During the past three decades, over thirty-five anti-HIV-1 therapies have been developed for use in humans and the progression from monotherapeutic treatment regimens to today’s highly active combination antiretroviral therapies has had a dramatic impact on disease progression in HIV-1-infected individuals. In spite of the success of AIDS therapies and the existence of inhibitors of HIV-1 reverse transcriptase, protease, entry and fusion, and integrase, HIV-1 therapies still have a variety of problems which require continued development efforts to improve efficacy and reduce toxicity, while making drugs that can be used throughout both the developed and developing world, in pediatric populations, and in pregnant women. Highly active antiretroviral therapies (HAARTs) have significantly delayed the progression to AIDS, and in the developed world HIV-1-infected individuals might be expected to live normal life spans while on lifelong therapies. However, the difficult treatment regimens, the presence of class-specific drug toxicities, and the emergence of drug-resistant virus isolates highlight the fact that improvements in our therapeutic regimens and the identification of new and novel viral and cellular targets for therapy are still necessary. Antiretroviral therapeutic strategies and targets continue to be explored, and the development of increasingly potent molecules within existing classes of drugs and the development of novel strategies are ongoing. 1. Introduction Since the approval of AZT for the treatment of HIV-1 infection, twenty-three additional therapeutic agents have been approved for use in humans [1]. The first drugs approved in the United States to treat HIV-1 infection inhibit the specific activity of the virally encoded reverse transcriptase, the viral enzyme essential for conversion of the viral RNA genome into a DNA provirus that integrates itself into the host genome. Two classes of reverse transcriptase inhibitors are currently marketed—nonnucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) [2]. Another approved and marketed class of HIV-1 antiviral therapeutics inhibits the HIV-1 protease, a viral enzyme required to process newly synthesized viral polyproteins into the mature viral gene products, enabling the virus to assemble itself into new infectious virus particles [3]. A third class of HIV-1 therapeutics inhibits viral infection by preventing virus attachment to the host cell CCR5 chemokine receptor or prevents the fusion of the viral and cellular membranes
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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[13]
M. Oette, R. Kaiser, M. D？umer, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[21]
J. Levin, “BI224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-na？ve 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[31]
R. Carmona, L. Pérez-Alvarez, M. Mu？oz 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[63]
A. Cochrane, “Controlling HIV-1 rev function,” Current Drug Targets, vol. 4, no. 4, pp. 287–295, 2004.
[64]
M. Baba, “Inhibitors of HIV-1 gene expression and transcription,” Current Topics in Medicinal Chemistry, vol. 4, no. 9, pp. 871–882, 2004.
[65]
J. R. Thomas and P. J. Hergenrother, “Targeting RNA with small molecules,” Chemical Reviews, vol. 108, no. 4, pp. 1171–1224, 2008.
[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 -methylphosphonate modified antisense oligo- -O-methylribonucleotide,” Oligonucleotides, vol. 17, no. 3, pp. 275–290, 2007.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[78]
H. C？té, 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.
[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.
[80]
R. Tung, “The development of deuterium-containing drugs,” Innovations in Pharmaceutical Technology, no. 32, pp. 24–28, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[100]
Z. Wang and G. Wang, “APD: the antimicrobial peptide database,” Nucleic Acids Research, vol. 32, pp. D590–D592, 2004.
[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.
[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.
[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.
[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.
[105]
Moore, et al., “CYT107 enters phase II clinical trial in HIV-infected patients,” Immunotherapy, vol. 2, no. 6, pp. 753–755, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
