Protease-mediated maturation of HIV-1 virus particles is essential for virus infectivity. Maturation occurs concomitant with immature virus particle release and is mediated by the viral protease (PR), which sequentially cleaves the Gag and Gag-Pol polyproteins into mature protein domains. Maturation triggers a second assembly event that generates a condensed conical capsid core. The capsid core organizes the viral RNA genome and viral proteins to facilitate viral replication in the next round of infection. The fundamental role of proteolytic maturation in the generation of mature infectious particles has made it an attractive target for therapeutic intervention. Development of small molecules that target the PR active site has been highly successful and nine protease inhibitors (PIs) have been approved for clinical use. This paper provides an overview of their development and clinical use together with a discussion of problems associated with drug resistance. The second-half of the paper discusses a novel class of antiretroviral drug termed maturation inhibitors, which target cleavage sites in Gag not PR itself. The paper focuses on bevirimat (BVM) the first-in-class maturation inhibitor: its mechanism of action and the implications of naturally occurring polymorphisms that confer reduced susceptibility to BVM in phase II clinical trials. 1. Introduction Human Immunodeficiency Virus Type 1 (HIV-1) is the causative agent of the worldwide Acquired Immunodeficiency Syndrome (AIDS) epidemic. Approximately 34 million people were estimated to be living with HIV at the end of 2010. The number of people infected is a consequence of continued large numbers of new HIV-1 infections together with a reduction in AIDS-related deaths due to a significant expansion in access to antiretroviral drug therapy [1]. In the absence of an effective vaccine or cure, antiviral drugs are currently the only treatment option available to HIV-infected patients. Therapeutic regimes commonly termed HAART (highly active antiretroviral therapy) suppress viral replication but do not eradicate the virus; therefore, treatment must be administered on a lifelong basis [2, 3]. HAART consists of the simultaneous use of a combination of three or four different antiretroviral drugs. This combinational approach is required due to the ease with which HIV-1 can acquire drug resistance to a single drug administered as monotherapy [3, 4]. Drug resistance arises due to the high degree of HIV-1 genetic diversity within the virus population (quasi-species) infecting an individual patient. This genetic
References
[1]
“UNAIDS World AIDS Day Report,” 2011.
[2]
L. F. Chen, J. Hoy, and S. R. Lewin, “Ten years of highly active antiretroviral therapy for HIV infection,” Medical Journal of Australia, vol. 186, no. 3, pp. 146–151, 2007.
[3]
V. Simon, D. D. Ho, and Q. Abdool Karim, “HIV/AIDS epidemiology, pathogenesis, prevention, and treatment,” Lancet, vol. 368, no. 9534, pp. 489–504, 2006.
[4]
Z. Temesgen, F. Cainelli, E. M. Poeschla, S. A. Vlahakis, and S. Vento, “Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults,” Lancet Infectious Diseases, vol. 6, no. 8, pp. 496–507, 2006.
[5]
W.-S. Hu, T. Rhodes, Q. Dang, and V. Pathak, “Retroviral recombination: review of genetic analyses,” Frontiers in Bioscience, vol. 8, pp. d143–d155, 2003.
[6]
E. S. Svarovskaia, S. R. Cheslock, W. H. Zhang, W. S. Hu, and V. K. Pathak, “Retroviral mutation rates and reverse transcriptase fidelity,” Frontiers in Bioscience, vol. 8, pp. d117–d134, 2003.
[7]
T. Cihlar and A. S. Ray, “Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine,” Antiviral Research, vol. 85, no. 1, pp. 39–58, 2010.
[8]
A. M. J. Wensing, N. M. van Maarseveen, and M. Nijhuis, “Fifteen years of HIV protease inhibitors: raising the barrier to resistance,” Antiviral Research, vol. 85, no. 1, pp. 59–74, 2010.
[9]
M. P. de Béthune, “Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009),” Antiviral Research, vol. 85, no. 1, pp. 75–90, 2010.
[10]
D. J. McColl and X. Chen, “Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy,” Antiviral Research, vol. 85, no. 1, pp. 101–118, 2010.
[11]
J. C. Tilton and R. W. Doms, “Entry inhibitors in the treatment of HIV-1 infection,” Antiviral Research, vol. 85, no. 1, pp. 91–100, 2010.
[12]
C. S. Adamson and E. O. Freed, “Novel approaches to inhibiting HIV-1 replication,” Antiviral Research, vol. 85, no. 1, pp. 119–141, 2010.
[13]
P. W. Keller, C. S. Adamson, J. Bernard Heymann, E. O. Freed, and A. C. Steven, “HIV-1 maturation inhibitor bevirimat stabilizes the immature gag lattice,” Journal of Virology, vol. 85, no. 4, pp. 1420–1428, 2011.
[14]
A. Wlodawer and J. W. Erickson, “Structure-based inhibitors of HIV-1 protease,” Annual Review of Biochemistry, vol. 62, pp. 543–585, 1993.
[15]
R. Swanstrom and J. W. Willis, “Synthesis, assembly and processing of viral proteins,” in Retroviruses, J. M. Coffin, S. H. Hughes, and H. E. Varmus, Eds., Cold Spring Harbor Laboratory Press, 1997.
[16]
C. S. Adamson and E. O. Freed, “HIV-1 assembly, release and maturation,” in Advances in Pharmacolgy, HIV-1: Molecular Biology and Pathogenesis: Viral Mechansims, K.-T. Jeang, Ed., Elsevier, 2007.
[17]
B. K. Ganser-Pornillos, M. Yeager, and W. I. Sundquist, “The structural biology of HIV assembly,” Current Opinion in Structural Biology, vol. 18, no. 2, pp. 203–217, 2008.
[18]
M. A. Navia, P. M. D. Fitzgerald, B. M. McKeever et al., “Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1,” Nature, vol. 337, no. 6208, pp. 615–620, 1989.
[19]
R. Lapatto, T. Blundell, A. Hemmings et al., “X-ray analysis of HIV-1 proteinase at 2.7 ？ resolution confirms structural homology among retroviral enzymes,” Nature, vol. 342, no. 6247, pp. 299–302, 1989.
[20]
A. Wlodawer, M. Miller, M. Jaskolski et al., “Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease,” Science, vol. 245, no. 4918, pp. 616–621, 1989.
[21]
M. Prabu-Jeyabalan, E. Nalivaika, and C. A. Schiffer, “Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes,” Structure, vol. 10, no. 3, pp. 369–381, 2002.
[22]
J. Anderson, “Viral protease inhibitors,” Handbook of Experimental Pharmacology, vol. 189, pp. 85–110, 2009.
[23]
V. A. Johnson, V. Calvez, H. F. Günthard et al., “2011 update of the drug resistance mutations in HIV-1,” Topics in Antiviral Medicine, vol. 19, no. 4, pp. 156–164, 2011.
[24]
J. C. Craig, I. B. Duncan, D. Hockley, C. Grief, N. A. Roberts, and J. S. Mills, “Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase,” Antiviral Research, vol. 16, no. 4, pp. 295–305, 1991.
[25]
D. J. Kempf, K. C. Marsh, J. F. Denissen et al., “ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 7, pp. 2484–2488, 1995.
[26]
J. P. Vacca, B. D. Dorsey, W. A. Schleif et al., “L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 9, pp. 4096–4100, 1994.
[27]
A. K. Patick, H. Mo, M. Markowitz et al., “Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease,” Antimicrobial Agents and Chemotherapy, vol. 40, no. 2, pp. 292–297, 1996.
[28]
V. S. Kitchen, C. Skinner, K. Ariyoshi et al., “Safety and activity of saquinavir in HIV infection,” Lancet, vol. 345, no. 8955, pp. 952–955, 1995.
[29]
H. Jacobsen, M. Haenggi, M. Ott et al., “Reduced sensitivity of saquinavir: an update on genotyping from phase I/II trials,” Antiviral Research, vol. 29, no. 1, pp. 95–97, 1996.
[30]
S. A. Danner, A. Carr, J. M. Leonard et al., “A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease,” New England Journal of Medicine, vol. 333, no. 23, pp. 1528–1533, 1995.
[31]
M. Markowitz, M. Saag, W. G. Powderly et al., “A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection,” New England Journal of Medicine, vol. 333, no. 23, pp. 1534–1539, 1995.
[32]
D. S. Stein, D. G. Fish, J. A. Bilello, S. L. Preston, G. L. Martineau, and G. L. Drusano, “A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir),” AIDS, vol. 10, no. 5, pp. 485–492, 1996.
[33]
M. Markowitz, M. Conant, A. Hurley et al., “A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection,” Journal of Infectious Diseases, vol. 177, no. 6, pp. 1533–1540, 1998.
[34]
A. C. Collier, R. W. Coombs, D. A. Schoenfeld et al., “Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine,” New England Journal of Medicine, vol. 334, no. 16, pp. 1011–1017, 1996.
[35]
D. W. Notermans, S. Jurriaans, F. De Wolf et al., “Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine,” AIDS, vol. 12, no. 2, pp. 167–173, 1998.
[36]
D. Mathez, et al., “Reductions in viral load and increases in T lymphocyte numbers in treatment-naive patients with advanced HIV-1 infection treated with ritonavir, zidovudine and zalcitabine triple therapy,” Antiviral Therapy, vol. 2, no. 3, pp. 175–183, 1997.
[37]
R. M. Gulick, J. W. Mellors, D. Havlir et al., “Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy,” New England Journal of Medicine, vol. 337, no. 11, pp. 734–739, 1997.
[38]
S. M. Hammer, K. E. Squires, M. D. Hughes et al., “A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less,” New England Journal of Medicine, vol. 337, no. 11, pp. 725–733, 1997.
[39]
M. Gartland, “AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients,” Antiviral Therapy, vol. 6, no. 2, pp. 127–134, 2001.
[40]
M. S. Saag, P. Tebas, M. Sension et al., “Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511),” AIDS, vol. 15, no. 15, pp. 1971–1978, 2001.
[41]
R. P. G. Van Heeswijk, A. I. Veldkamp, J. W. Mulder et al., “Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience,” Antiviral Therapy, vol. 6, no. 4, pp. 201–229, 2001.
[42]
C. Falcoz, J. M. Jenkins, C. Bye et al., “Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers,” Journal of Clinical Pharmacology, vol. 42, no. 8, pp. 887–898, 2002.
[43]
M. H. St. Clair, J. Millard, J. Rooney et al., “In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents,” Antiviral Research, vol. 29, no. 1, pp. 53–56, 1996.
[44]
H. L. Sham, D. J. Kempf, A. Molla et al., “ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease,” Antimicrobial Agents and Chemotherapy, vol. 42, no. 12, pp. 3218–3224, 1998.
[45]
B. S. Robinson, K. A. Riccardi, Y. F. Gong et al., “BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 8, pp. 2093–2099, 2000.
[46]
S. M. Poppe, D. E. Slade, K. T. Chong et al., “Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor,” Antimicrobial Agents and Chemotherapy, vol. 41, no. 5, pp. 1058–1063, 1997.
[47]
Y. Koh, H. Nakata, K. Maeda et al., “Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 10, pp. 3123–3129, 2003.
[48]
A. Rodriguez-French, J. Boghossian, G. E. Gray et al., “The NEAT Study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients,” Journal of Acquired Immune Deficiency Syndromes, vol. 35, no. 1, pp. 22–32, 2004.
[49]
S. Walmsley, B. Bernstein, M. King et al., “Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection,” New England Journal of Medicine, vol. 346, no. 26, pp. 2039–2046, 2002.
[50]
R. L. Murphy, I. Sanne, P. Cahn et al., “Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results,” AIDS, vol. 17, no. 18, pp. 2603–2614, 2003.
[51]
C. B. Hicks, P. Cahn, D. A. Cooper et al., “Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials,” Lancet, vol. 368, no. 9534, pp. 466–475, 2006.
[52]
A. M. Mills, M. Nelson, D. Jayaweera et al., “Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis,” AIDS, vol. 23, no. 13, pp. 1679–1688, 2009.
[53]
A. Ali, R. M. Bandaranayake, Y. Cai et al., “Molecular basis for drug resistance in HIV-1 protease,” Viruses, vol. 2, no. 11, pp. 2509–2535, 2010.
[54]
F. Clavel and F. Mammano, “Role of gag in HIV resistance to protease inhibitors,” Viruses, vol. 2, no. 7, pp. 1411–1426, 2010.
[55]
J. L. Martinez-Cajas and M. A. Wainberg, “Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives,” Antiviral Research, vol. 76, no. 3, pp. 203–221, 2007.
[56]
N. M. King, M. Prabu-Jeyabalan, E. A. Nalivaika, and C. A. Schiffer, “Combating susceptibility to drug resistance: lessons from HIV-1 protease,” Chemistry and Biology, vol. 11, no. 10, pp. 1333–1338, 2004.
[57]
M. Ko？í？ek, K. G. ？a？ková, P. ？ezá？ová et al., “Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region,” Journal of Virology, vol. 82, no. 12, pp. 5869–5878, 2008.
[58]
J. Martinez-Picado, A. V. Savara, L. Sutton, and R. T. D'Aquila, “Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1,” Journal of Virology, vol. 73, no. 5, pp. 3744–3752, 1999.
[59]
M. Nijhuis, R. Schuurman, D. De Jong et al., “Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy,” AIDS, vol. 13, no. 17, pp. 2349–2359, 1999.
[60]
G. Croteau, L. Doyon, D. Thibeault, G. Mckercher, L. Pilote, and D. Lamarre, “Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors,” Journal of Virology, vol. 71, no. 2, pp. 1089–1096, 1997.
[61]
F. Mammano, V. Trouplin, V. Zennou, and F. Clavel, “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,” Journal of Virology, vol. 74, no. 18, pp. 8524–8531, 2000.
[62]
L. Menéndez-Arias, M. A. Martínez, M. E. Qui？ones-Mateu, and J. Martinez-Picado, “Fitness variations and their impact on the evolution of antiretroviral drug resistance,” Current Drug Targets-Infectious Disorders, vol. 3, no. 4, pp. 355–371, 2003.
[63]
J. D. Barbour, T. Wrin, R. M. Grant et al., “Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults,” Journal of Virology, vol. 76, no. 21, pp. 11104–11112, 2002.
[64]
G. Bleiber, M. Munoz, A. Ciuffi, P. Meylan, and A. Telenti, “Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1,” Journal of Virology, vol. 75, no. 7, pp. 3291–3300, 2001.
[65]
F. Mammano, C. Petit, and F. Clavel, “Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients,” Journal of Virology, vol. 72, no. 9, pp. 7632–7637, 1998.
[66]
Y. M. Zhang, H. Imamichi, T. Imamichi et al., “Drug resistance during Indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites,” Journal of Virology, vol. 71, no. 9, pp. 6662–6670, 1997.
[67]
L. Doyon, G. Croteau, D. Thibeault, F. Poulin, L. Pilote, and D. Lamarre, “Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors,” Journal of Virology, vol. 70, no. 6, pp. 3763–3769, 1996.
[68]
F. Bally, R. Martinez, S. Peters, P. Sudre, and A. Telenti, “Polymorphism of HIV type 1 Gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors,” AIDS Research and Human Retroviruses, vol. 16, no. 13, pp. 1209–1213, 2000.
[69]
M. F. Maguire, R. Guinea, P. Griffin et al., “Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro,” Journal of Virology, vol. 76, no. 15, pp. 7398–7406, 2002.
[70]
H. C. F. C？té, Z. L. Brumme, and P. R. Harrigan, “Human immunodeficiency virus type 1 protease cleavage site mutations associated with protease inhibitor cross-resistance selected by indinavir, ritonavir, and/or saquinavir,” Journal of Virology, vol. 75, no. 2, pp. 589–594, 2001.
[71]
I. Malet, B. Roquebert, C. Dalban et al., “Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients,” Journal of Infection, vol. 54, no. 4, pp. 367–374, 2007.
[72]
J. Verheyen, E. Litau, T. Sing et al., “Compensatory mutations at the HIV cleavage sites p7/p1 and p1/p6-gag in therapy-naive and therapy-experienced patients,” Antiviral Therapy, vol. 11, no. 7, pp. 879–887, 2006.
[73]
M. Nijhuis, N. M. Van Maarseveen, S. Lastere et al., “A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism,” PLoS Medicine, vol. 4, no. 1, article e36, 2007.
[74]
C. M. Parry, A. Kohli, C. J. Boinett, G. J. Towers, A. L. McCormick, and D. Pillay, “Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1,” Journal of Virology, vol. 83, no. 18, pp. 9094–9101, 2009.
[75]
H. Gatanaga, Y. Suzuki, H. Tsang et al., “Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors,” Journal of Biological Chemistry, vol. 277, no. 8, pp. 5952–5961, 2002.
[76]
L. Myint, M. Matsuda, Z. Matsuda et al., “Gag non-cleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 2, pp. 444–452, 2004.
[77]
E. Dam, R. Quercia, B. Glass et al., “Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss,” PLoS Pathogens, vol. 5, no. 3, Article ID e1000345, 2009.
[78]
M. Prabu-Jeyabalan, E. A. Nalivaika, N. M. King, and C. A. Schiffer, “Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease,” Journal of Virology, vol. 78, no. 22, pp. 12446–12454, 2004.
[79]
S. V. Gulnik and M. Eissenstat, “Approaches to the design of HIV protease inhibitors with improved resistance profiles,” Current Opinion in HIV and AIDS, vol. 3, no. 6, pp. 633–641, 2008.
[80]
C. Callebaut, K. Stray, L. Tsai et al., “In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 4, pp. 1366–1376, 2011.
[81]
M. N. L. Nalam, A. Peeters, T. H. M. Jonckers, I. Dierynck, and C. A. Schiffer, “Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease,” Journal of Virology, vol. 81, no. 17, pp. 9512–9518, 2007.
[82]
S. Dandache, G. Sévigny, J. Yelle et al., “In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 11, pp. 4036–4043, 2007.
[83]
M. W. Chang, M. J. Giffin, R. Muller et al., “Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries,” Biochemical Journal, vol. 429, no. 3, pp. 527–532, 2010.
[84]
F. Li, R. Goila-Gaur, K. Salzwedel et al., “PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 23, pp. 13555–13560, 2003.
[85]
J. Zhou, X. Yuan, D. Dismuke et al., “Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation,” Journal of Virology, vol. 78, no. 2, pp. 922–929, 2004.
[86]
C. S. Adamson, S. D. Ablan, I. Boeras et al., “In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Beviriniat),” Journal of Virology, vol. 80, no. 22, pp. 10957–10971, 2006.
[87]
J. Zhou, C. H. Chen, and C. Aiken, “The sequence of the CA-SP1 junction accounts for the differential sensitivity of HIV-1 and SIV to the small molecule maturation inhibitor 3-O-{3′, 3′-dimethylsuccinyl}-betulinic acid,” Retrovirology, vol. 1, article 15, 2004.
[88]
C. S. Adamson, M. Sakalian, K. Salzwedel, and E. O. Freed, “Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV-1maturation inhibitor bevirimat,” Retrovirology, vol. 7, article 36, 2010.
[89]
C. S. Adamson, K. Waki, S. D. Ablan, K. Salzwedel, and E. O. Freed, “Impact of human immunodeficiency virus type 1 resistance to protease inhibitors on evolution of resistance to the maturation inhibitor bevirimat (PA-457),” Journal of Virology, vol. 83, no. 10, pp. 4884–4894, 2009.
[90]
A. Fun, “HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat,” Retrovirology, vol. 8, article 70, 2011.
[91]
D. J. H. F. Knapp, P. R. Harrigan, A. F. Y. Poon, Z. L. Brumme, M. Brockman, and P. K. Cheung, “In vitro selection of clinically relevant bevirimat resistance mutations revealed by “deep” sequencing of serially passaged, quasispecies-containing recombinant HIV-1,” Journal of Clinical Microbiology, vol. 49, no. 1, pp. 201–208, 2011.
[92]
N. A. Margot, C. S. Gibbs, and M. D. Miller, “Phenotypic susceptibility to bevirimat in isolates from HIV-1-infected patients without prior exposure to bevirimat,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 6, pp. 2345–2353, 2010.
[93]
S. McCallister, “HIV-1 Gag polymorphisms determine treatment respose to bevirimat (PA-457),” Antiviral Therapy, vol. 13, p. A10, 2008.
[94]
W. Lu, K. Salzwedel, D. Wang et al., “A single polymorphism in HIV-1 subtype C SP1 is sufficient to confer natural resistance to the maturation inhibitor bevirimat,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 7, pp. 3324–3329, 2011.
[95]
K. Van Baelen, K. Salzwedel, E. Rondelez et al., “Susceptibility of human immunodeficiency virus type 1 to the maturation inhibitor bevirimat is modulated by baseline polymorphisms in Gag spacer peptide,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 5, pp. 2185–2188, 2009.
[96]
W. S. Blair, J. Cao, J. Fok-Seang et al., “New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 12, pp. 5080–5087, 2009.
[97]
K. Wiegers, G. Rutter, H. Kottler, U. Tessmer, H. Hohenberg, and H. G. Kr？usslich, “Sequential steps in human immunodeficiency virus particle maturation revealed by alterations of individual Gag polyprotein cleavage sites,” Journal of Virology, vol. 72, no. 4, pp. 2846–2854, 1998.
[98]
M. Sakalian, C. P. McMurtrey, F. J. Deeg et al., “3-O-(3′, 3′-dimethysuccinyl) betulinic acid inhibits maturation of the human immunodeficiency virus type 1 gag precursor assembled in vitro,” Journal of Virology, vol. 80, no. 12, pp. 5716–5722, 2006.
[99]
J. Zhou, L. Huang, D. L. Hachey, C. H. Chen, and C. Aiken, “Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles,” Journal of Biological Chemistry, vol. 280, no. 51, pp. 42149–42155, 2005.
[100]
A. T. Nguyen, C. L. Feasley, K. W. Jackson et al., “The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles,” Retrovirology, vol. 8, article 101, 2011.
[101]
J. Zhou, H. C. Chin, and C. Aiken, “Human immunodeficiency virus type 1 resistance to the small molecule maturation inhibitor 3-O-(3′, 3′-dimethylsuccinyl)-betulinic acid is conferred by a variety of single amino acid substitutions at the CA-SP1 cleavage site in Gag,” Journal of Virology, vol. 80, no. 24, pp. 12095–12101, 2006.
[102]
S. DaFonseca, A. Blommaert, P. Coric, S. H. Saw, S. Bouaziz, and P. Boulanger, “The 3-O-(3′, 3′-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells,” Antiviral Therapy, vol. 12, no. 8, pp. 1185–1203, 2007.
[103]
T. R. Gamble, S. Yoo, F. F. Vajdos et al., “Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein,” Science, vol. 278, no. 5339, pp. 849–853, 1997.
[104]
D. K. Worthylake, H. Wang, S. Yoo, W. I. Sundquist, and C. P. Hill, “Structures of the HIV-1 capsid protein dimerization domain at 2.6 ？ resolution,” Acta Crystallographica Section D, vol. 55, no. 1, pp. 85–92, 1999.
[105]
X. Guo, A. Roldan, J. Hu, M. A. Wainberg, and C. Liang, “Mutation of the SP1 sequence impairs both multimerization and membrane-binding activities of human immunodeficiency virus type 1 Gag,” Journal of Virology, vol. 79, no. 3, pp. 1803–1812, 2005.
[106]
C. Liang, J. Hu, R. S. Russell, A. Roldan, L. Kleiman, and M. A. Wainberg, “Characterization of a putative α-helix across the capsid-SP1 boundary that is critical for the multimerization of human immunodeficiency virus type 1 Gag,” Journal of Virology, vol. 76, no. 22, pp. 11729–11737, 2002.
[107]
C. Liang, J. Hu, J. B. Whitney, L. Kleiman, and M. A. Wainberg, “A structurally disordered region at the C terminus of capsid plays essential roles in multimerization and membrane binding of the Gag protein of human immunodeficiency virus type 1,” Journal of Virology, vol. 77, no. 3, pp. 1772–1783, 2003.
[108]
Y. Morikawa, D. J. Hockley, M. V. Nermut, and I. M. Jones, “Roles of matrix, p2, and N-terminal myristoylation in human immunodeficiency virus type 1 Gag assembly,” Journal of Virology, vol. 74, no. 1, pp. 16–23, 2000.
[109]
A. Ono, D. Demirov, and E. O. Freed, “Relationship between human immunodeficiency virus type 1 Gag multimerization and membrane binding,” Journal of Virology, vol. 74, no. 11, pp. 5142–5150, 2000.
[110]
S. A. K. Datta, L. G. Temeselew, R. M. Crist et al., “On the role of the SP1 domain in HIV-1 particle assembly: a molecular switch?” Journal of Virology, vol. 85, no. 9, pp. 4111–4121, 2011.
[111]
M. A. Accola, S. H？glund, and H. G. G？ttlinger, “A putative α-helical structure which overlaps the capsid-p2 boundary in the human immunodeficiency virus type 1 Gag precursor is crucial for viral particle assembly,” Journal of Virology, vol. 72, no. 3, pp. 2072–2078, 1998.
[112]
J. L. Newman, E. W. Butcher, D. T. Patel, Y. Mikhaylenko, and M. F. Summers, “Flexibility in the P2 domain of the HIV-1 Gag polyprotein,” Protein Science, vol. 13, no. 8, pp. 2101–2107, 2004.
[113]
N. Morellet, S. Druillennec, C. Lenoir, S. Bouaziz, and B. P. Roques, “Helical structure determined by NMR of the HIV-1 (345-392)Gag sequence, surrounding p2: implications for particle assembly and RNA packaging,” Protein Science, vol. 14, no. 2, pp. 375–386, 2005.
[114]
E. R. Wright, J. B. Schooler, H. J. Ding et al., “Electron cryotomography of immature HIV-1 virions reveals the structure of the CA and SP1 Gag shells,” EMBO Journal, vol. 26, no. 8, pp. 2218–2226, 2007.
[115]
P. F. Smith, A. Ogundele, A. Forrest et al., “Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus Infection,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 10, pp. 3574–3581, 2007.
[116]
C. A. Stoddart, P. Joshi, B. Sloan et al., “Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice,” PLoS ONE, vol. 2, no. 11, Article ID e1251, 2007.
[117]
E. Seclén, M. D. M. González, A. Corral, C. De Mendoza, V. Soriano, and E. Poveda, “High prevalence of natural polymorphisms in Gag (CA-SP1) associated with reduced response to Bevirimat, an HIV-1 maturation inhibitor,” AIDS, vol. 24, no. 3, pp. 467–469, 2010.
[118]
J. Verheyen, C. Verhofstede, E. Knops et al., “High prevalence of bevirimat resistance mutations in protease inhibitor-resistant HIV isolates,” AIDS, vol. 24, no. 5, pp. 669–673, 2010.
[119]
S. K. Lee, J. Harris, and R. Swanstrom, “A strongly transdominant mutation in the human immunodeficiency virus type 1 gag gene defines an achilles heel in the virus life cycle,” Journal of Virology, vol. 83, no. 17, pp. 8536–8543, 2009.
