. J. Virol. 76: 7000-7009 [Abstract] [Full Text]  
  • Van Rompay, K. K. A., Matthews, T. B., Higgins, J., Canfield, D. R., Tarara, R. P., Wainberg, M. A., Schinazi, R. F., Pedersen, N. C., North, T. W. (2002). Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase. J. Virol. 76: 6083-6092 [Abstract] [Full Text]  
  • Shafer, R. W. (2002). Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clin. Microbiol. Rev. 15: 247-277 [Abstract] [Full Text]  
  • Brenner, B. G., Routy, J.-P., Petrella, M., Moisi, D., Oliveira, M., Detorio, M., Spira, B., Essabag, V., Conway, B., Lalonde, R., Sekaly, R.-P., Wainberg, M. A. (2002). Persistence and Fitness of Multidrug-Resistant Human Immunodeficiency Virus Type 1 Acquired in Primary Infection. J. Virol. 76: 1753-1761 [Abstract] [Full Text]  
  • Kim, E.-Y., Winters, M. A., Kagan, R. M., Merigan, T. C. (2001). Functional Correlates of Insertion Mutations in the Protease Gene of Human Immunodeficiency Virus Type 1 Isolates from Patients. J. Virol. 75: 11227-11233 [Abstract] [Full Text]  
  • Buhler, B., Lin, Y.-C., Morris, G., Olson, A. J., Wong, C.-H., Richman, D. D., Elder, J. H., Torbett, B. E. (2001). Viral Evolution in Response to the Broad-Based Retroviral Protease Inhibitor TL-3. J. Virol. 75: 9502-9508 [Abstract] [Full Text]  
  • Deeks, S. G. (2001). Durable HIV Treatment Benefit Despite Low-Level Viremia: Reassessing Definitions of Success or Failure. JAMA 286: 224-226 [Full Text]  
  • Sarmati, L., d'Ettorre, G., Nicastri, E., Ercoli, L., Uccella, I., Massetti, P., Parisi, S. G., Vullo, V., Andreoni, M. (2001). Neutralizing Antibodies against Autologous Human Immunodeficiency Virus Type 1 Isolates in Patients with Increasing CD4 Cell Counts despite Incomplete Virus Suppression during Antiretroviral Treatment. CVI 8: 822-824 [Abstract] [Full Text]  
  • Bleiber, G., Munoz, M., Ciuffi, A., Meylan, P., Telenti, A. (2001). Individual Contributions of Mutant Protease and Reverse Transcriptase to Viral Infectivity, Replication, and Protein Maturation of Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1. J. Virol. 75: 3291-3300 [Abstract] [Full Text]  
  • Servais, J., Lambert, C., Fontaine, E., Plesséria, J.-M., Robert, I., Arendt, V., Staub, T., Schneider, F., Hemmer, R., Burtonboy, G., Schmit, J.-C. (2001). Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor. Antimicrob. Agents Chemother. 45: 893-900 [Abstract] [Full Text]  
  • La Seta Catamancio, S., De Pasquale, M. P., Citterio, P., Kurtagic, S., Galli, M., Rusconi, S. (2001). In Vitro Evolution of the Human Immunodeficiency Virus Type 1 Gag-Protease Region and Maintenance of Reverse Transcriptase Resistance following Prolonged Drug Exposure. J. Clin. Microbiol. 39: 1124-1129 [Abstract] [Full Text]  
  • Deeks, S. G., Wrin, T., Liegler, T., Hoh, R., Hayden, M., Barbour, J. D., Hellmann, N. S., Petropoulos, C. J., McCune, J. M., Hellerstein, M. K., Grant, R. M. (2001). Virologic and Immunologic Consequences of Discontinuing Combination Antiretroviral-Drug Therapy in HIV-Infected Patients with Detectable Viremia. NEJM 344: 472-480 [Abstract] [Full Text]  
  • Frenkel, L. M., Mullins, J. I. (2001). Should Patients with Drug-Resistant HIV-1 Continue to Receive Antiretroviral Therapy?. NEJM 344: 520-522 [Full Text]  
  • García-Lerma, J. G., Gerrish, P. J., Wright, A. C., Qari, S. H., Heneine, W. (2000). Evidence of a Role for the Q151L Mutation and the Viral Background in Development of Multiple Dideoxynucleoside-Resistant Human Immunodeficiency Virus Type 1. J. Virol. 74: 9339-9346 [Abstract] [Full Text]  
  • Quiñones-Mateu, M. E., Ball, S. C., Marozsan, A. J., Torre, V. S., Albright, J. L., Vanham, G., van der Groen, G., Colebunders, R. L., Arts, E. J. (2000). A Dual Infection/Competition Assay Shows a Correlation between Ex Vivo Human Immunodeficiency Virus Type 1 Fitness and Disease Progression. J. Virol. 74: 9222-9233 [Abstract] [Full Text]  
  • Mammano, F., Trouplin, V., Zennou, V., Clavel, F. (2000). Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug. J. Virol. 74: 8524-8531 [Abstract] [Full Text]  
  • Hirsch, M. S., Brun-Vezinet, F., D'Aquila, R. T., Hammer, S. M., Johnson, V. A., Kuritzkes, D. R., Loveday, C., Mellors, J. W., Clotet, B., Conway, B., Demeter, L. M., Vella, S., Jacobsen, D. M., Richman, D. D. (2000). Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel. JAMA 283: 2417-2426 [Abstract] [Full Text]  
  • Martínez, M.-A., Cabana, M., Parera, M., Gutierrez, A., Esté, J. A., Clotet, B. (2000). A Bacteriophage Lambda-Based Genetic Screen for Characterization of the Activity and Phenotype of the Human Immunodeficiency Virus Type 1 Protease. Antimicrob. Agents Chemother. 44: 1132-1139 [Abstract] [Full Text]  
  • Ibáñez, A., Clotet, B., Martínez, M.-A. (2000). Human immunodeficiency virus type 1 population bottleneck during indinavir therapy causes a genetic drift in the env quasispecies. J. Gen. Virol. 81: 85-95 [Abstract] [Full Text]  
  • Little, S. J., Daar, E. S., D'Aquila, R. T., Keiser, P. H., Connick, E., Whitcomb, J. M., Hellmann, N. S., Petropoulos, C. J., Sutton, L., Pitt, J. A., Rosenberg, E. S., Koup, R. A., Walker, B. D., Richman, D. D. (1999). Reduced Antiretroviral Drug Susceptibility Among Patients With Primary HIV Infection. JAMA 282: 1142-1149 [Abstract] [Full Text]  
  • Martinez-Picado, J., Sutton, L., De Pasquale, M. P., Savara, A. V., D'Aquila, R. T. (1999). Human Immunodeficiency Virus Type 1 Cloning Vectors for Antiretroviral Resistance Testing. J. Clin. Microbiol. 37: 2943-2951 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»