Table of Contents
Molecular Biology International
Volume 2012 (2012), Article ID 401965, 17 pages
http://dx.doi.org/10.1155/2012/401965
Review Article

The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets

Anti-Infective Research Department, ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, MD 21704, USA

Received 9 January 2012; Revised 24 April 2012; Accepted 11 May 2012

Academic Editor: Gilda Tachedjian

Copyright © 2012 Tracy L. Hartman and Robert W. Buckheit Jr. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Food and Drug Administration, http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm.
  2. E. De Clercq, “HIV inhibitors targeted at the reverse transcriptase,” AIDS Research and Human Retroviruses, vol. 8, no. 2, pp. 119–134, 1992. View at Google Scholar · View at Scopus
  3. A. Molla, G. Richard Granneman, E. Sun, and D. J. Kempf, “Recent developments in HIV protease inhibitor therapy,” Antiviral Research, vol. 39, no. 1, pp. 1–23, 1998. View at Publisher · View at Google Scholar · View at Scopus
  4. H. J. P. Ryser and R. Flückiger, “Keynote review: progress in targeting HIV-1 entry,” Drug Discovery Today, vol. 10, no. 16, pp. 1085–1094, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. B. A. Larder, “Viral resistance and the selection of antiretroviral combinations,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 10, supplement 1, pp. S28–S33, 1995. View at Google Scholar · View at Scopus
  6. D. L. Mayers, “Drug-resistant HIV-1: the virus strikes back,” Journal of the American Medical Association, vol. 279, no. 24, pp. 2000–2002, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. D. Boden, A. Hurley, L. Zhang et al., “HIV-1 drug resistance in newly infected individuals,” Journal of the American Medical Association, vol. 282, no. 12, pp. 1135–1141, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. R. L. Murphy, “Defining the toxicity profile of nevirapine and other antiretroviral drugs,” Journal of Acquired Immune Deficiency Syndromes, vol. 34, no. 1, pp. S15–S20, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. B. P. Sabundayo, J. H. McArthur, S. J. Langan, J. E. Gallant, and J. B. Margolick, “High frequency of highly active antiretroviral therapy modifications in patients with acute or early human immunodeficiency virus infection,” Pharmacotherapy, vol. 26, no. 5, pp. 674–681, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. J. E. Gallant, E. Dejesus, J. R. Arribas et al., “Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV,” The New England Journal of Medicine, vol. 354, no. 3, pp. 251–260, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. P. D. Ghys, T. Saidel, H. T. Vu et al., “Growing in silence: selected regions and countries with expanding HIV/AIDS epidemics,” AIDS, vol. 17, supplement 4, pp. S45–50, 2003. View at Google Scholar · View at Scopus
  12. S. L. Lard-Whiteford, D. Matecka, J. J. O'Rear, I. S. Yuen, C. Litterst, and P. Reichelderfer, “Recommendations for the nonclinical development of topical microbicides for prevention of HIV transmission: an update,” Journal of Acquired Immune Deficiency Syndromes, vol. 36, no. 1, pp. 541–552, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Oette, R. Kaiser, M. Däumer et al., “Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing,” Journal of Acquired Immune Deficiency Syndromes, vol. 41, no. 5, pp. 573–581, 2006. View at Google Scholar
  14. F. D. Bushman, N. Malani, J. Fernandes et al., “Host cell factors in HIV replication: meta-analysis of genome-wide studies,” PLoS Pathogens, vol. 5, no. 5, Article ID e1000437, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Hladik and M. J. McElrath, “Setting the stage: host invasion by HIV,” Nature Reviews Immunology, vol. 8, no. 6, pp. 447–457, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Xu, L. Lecanu, M. Tan, W. Yao, J. Greeson, and V. Papadopoulos, “The benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4- cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10) reduces HIV-1 infectivity in vitro by modifying actin dynamics,” Antiviral Chemistry and Chemotherapy, vol. 17, no. 6, pp. 331–342, 2006. View at Google Scholar · View at Scopus
  17. C. Lackman-Smith, C. Osterling, K. Luckenbaugh et al., “Development of a comprehensive human immunodeficiency virus type 1 screening algorithm for discovery and preclinical testing of topical microbicides,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 5, pp. 1768–1781, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. F. Huang, M. Koenen-Bergmann, T. R. MacGregor, A. Ring, S. Hattox, and P. Robinson, “Pharmacokinetic and safety evaluation of BILR 355, a second-generation nonnucleoside reverse transcriptase inhibitor, in healthy volunteers,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 12, pp. 4300–4307, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Mahalingam, A. P. Simmons, S. R. Ugaonkar et al., “Vaginal microbicide gel for delivery of IQP-0528, a pyrimidinedione analog with a dual mechanism of action against HIV-1,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 4, pp. 1650–1660, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. D. M. Himmel, S. G. Sarafianos, S. Dharmasena et al., “HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site,” ACS Chemical Biology, vol. 1, no. 11, pp. 702–712, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Levin, “BI224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-naïve and raltegravir-resistant clinical isolates of HIV-1,” in Proceedings of the 51th ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill, USA, September 2011.
  22. E. P. Garvey, B. A. Johns, M. J. Gartland et al., “The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 3, article 901, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Hare, A. M. Vos, R. F. Clayton, J. W. Thuring, M. D. Cummings, and P. Cherepanov, “Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 46, pp. 20057–20062, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. F. Hamy, E. R. Felder, G. Heizmann et al., “An inhibitor of the tat/TAR RNA interaction that effectively suppresses HIV-1 replication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 8, pp. 3548–3553, 1997. View at Publisher · View at Google Scholar · View at Scopus
  25. O. W. Lindwasser, W. J. Smith, R. Chaudhuri, P. Yang, J. H. Hurley, and J. S. Bonifacino, “A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2,” Journal of Virology, vol. 82, no. 3, pp. 1166–1174, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. P.-H. Lin, Y.-Y. Ke, C.-T. Su et al., “Inhibition of HIV-1 Tat-mediated transcription by a coumarin derivative, BPRHIV001, through the Akt pathway,” Journal of Virology, vol. 85, no. 17, pp. 9114–9126, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Breuer, S. I. Schievink, A. Schulte, W. Blankenfeldt, O. T. Fackler, and M. Geyer, “Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef,” PLoS ONE, vol. 6, no. 5, Article ID e20033, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. D. Lu, Y. Y. Sham, and R. Vince, “Design, asymmetric synthesis, and evaluation of pseudosymmetric sulfoximine inhibitors against HIV-1 protease,” Bioorganic and Medicinal Chemistry, vol. 18, no. 5, pp. 2037–2048, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Gulnik, M. Eissenstat, and E. Afonina, “Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer,” in Proceedings of the 16th CROI Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 2009.
  30. R. Klein, “New class of medications approved for advance HIV,” FDA Consumer, vol. 37, no. 3, p. 5, 2003. View at Google Scholar · View at Scopus
  31. R. Carmona, L. Pérez-Alvarez, M. Muñoz et al., “Natural resistance-associated mutations to Enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients,” Journal of Clinical Virology, vol. 32, no. 3, pp. 248–253, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Krauskof, “Pfizer wins U.S. approval for new HIV drug,” Reuters, 2007, http://www.reuters.com/article/2007/08/06/businesspro-pfizer-hiv-dc-idUSN0642522320070806.
  33. W. D. Hardy, R. M. Gulick, H. Mayer et al., “Two-year safety and virologic efficacy of maraviroc in treatment- experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2,” Journal of Acquired Immune Deficiency Syndromes, vol. 55, no. 5, pp. 558–564, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. J. M. Jacobson, D. R. Kuritzkes, E. Godofsky et al., “Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 2, pp. 450–457, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. W. Popik, T. M. Alce, and W. C. Au, “Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4+ T cells,” Journal of Virology, vol. 76, no. 10, pp. 4709–4722, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. J. P. Moore and R. F. Jarrett, “Sensitive ELISA for the gp120 and gp160 surface glycoproteins of HIV-1,” AIDS Research and Human Retroviruses, vol. 4, no. 5, pp. 369–379, 1988. View at Google Scholar · View at Scopus
  37. R. W. Shafer, A. K. N. Iversen, M. A. Winters, E. Aguiniga, D. A. Katzenstein, and T. C. Merigan, “Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy,” Journal of Infectious Diseases, vol. 172, no. 1, pp. 70–78, 1995. View at Google Scholar · View at Scopus
  38. A. Hachiya, E. N. Kodama, M. M. Schuckmann et al., “K70Q adds high-level tenofovir resistance to “Q151M complex” HIV reverse transcriptase through the enhanced discrimination mechanism,” PLoS ONE, vol. 6, no. 1, Article ID e16242, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Das, R. P. Bandwar, K. L. White et al., “Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance,” Journal of Biological Chemistry, vol. 284, no. 50, pp. 35092–35100, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. S. G. Sarafianos, S. H. Hughes, and E. Arnold, “Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to nucleoside analog drugs,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 9, pp. 1706–1715, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. E. R. Lanier, R. G. Ptak, B. M. Lampert et al., “Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 7, pp. 2901–2909, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Markowitz, “GS-7340 demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects,” in Proceedings of the 18th Conference on Retroviruses and Opportunistic Infections, March 2011.
  43. C. Chu, “Unique antiviral activity of dioxolane-thymine (DOT) against HIV drug resistant mutants,” in Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 2007.
  44. P. L. Boyer, M. J. Currens, J. B. McMahon, M. R. Boyd, and S. H. Hughes, “Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase,” Journal of Virology, vol. 67, no. 4, pp. 2412–2420, 1993. View at Google Scholar · View at Scopus
  45. J. Radzio and N. Sluis-Cremer, “Efavirenz accelerates HIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision,” Molecular Pharmacology, vol. 73, no. 2, pp. 601–606, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. G. N. Nikolenko, S. Palmer, F. Maldarelli, J. W. Mellors, J. M. Coffin, and V. K. Pathak, “Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 6, pp. 2093–2098, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. W. Yang and T. A. Steitz, “Recombining the structures of HIV integrase, RuvC and RNase H,” Structure, vol. 3, no. 2, pp. 131–134, 1995. View at Google Scholar · View at Scopus
  48. M. Wendeler, H. F. Lee, A. Bermingham et al., “Vinylogous ureas as a novel class of inhibitors of reverse transcriptase-associated ribonuclease H activity,” ACS Chemical Biology, vol. 3, no. 10, pp. 635–644, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. C. A. Shaw-Reid, V. Munshi, P. Graham et al., “Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid,” Journal of Biological Chemistry, vol. 278, no. 5, pp. 2777–2780, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. J. A. Turpin, S. J. Terpening, C. A. Schaeffer et al., “Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of gag precursors and result in the release of noninfectious virus particles,” Journal of Virology, vol. 70, no. 9, pp. 6180–6189, 1996. View at Google Scholar · View at Scopus
  51. W. G. Rice, J. A. Turpin, M. Huang et al., “Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein,” Nature Medicine, vol. 3, no. 3, pp. 341–345, 1997. View at Publisher · View at Google Scholar · View at Scopus
  52. M. L. Schito, A. C. Soloff, D. Slovitz et al., “Preclinical evaluation of a zinc finger inhibitor targeting lentivirus nucleocapsid protein in SIV-infected monkeys,” Current HIV Research, vol. 4, no. 3, pp. 379–386, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Pannecouque, B. Szafarowicz, N. Volkova et al., “Inhibition of HIV-1 replication by a bis-thiadiazolbenzene-1,2-diamine that chelates zinc ions from retroviral nucleocapsid zinc fingers,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 4, pp. 1461–1468, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. J. A. Grobler, K. Stillmock, B. Hu et al., “Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 10, pp. 6661–6666, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. Z. Wang, J. Tang, C. E. Salomon, C. D. Dreis, and R. Vince, “Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase,” Bioorganic and Medicinal Chemistry, vol. 18, no. 12, pp. 4202–4211, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. O. Goethals, A. Vos, M. Van Ginderen et al., “Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles,” Virology, vol. 402, no. 2, pp. 338–346, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. T. M. Fletcher, M. A. Soares, S. McPhearson et al., “Complementation of integrase function in HIV-1 virions,” EMBO Journal, vol. 16, no. 16, pp. 5123–5138, 1997. View at Publisher · View at Google Scholar · View at Scopus
  58. T. P. Cujec, H. Okamoto, K. Fujinaga et al., “The HIV transactivator TAT binds to the CDK-activating kinase and activates the phosphorylation of the carboxy-terminal domain of RNA polymerase II,” Genes and Development, vol. 11, no. 20, pp. 2645–2657, 1997. View at Google Scholar · View at Scopus
  59. L. M. Bedoya, M. Beltrán, R. Sancho et al., “4-Phenylcoumarins as HIV transcription inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 20, pp. 4447–4450, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. Y. B. Tang, C. M. Zhang, C. Fang et al., “Design, synthesis and evaluation of novel 2H-1, 4-benzodiazepine-2-ones as inhibitors of HIV-1 transcription,” Yaoxue Xuebao, vol. 46, no. 6, pp. 688–694, 2011. View at Google Scholar · View at Scopus
  61. Y. Cao, X. Liu, and E. De Clercq, “Cessation of HIV-1 transcription by inhibiting regulatory protein Rev-mediated RNA transport,” Current HIV Research, vol. 7, no. 1, pp. 101–108, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. B. Wolff, J. J. Sanglier, and Y. Wang, “Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA,” Chemistry and Biology, vol. 4, no. 2, pp. 139–147, 1997. View at Google Scholar · View at Scopus
  63. A. Cochrane, “Controlling HIV-1 rev function,” Current Drug Targets, vol. 4, no. 4, pp. 287–295, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Baba, “Inhibitors of HIV-1 gene expression and transcription,” Current Topics in Medicinal Chemistry, vol. 4, no. 9, pp. 871–882, 2004. View at Google Scholar · View at Scopus
  65. J. R. Thomas and P. J. Hergenrother, “Targeting RNA with small molecules,” Chemical Reviews, vol. 108, no. 4, pp. 1171–1224, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. C. E. Prater, A. D. Saleh, M. P. Wear, and P. S. Miller, “Allosteric inhibition of the HIV-1 Rev/RRE interaction by a 3-methylphosphonate modified antisense oligo-2-O-methylribonucleotide,” Oligonucleotides, vol. 17, no. 3, pp. 275–290, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. TRANA Discovery, http://www.tranadiscovery.com/.
  68. J. Zaunders, W. B. Dyer, and M. Churchill, “The Sydney Blood Bank Cohort: implications for viral fitness as a cause of elite control,” Current Opinion in HIV and AIDS, vol. 6, no. 3, pp. 151–156, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. R. G. Ptak, B. G. Gentry, T. L. Hartman et al., “Inhibition of human immunodeficiency virus type 1 by triciribine involves the accessory protein nef,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 4, pp. 1512–1519, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. L. G. Feun, N. Savaraj, and G. P. Bodey, “Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule,” Cancer Research, vol. 44, no. 8, pp. 3608–3612, 1984. View at Google Scholar · View at Scopus
  71. M. Dubé, M. G. Bego, C. Paquay, and É. A. Cohen, “Modulation of HIV-1-host interaction: Role of the Vpu accessory protein,” Retrovirology, vol. 7, article 144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. B. D. Kuhl, V. Cheng, D. A. Donahue et al., “The HIV-1 Vpu viroporin inhibitor BIT225 does not affect Vpu-mediated tetherin antagonism,” PLoS ONE, vol. 6, no. 11, Article ID e27660, 2011. View at Google Scholar · View at Scopus
  73. M. Kogan and J. Rappaport, “HIV-1 Accessory Protein Vpr: relevance in the pathogenesis of HIV and potential for therapeutic intervention,” Retrovirology, vol. 8, article 25, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. X. J. Yao, J. Lemay, N. Rougeau et al., “Genetic selection of peptide inhibitors of human immunodeficiency virus type 1 Vpr,” Journal of Biological Chemistry, vol. 277, no. 50, pp. 48816–48826, 2002. View at Publisher · View at Google Scholar · View at Scopus
  75. E. B. B. Ong, N. Watanabe, A. Saito et al., “Vipirinin, a coumarin-based HIV-1 Vpr inhibitor, interacts with a hydrophobic region of Vpr,” Journal of Biological Chemistry, vol. 286, no. 16, pp. 14049–14056, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Kamata, R. P. Wu, D. S. An et al., “Cell-based chemical genetic screen identifies damnacanthal as an inhibitor of HIV-1 Vpr induced cell death,” Biochemical and Biophysical Research Communications, vol. 351, no. 3, p. 791, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. Z. Y. Li, P. Zhan, and X. Y. Liu, “Progress in the study of HIV-1 Vif and related inhibitors,” Yaoxue Xuebao, vol. 45, no. 6, pp. 684–693, 2010. View at Google Scholar · View at Scopus
  78. H. Côté, Z. Brumme, and P. 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. View at Google Scholar
  79. M. Kolli, E. Stawiski, C. Chappey, and C. A. Schiffer, “Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance,” Journal of Virology, vol. 83, no. 21, pp. 11027–11042, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Tung, “The development of deuterium-containing drugs,” Innovations in Pharmaceutical Technology, no. 32, pp. 24–28, 2010. View at Google Scholar · View at Scopus
  81. K. Lindsten, T. Uhlíková, J. Konvalinka, M. G. Massuci, and N. P. Dantuma, “Cell-based fluorescence assay for human immunodeficiency virus type 1 protease activity,” Antimicrobial Agents and Chemotherapy, vol. 45, no. 9, pp. 2616–2622, 2001. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Bryant and L. Ratner, “Myristoylation-dependent replication and assembly of human immunodeficiency virus 1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 2, pp. 523–527, 1990. View at Google Scholar · View at Scopus
  83. G. B. Dreyer, B. W. Metcalf, T. A. Tomaszek et al., “Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 24, pp. 9752–9756, 1989. View at Publisher · View at Google Scholar · View at Scopus
  84. O. W. Lindwasser and M. D. Resh, “Myristoylation as a target for inhibiting HIV assembly: unsaturated fatty acids block viral budding,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 20, pp. 13037–13042, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. M. L. Bryant, R. O. Heuckeroth, J. T. Kimata, L. Ratner, and J. I. Gordon, “Replication of human immunodeficiency virus 1 and Moloney murine leukemia virus is inhibited by different heteroatom-containing analogs of myristic acid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 22, pp. 8655–8659, 1989. View at Publisher · View at Google Scholar · View at Scopus
  86. 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, Article ID 8, p. 101, 2011. View at Publisher · View at Google Scholar · View at Scopus
  87. 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. View at Publisher · View at Google Scholar · View at Scopus
  88. C. Jolly, N. J. Booth, and S. J. D. Neil, “Cell-cell spread of human immunodeficiency virus type 1 overcomes tetherin/BST-2-mediated restriction in T cells,” Journal of Virology, vol. 84, no. 23, pp. 12185–12199, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. S. J. D. Neil, T. Zang, and P. D. Bieniasz, “Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu,” Nature, vol. 451, no. 7177, pp. 425–430, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. S. Neil and P. Bieniasz, “Human immunodeficiency virus, restriction factors, and interferon,” Journal of Interferon and Cytokine Research, vol. 29, no. 9, pp. 569–580, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. A. M. Sheehy, N. C. Gaddis, J. D. Choi, and M. H. Malim, “Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein,” Nature, vol. 418, no. 6898, pp. 646–650, 2002. View at Publisher · View at Google Scholar · View at Scopus
  92. R. S. Harris, K. N. Bishop, A. M. Sheehy et al., “DNA deamination mediates innate immunity to retroviral infection,” Cell, vol. 113, no. 6, pp. 803–809, 2003. View at Publisher · View at Google Scholar · View at Scopus
  93. R. Nathans, H. Cao, N. Sharova et al., “Small-molecule inhibitionof HIV-1 Vif,” Nature Biotechnology, vol. 26, no. 10, pp. 1187–1192, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. G. Maertens, P. Cherepanov, W. Pluymers et al., “LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells,” Journal of Biological Chemistry, vol. 278, no. 35, pp. 33528–33539, 2003. View at Publisher · View at Google Scholar · View at Scopus
  95. J. E. Garrus, U. K. Von Schwedler, O. W. Pornillos et al., “Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding,” Cell, vol. 107, no. 1, pp. 55–65, 2001. View at Publisher · View at Google Scholar · View at Scopus
  96. G. Maga, F. Falchi, M. Radi et al., “Toward the discovery of novel anti-HIV drugs. second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation,” ChemMedChem, vol. 6, no. 8, pp. 1371–1389, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. A. Garbelli, S. Beermann, G. Di Cicco, U. Dietrich, and G. Maga, “A motif unique to the human dead-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication,” PLoS ONE, vol. 6, no. 5, Article ID e19810, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. J. B. Whitney, M. Asmal, and R. Geiben-Lynn, “Serpin induced antiviral activity of prostaglandin synthetase-2 against HIV-1 replication,” PLoS ONE, vol. 6, no. 4, Article ID e18589, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. G. Wang, K. M. Watson, and R. W. Buckheit Jr., “Anti-human immunodeficiency virus type 1 activities of antimicrobial peptides derived from human and bovine cathelicidins,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 9, pp. 3438–3440, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. Z. Wang and G. Wang, “APD: the antimicrobial peptide database,” Nucleic Acids Research, vol. 32, pp. D590–D592, 2004. View at Google Scholar · View at Scopus
  101. T. Murali, M. D. Dyer, D. Badger, B. M. Tyler, and M. G. Katze, “Network-based prediction and analysis of HIV dependency factors,” PLoS Computational Biology, vol. 7, no. 9, Article ID e1002164, 2011. View at Google Scholar · View at Scopus
  102. R. G. Ptak, W. Fu, B. E. Sanders-Beer et al., “Cataloguing the HIV type 1 human protein interaction network,” AIDS Research and Human Retroviruses, vol. 24, no. 12, pp. 1497–1502, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. B. Alston, J. H. Ellenberg, H. C. Standiford et al., “A multicenter, randomized, controlled trial of three preparations of low-dose oral α-interferon in HIV-infected patients with CD4+ counts between 50 and 350 cells/mm3,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 22, no. 4, pp. 348–357, 1999. View at Google Scholar · View at Scopus
  104. J. A. Tavel, A. Babiker, C. Carey et al., “Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study,” PLoS ONE, vol. 5, no. 2, Article ID e9334, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. Moore et al., “CYT107 enters phase II clinical trial in HIV-infected patients,” Immunotherapy, vol. 2, no. 6, pp. 753–755, 2010. View at Google Scholar · View at Scopus
  106. S. Heringer-Walther, K. Eckert, S. M. Schumacher et al., “Angiotensin-(1–7) stimulates hematopoietic progenitor cells in vitro and in vivo,” Haematologica, vol. 94, no. 6, pp. 857–860, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. D. Liu, “Engraftment and development of HGTV43-transduced CD34+ PBSC in HIV-1 seropositive individuals,” in Proceedings of the 14th International Conference on AIDS, September 2011.
  108. C. June, “Gene modification at clinical scale: engineering resistance to HIV infection via targeted disruption of the HIV co-receptor CCR5 gene in CD4+ T cells using modified zinc finger protein nucleases,” in Proceedings of the 11th Annual Meeting ofthe American Society of Gene Therapy, Boston, Mass, USA, May 2008.
  109. M. Tuomela, I. Stanescu, and K. Krohn, “Validation overview of bio-analytical methods,” Gene Therapy, vol. 12, no. 1, pp. S131–S138, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Jones et al., “No decrease in residual viremia during raltegravir intensification in patients on standard ART,” in Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections (CROI), Montreal, Canada, February 2009.
  111. T. W. Chun and A. S. Fauci, “Latent reservoirs of HIV: obstacles to the eradication of virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 20, pp. 10958–10961, 1999. View at Publisher · View at Google Scholar · View at Scopus
  112. S. Matalon, T. A. Rasmussen, and C. A. Dinarello, “Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir,” Molecular Medicine, vol. 17, no. 5-6, pp. 466–472, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. J. Kulkosky, D. M. Culnan, J. Roman et al., “Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART,” Blood, vol. 98, no. 10, pp. 3006–3015, 2001. View at Publisher · View at Google Scholar · View at Scopus
  114. M. J. Pace, L. Agosto, E. H. Graf, and U. O'Doherty, “HIV reservoirs and latency models,” Virology, vol. 411, no. 2, pp. 344–354, 2011. View at Publisher · View at Google Scholar · View at Scopus