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Review

Improving combination antiretroviral therapy by targeting HIV-1 gene transcription

, , , , , , , , & show all
Pages 1311-1324 | Received 10 Feb 2016, Accepted 03 Jun 2016, Published online: 18 Jun 2016

References

  • Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997;94(24):13193–13197.
  • Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med. 1999;340(21):1605–1613.
  • Di Mascio M, Dornadula G, Zhang H, et al. In a subset of subjects on highly active antiretroviral therapy, human immunodeficiency virus type 1 RNA in plasma decays from 50 to <5 copies per milliliter, with a half-life of 6 months. J Virol. 2003;77(3):2271–2275.
  • Dornadula G, Zhang H, VanUitert B, et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA. 1999;282(17):1627–1632.
  • Harrigan PR, Whaley M, Montaner JS. Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy. Aids. 1999;13(8):F59–F62.
  • Zhang L, Chung C, Hu BS, et al. Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J Clin Invest. 2000;106(7):839–845.
  • Crowe S, Zhu T, Muller WA. The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection. J Leukoc Biol. 2003;74(5):635–641.
  • Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J Allergy Clin Immunol. 2008;122(1):22–28.
  • Maldarelli F. Targeting viral reservoirs: ability of antiretroviral therapy to stop viral replication. Curr Opin HIV AIDS. 2010;6(1):49–56.
  • Redel L, Le Douce V, Cherrier T, et al. HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes. J Leukoc Biol. 2010;87(4):575–588.
  • Varatharajan L, Thomas SA. The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res. 2009;82(2):A99–109.
  • Sigal A, Kim JT, Balazs AB, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011;477(7362):95–98.
  • Vella S, Palmisano L. The global status of resistance to antiretroviral drugs. Clin Infect Dis. 2005;41(Suppl 4):S239–S246.
  • Kozal MJ. Drug-resistant human immunodefiency virus. Clin Microbiol Infect. 2009;15(Suppl 1):69–73.
  • Griffiths PD. A perspective on antiviral resistance. J Clin Virol. 2009;46(1):3–8.
  • Nijhuis M, van Maarseveen NM, Boucher CA. Antiviral resistance and impact on viral replication capacity: evolution of viruses under antiviral pressure occurs in three phases. Handb Exp Pharmacol. 2009;189:299–320.
  • Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376(9734):49–62.
  • Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009;338:a3172.
  • Bagashev A, Sawaya BE. Roles and functions of HIV-1 Tat protein in the CNS: an overview. Virol J. 2013;10:358. doi:10.1186/1743-422X-10-358.
  • Le Douce V, Janossy A, Hallay H, et al. Achieving a cure for HIV infection: do we have reasons to be optimistic? J Antimicrob Chemother. 2012;67(5):1063–1074. doi:10.1093/jac/dkr599.
  • Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? Aids. 2011;25(7):885–897.
  • Lichterfeld M, Zachary KC. Treating HIV-1 infection: what might the future hold? Ther Adv Chronic Dis. 2011;2:293–305.
  • Campos N, Myburgh R, Garcel A, et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis. Retrovirology. 2015;12:30. doi:10.1186/s12977-015-0159-3.
  • Berkhout B, van der Velden YU. ABX464: a good drug candidate instead of a magic bullet. Retrovirology. 2015;12:64. doi:10.1186/s12977-015-0189-x.
  • Kilareski EM, Shah S, Nonnemacher MR, et al. Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage. Retrovirology. 2009;6:118.
  • Rohr O, Marban C, Aunis D, et al. Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells. J Leukoc Biol. 2003;74(5):736–749.
  • Schwartz C, Canonne-Hergaux F, Aunis D, et al. Characterization of nuclear proteins that bind to the regulatory TGATTGGC motif in the human immunodeficiency virus type 1 long terminal repeat. Nucleic Acids Res. 1997;25(6):1177–1184.
  • Rabson AB, Lin HC. NF-kappa B and HIV: linking viral and immune activation. Adv Pharmacol. 2000;48:161–207.
  • Mingyan Y, Xinyong L, De Clercq E. NF-kappaB: the inducible factors of HIV-1 transcription and their inhibitors. Mini Rev Med Chem. 2009;9(1):60–69.
  • Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23(3):297–305.
  • Bres V, Yoh SM, Jones KA. The multi-tasking P-TEFb complex. Curr Opin Cell Biol. 2008;20(3):334–340.
  • Ping YH, Rana TM. DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and DSIF during transcription elongation. J Biol Chem. 2001;276(16):12951–12958.
  • Zhang Z, Klatt A, Gilmour DS, et al. Negative elongation factor NELF represses human immunodeficiency virus transcription by pausing the RNA polymerase II complex. J Biol Chem. 2007;282(23):16981–16988.
  • Sobhian B, Laguette N, Yatim A, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38(3):439–451.
  • Lu H, Li Z, Xue Y, et al. Viral-host interactions that control HIV-1 transcriptional elongation. Chem Rev. 2013;113(11):8567–8582. doi:10.1021/cr400120z.
  • Zhou Q, Yik JH. The Yin and Yang of P-TEFb regulation: implications for human immunodeficiency virus gene expression and global control of cell growth and differentiation. Microbiol Mol Biol Rev. 2006;70(3):646–659.
  • Krueger BJ, Jeronimo C, Roy BB, et al. LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic Acids Res. 2008;36:2219–2229.
  • Diribarne G, Bensaude O. 7SK RNA, a non-coding RNA regulating P-TEFb, a general transcription factor. RNA Biol. 2009;6(2):122–128.
  • Lu H, Li Z, Xue Y, et al. AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc Natl Acad Sci U S A. 2014;111(1):E15–24. doi:10.1073/pnas.1318503111.
  • Sedore SC, Byers SA, Biglione S, et al. Manipulation of P-TEFb control machinery by HIV: recruitment of P-TEFb from the large form by Tat and binding of HEXIM1 to TAR. Nucleic Acids Res. 2007;35(13):4347–4358.
  • D’Orso I, Frankel AD. RNA-mediated displacement of an inhibitory snRNP complex activates transcription elongation. Nat Struct Mol Biol. 2010;17(7):815–821.
  • Barboric M, Yik JH, Czudnochowski N, et al. Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription. Nucleic Acids Res. 2007;35(6):2003–2012.
  • Brady J, Kashanchi F. Tat gets the “green” light on transcription initiation. Retrovirology. 2005;2:69.
  • Raha T, Cheng SW, Green MR. HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. PLoS Biol. 2005;3(2):e44.
  • Sune C, Garcia-Blanco MA. Transcriptional trans activation by human immunodeficiency virus type 1 Tat requires specific coactivators that are not basal factors. J Virol. 1995;69(5):3098–3107.
  • Kamine J, Chinnadurai G. Synergistic activation of the human immunodeficiency virus type 1 promoter by the viral Tat protein and cellular transcription factor Sp1. J Virol. 1992;66(6):3932–3936.
  • Jeang KT, Chun R, Lin NH, et al. In vitro and in vivo binding of human immunodeficiency virus type 1 Tat protein and Sp1 transcription factor. J Virol. 1993;67(10):6224–6233.
  • Johri MK, Mishra R, Chhatbar C, et al. Tits and bits of HIV Tat protein. Expert Opin Biol Ther. 2011;11(3):269–283.
  • Li JC, Yim HC, Lau AS. Role of HIV-1 Tat in AIDS pathogenesis: its effects on cytokine dysregulation and contributions to the pathogenesis of opportunistic infection. Aids. 2010;24(11):1609–1623.
  • Marban C, Su T, Ferrari R, et al. Genome-wide binding map of the HIV-1 Tat protein to the human genome. PLoS one. 2011;6(11):e26894. doi:10.1371/journal.pone.0026894.
  • Kukkonen S, Martinez-Viedma MDP, Kim N, et al. HIV-1 Tat second exon limits the extent of Tat-mediated modulation of interferon-stimulated genes in antigen presenting cells. Retrovirology. 2014;11:30. doi:10.1186/1742-4690-11-30.
  • Kim N, Kukkonen S, Martinez-Viedma MDP, et al. Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells. Blood. 2013;121(20):4090–4100. doi:10.1182/blood-2012-10-461566.
  • Reeder JE, Kwak Y-T, McNamara RP, et al. HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells. eLife. 2015;4. doi:10.7554/eLife.08955.
  • Romani B, Engelbrecht S, Glashoff RH. Functions of Tat: the versatile protein of human immunodeficiency virus type 1. J Gen Virol. 2010;91(Pt 1):1–12. doi:10.1099/vir.0.016303-0.
  • Fields J, Dumaop W, Eleuteri S, et al. HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci. 2015;35(5):1921–1938. doi:10.1523/JNEUROSCI.3207-14.2015.
  • Bagashev A, Mukerjee R, Santerre M, et al. Involvement of miR-196a in HIV-associated neurocognitive disorders. Apoptosis. 2014;19(8):1202–1214. doi:10.1007/s10495-014-1003-2.
  • Friedman J, Cho WK, Chu CK, et al. Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol. 2011;85(17):9078–9089.
  • du Chene I, Basyuk E, Lin YL, et al. Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J. 2007;26(2):424–435.
  • Marban C, Suzanne S, Dequiedt F, et al. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J. 2007;26(2):412–423.
  • Le Douce V, Colin L, Redel L, et al. LSD1 cooperates with CTIP2 to promote HIV-1 transcriptional silencing. Nucleic Acids Res. 2011;5:1904–1915.
  • Van Lint C, Bouchat S, Marcello A. HIV-1 transcription and latency: an update. Retrovirology. 2013;10:67. doi:10.1186/1742-4690-10-67.
  • Le Douce V, Cherrier T, Riclet R, et al. The many lives of CTIP2: from AIDS to cancer and cardiac hypertrophy. J Cell Physiol. 2014;229(5):533–537. doi:10.1002/jcp.24490.
  • Le Douce V, Herbein G, Rohr O, et al. Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage. Retrovirology. 2010;7(1):32.
  • Marban C, Redel L, Suzanne S, et al. COUP-TF interacting protein 2 represses the initial phase of HIV-1 gene transcription in human microglial cells. Nucleic Acids Res. 2005;33(7):2318–2331.
  • Cherrier T, Le Douce V, Eilebrecht S, et al. CTIP2 is a negative regulator of P-TEFb. Proc Natl Acad Sci U S A. 2013;110(31):12655–12660. doi:10.1073/pnas.1220136110.
  • Eilebrecht S, Le Douce V, Riclet R, et al. HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters. Nucleic Acids Res. 2014;42(8):4962–4971. doi:10.1093/nar/gku168.
  • Kumar A, Darcis G, Van Lint C, et al. Epigenetic control of HIV-1 post integration latency: implications for therapy. Clin Epigenetics. 2015;7(1):103. doi:10.1186/s13148-015-0137-6.
  • Darcis G, Kula A, Bouchat S, et al. An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and ingenol-B+JQ1 to potently reactivate viral gene expression. PLoS Pathog. 2015;11(7):e1005063. doi:10.1371/journal.ppat.1005063.
  • Spivak AM, Planelles V. HIV-1 eradication: early trials (and tribulations). Trends Mol Med. 2016;22(1):10–27. doi:10.1016/j.molmed.2015.11.004.
  • Dahiya S, Nonnemacher MR, Wigdahl B. Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development. J Gen Virol. 2012;93(Pt 6):1151–1172. doi:10.1099/vir.0.041186-0.
  • Schwartz C, Catez P, Rohr O, et al. Functional interactions between C/EBP, Sp1, and COUP-TF regulate human immunodeficiency virus type 1 gene transcription in human brain cells. J Virol. 2000;74(1):65–73.
  • Méndez C, Ahlenstiel CL, Kelleher AD. Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus. World J Virol. 2015;4(3):219–244. doi:10.5501/wjv.v4.i3.219.
  • Chung J, Scherer LJ, Gu A, et al. Optimized lentiviral vectors for HIV gene therapy: multiplexed expression of small RNAs and inclusion of MGMT(P140K) drug resistance gene. Mol Ther. 2014;22(5):952–963. doi:10.1038/mt.2014.32.
  • Baba M. Recent status of HIV-1 gene expression inhibitors. Antiviral Res. 2006;71(2–3):301–306.
  • Tabarrini O, Massari S, Daelemans D, et al. Structure-activity relationship study on anti-HIV 6-desfluoroquinolones. J Med Chem. 2008;51(17):5454–5458.
  • Stevens M, Pollicita M, Pannecouque C, et al. Novel in vivo model for the study of human immunodeficiency virus type 1 transcription inhibitors: evaluation of new 6-desfluoroquinolone derivatives. Antimicrob Agents Chemother. 2007;51(4):1407–1413.
  • Stevens M, Balzarini J, Tabarrini O, et al. Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation. J Antimicrob Chemother. 2005;56(5):847–855.
  • Tabarrini O, Stevens M, Cecchetti V, et al. Structure modifications of 6-aminoquinolones with potent anti-HIV activity. J Med Chem. 2004;47(22):5567–5578.
  • Bedoya LM, Abad MJ, Calonge E, et al. Quinoline-based compounds as modulators of HIV transcription through NF-kappaB and Sp1 inhibition. Antiviral Res. 2010;87(3):338–344.
  • Osorio AA, Muñóz A, Torres-Romero D, et al. Olean-18-ene triterpenoids from Celastraceae species inhibit HIV replication targeting NF-kB and Sp1 dependent transcription. Eur J Med Chem. 2012;52:295–303. doi:10.1016/j.ejmech.2012.03.035.
  • Miyake A, Ishida T, Yamagishi M, et al. Inhibition of active HIV-1 replication by NF-kappaB inhibitor DHMEQ. Microbes Infect. 2010;12(5):400–408.
  • Watanabe M, Nakashima M, Togano T, et al. Identification of the RelA domain responsible for action of a new NF-kappaB inhibitor DHMEQ. Biochem Biophys Res Commun. 2008;376(2):310–314.
  • Yamamoto M, Horie R, Takeiri M, et al. Inactivation of NF-kappaB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem. 2008;51(18):5780–5788.
  • Molinari G. Natural products in drug discovery: present status and perspectives. Adv Exp Med Biol. 2009;655:13–27. doi:10.1007/978-1-4419-1132-2_2.
  • Sánchez-Duffhues G, Calzado MA, de Vinuesa AG, et al. Denbinobin, a naturally occurring 1,4-phenanthrenequinone, inhibits HIV-1 replication through an NF-kappaB-dependent pathway. Biochem Pharmacol. 2008;76(10):1240–1250. doi:10.1016/j.bcp.2008.09.006.
  • Sánchez-Duffhues G, Calzado MA, de Vinuesa AG, et al. Denbinobin inhibits nuclear factor-kappaB and induces apoptosis via reactive oxygen species generation in human leukemic cells. Biochem Pharmacol. 2009;77(8):1401–1409. doi:10.1016/j.bcp.2009.01.004.
  • Mitsuhashi S, Kishimoto T, Uraki Y, et al. Low molecular weight lignin suppresses activation of NF-kappaB and HIV-1 promoter. Bioorg Med Chem. 2008;16(5):2645–2650. doi:10.1016/j.bmc.2007.11.041.
  • Manganaro L, Pache L, Herrmann T, et al. Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-κB-dependent manner. J Virol. 2014;88(13):7528–7540. doi:10.1128/JVI.00239-14.
  • Taura M, Kudo E, Kariya R, et al. COMMD1/murr1 reinforces HIV-1 latent infection through IκB-α stabilization. J Virol. 2015;89(5):2643–2658. doi:10.1128/JVI.03105-14.
  • Vitiello M, Galdiero M, Finamore E, et al. NF-κB as a potential therapeutic target in microbial diseases. Mol Biosyst. 2012;8(4):1108–1120. doi:10.1039/c2mb05335g.
  • Pateras I, Giaginis C, Tsigris C, et al. NF-κB signaling at the crossroads of inflammation and atherogenesis: searching for new therapeutic links. Expert Opin Ther Targets. 2014;18(9):1089–1101. doi:10.1517/14728222.2014.938051.
  • Verhoef K, Sanders RW, Fontaine V, et al. Evolution of the human immunodeficiency virus type 1 long terminal repeat promoter by conversion of an NF-kappaB enhancer element into a GABP binding site. J Virol. 1999;73(2):1331–1340.
  • Stevens M, De Clercq E, Balzarini J. The regulation of HIV-1 transcription: molecular targets for chemotherapeutic intervention. Med Res Rev. 2006;26(5):595–625.
  • Gatignol A. Transcription of HIV: Tat and cellular chromatin. Adv Pharmacol. 2007;55:137–159.
  • Tahirov TH, Babayeva ND, Varzavand K, et al. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature. 2010;465(7299):747–751. doi:10.1038/nature09131.
  • D’Orso I, Frankel AD. HIV-1 Tat: its dependence on host factors is crystal clear. Viruses. 2010;2(10):2226–2234. doi:10.3390/v2102226.
  • Mousseau G, Mediouni S, Valente ST. Targeting HIV transcription: the quest for a functional cure. Curr Top Microbiol Immunol. 2015;389:121–145. doi:10.1007/82_2015_435.
  • Sancineto L, Iraci N, Massari S, et al. Computer-aided design, synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 Tat-mediated transcription activity. ChemMedChem. 2013;8(12):1941–1953. doi:10.1002/cmdc.201300287.
  • Narayan V, Ravindra KC, Chiaro C, et al. Celastrol inhibits Tat-mediated human immunodeficiency virus (HIV) transcription and replication. J Mol Biol. 2011;410(5):972–983. doi:10.1016/j.jmb.2011.04.013.
  • Kalantari P, Narayan V, Henderson AJ, et al. 15-Deoxy-Delta12,14-prostaglandin J2 inhibits HIV-1 transactivating protein, Tat, through covalent modification. FASEB J. 2009;23(8):2366–2373. doi:10.1096/fj.08-124982.
  • Van Duyne R, Guendel I, Jaworski E, et al. Effect of mimetic CDK9 inhibitors on HIV-1-activated transcription. J Mol Biol. 2013;425(4):812–829. doi:10.1016/j.jmb.2012.12.005.
  • Hamasaki T, Okamoto M, Baba M. Identification of novel inhibitors of human immunodeficiency virus type 1 replication by in silico screening targeting cyclin T1/Tat interaction. Antimicrob Agents Chemother. 2013;57(3):1323–1331. doi:10.1128/AAC.01711-12.
  • Pascale L, López González A, DiGiorgio A, et al. Deciphering structure-activity relationships in a series of Tat/TAR inhibitors. J Biomol Struct Dyn. 2015;1–54. doi:10.1080/07391102.2015.1114971.
  • Tiefendbrunn T, Stout CD. Towards novel therapeutics for HIV through fragment-based screening and drug design. Prog Biophys Mol Biol. 2014;116(2–3):124–140. doi:10.1016/j.pbiomolbio.2014.09.009.
  • Davidson A, Begley DW, Lau C, et al. A small-molecule probe induces a conformation in HIV TAR RNA capable of binding drug-like fragments. J Mol Biol. 2011;410(5):984–996. doi:10.1016/j.jmb.2011.03.039.
  • Lin PH, Ke YY, Su CT, et al. Inhibition of HIV-1 Tat-mediated transcription by a coumarin derivative, BPRHIV001, through the Akt pathway. J Virol. 2011;85(17):9114–9126.
  • Wan Z, Chen X. Triptolide inhibits human immunodeficiency virus type 1 replication by promoting proteasomal degradation of Tat protein. Retrovirology. 2014;11:88. doi:10.1186/s12977-014-0088-6.
  • Zhang H-S, Chen X-Y, Wu T-C, et al. Tanshinone II A inhibits tat-induced HIV-1 transactivation through redox-regulated AMPK/Nampt pathway. J Cell Physiol. 2014;229(9):1193–1201. doi:10.1002/jcp.24552.
  • Guendel I, Iordanskiy S, Van Duyne R, et al. Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication. J Virol. 2014;88(2):1189–1208. doi:10.1128/JVI.01940-13.
  • Cupelli LA, Hsu MC. The human immunodeficiency virus type 1 Tat antagonist, Ro 5-3335, predominantly inhibits transcription initiation from the viral promoter. J Virol. 1995;69(4):2640–2643.
  • Hwang S, Tamilarasu N, Kibler K, et al. Discovery of a small molecule Tat-trans-activation-responsive RNA antagonist that potently inhibits human immunodeficiency virus-1 replication. J Biol Chem. 2003;278(40):39092–39103.
  • Murchie AI, Davis B, Isel C, et al. Structure-based drug design targeting an inactive RNA conformation: exploiting the flexibility of HIV-1 TAR RNA. J Mol Biol. 2004;336(3):625–638.
  • Davis B, Afshar M, Varani G, et al. Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic ‘hot spots.’ J Mol Biol. 2004;336(2):343–356.
  • Hamy F, Brondani V, Florsheimer A, et al. A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. Biochemistry. 1998;37(15):5086–5095.
  • Hsu MC, Schutt AD, Holly M, et al. Inhibition of HIV replication in acute and chronic infections in vitro by a Tat antagonist. Science. 1991;254(5039):1799–1802.
  • Hsu MC, Schutt AD, Holly M, et al. Discovery and characterization of an HIV-1 Tat antagonist. Biochem Soc Trans. 1992;20(2):525–531.
  • Hamy F, Felder ER, Heizmann G, et al. An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proc Natl Acad Sci U S A. 1997;94(8):3548–3553.
  • Lee CW, Cao H, Ichiyama K, et al. Design and synthesis of a novel peptidomimetic inhibitor of HIV-1 Tat-TAR interactions: squaryldiamide as a new potential bioisostere of unsubstituted guanidine. Bioorg Med Chem Lett. 2005;15(19):4243–4246.
  • Davidson A, Leeper TC, Athanassiou Z, et al. Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. Proc Natl Acad Sci U S A. 2009;106(29):11931–11936.
  • Athanassiou Z, Dias RL, Moehle K, et al. Structural mimicry of retroviral tat proteins by constrained beta-hairpin peptidomimetics: ligands with high affinity and selectivity for viral TAR RNA regulatory elements. J Am Chem Soc. 2004;126(22):6906–6913.
  • Athanassiou Z, Patora K, Dias RL, et al. Structure-guided peptidomimetic design leads to nanomolar beta-hairpin inhibitors of the Tat-TAR interaction of bovine immunodeficiency virus. Biochemistry. 2007;46(3):741–751.
  • Leeper TC, Athanassiou Z, Dias RL, et al. TAR RNA recognition by a cyclic peptidomimetic of Tat protein. Biochemistry. 2005;44(37):12362–12372.
  • Lalonde MS, Lobritz MA, Ratcliff A, et al. Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR) RNA. PLoS Pathog. 2011;7(5):e1002038.
  • Aoki S, Watanabe Y, Sanagawa M, et al. Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J Am Chem Soc. 2006;128(10):3148–3149. doi:10.1021/ja057404h.
  • Mediouni S, Jablonski J, Paris JJ, et al. Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice. Curr HIV Res. 2015;13(1):64–79.
  • Mousseau G, Kessing CF, Fromentin R, et al. The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. mBio. 2015;6(4):e00465. doi:10.1128/mBio.00465-15.
  • Mousseau G, Valente ST. Didehydro-Cortistatin A: a new player in HIV-therapy? Expert Rev Anti Infect Ther. 2015;1–4. doi:10.1586/14787210.2016.1122525.
  • Darbinian-Sarkissian N, Darbinyan A, Otte J, et al. p27(SJ), a novel protein in St John’s Wort, that suppresses expression of HIV-1 genome. Gene Ther. 2006;13(4):288–295.
  • Lesner A, Shilpi R, Ivanova A, et al. Identification of X-DING-CD4, a new member of human DING protein family that is secreted by HIV-1 resistant CD4(+) T cells and has anti-viral activity. Biochem Biophys Res Commun. 2009;389(2):284–289.
  • Cherrier T, Elias M, Jeudy A, et al. Human-Phosphate-Binding-Protein inhibits HIV-1 gene transcription and replication. Virol J. 2011;8:352.
  • Shilpi RY, Sachdeva R, Simm M. Cellular resistance to HIV-1 infection in target cells coincides with a rapid induction of X-DING-CD4 mRNA: indication of the unique host innate response to virus regulated through function of the X-DING-CD4 gene. Innate Immun. 2012;18(4):563–570.
  • Suh A, Le Douce V, Rohr O, et al. Pseudomonas DING proteins as human transcriptional regulators and HIV-1 antagonists. Virol J. 2013;10:234. doi:10.1186/1743-422X-10-234.
  • Berna A, Bernier F, Chabriere E, et al. For whom the bell tolls? DING proteins in health and disease. Cell Mol Life Sci. 2009;66(14):2205–2218.
  • Berna A, Bernier F, Chabriere E, et al. DING proteins; novel members of a prokaryotic phosphate-binding protein superfamily which extends into the eukaryotic kingdom. Int J Biochem Cell Biol. 2008;40(2):170–175.
  • Bernier F. DING proteins: numerous functions, elusive genes, a potential for health. Cell Mol Life Sci. 2013;70(17):3045–3056. doi:10.1007/s00018-013-1377-2.
  • Berna A, Scott K, Chabriere E, et al. The DING family of proteins: ubiquitous in eukaryotes, but where are the genes? Bioessays. 2009;31(5):570–580.
  • Darbinian N, Czernik M, Darbinyan A, et al. Evidence for phosphatase activity of p27SJ and its impact on the cell cycle. J Cell Biochem. 2009;107(3):400–407.
  • Darbinian N, Gomberg R, Mullen L, et al. Suppression of HIV-1 transcriptional elongation by a DING phosphatase. J Cell Biochem. 2011;112(1):225–232.
  • Lesner A, Li Y, Nitkiewicz J, et al. A soluble factor secreted by an HIV-1-resistant cell line blocks transcription through inactivating the DNA-binding capacity of the NF-kappa B p65/p50 dimer. J Immunol. 2005;175(4):2548–2554.
  • Simm M, Miller LS, Durkin HG, et al. Induction of secreted human immunodeficiency virus type 1 (HIV-1) resistance factors in CD4-positive T lymphocytes by attenuated HIV-1 infection. Virology. 2002;294(1):1–12.
  • Djeghader A, Gotthard G, Suh A, et al. Crystallization and preliminary X-ray diffraction analysis of a DING protein from Pseudomonas aeruginosa PA14. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013;69(Pt 4):425–429. doi:10.1107/S1744309113005356.
  • Sachdeva R, Shilpi RY, Simm M. The interplay between the X-DING-CD4, IFN-α and IL-8 gene activity in quiescent and mitogen- or HIV-1-exposed PBMCs from HIV-1 elite controllers, AIDS progressors and HIV-negative controls. Innate Immun. 2013. doi:10.1177/1753425913486162.
  • Sachdeva R, Li Y, Shilpi RY, et al. Human X-DING-CD4 mediates resistance to HIV-1 infection through novel paracrine-like signaling. FEBS J. 2015;282:937–950. doi:10.1111/febs.13192.
  • Ivanova A, Shilpi RY, Sachdeva R, et al. Native X-DING-CD4 protein secreted by HIV-1 resistant CD4+ T cells blocks activity of IL-8 promoter in human endothelial cells infected with enteric bacteria. Innate Immun. 2012;18(4):571–579.
  • Gonzalez D, Elias M, Chabrière E. The DING family of phosphate binding proteins in inflammatory diseases. Adv Exp Med Biol. 2014;824:27–32. doi:10.1007/978-3-319-07320-0_4.
  • Simm M. The innate cellular responses to HIV-1 invasion: emerging molecules of ancient defense mechanisms. Arch Immunol Ther Exp (Warsz). 2007;55(3):131–138.
  • Laskey SB, Siliciano RF. A mechanistic theory to explain the efficacy of antiretroviral therapy. Nat Rev Microbiol. 2014;12(11):772–780. doi:10.1038/nrmicro3351.
  • Shan L, Deng K, Shroff NS, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36(3):491–501. doi:10.1016/j.immuni.2012.01.014.
  • Deng K, Pertea M, Rongvaux A, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517(7534):381–385. doi:10.1038/nature14053.
  • Bruce JW, Reddington R, Mathieu E, et al. ZASC1 stimulates HIV-1 transcription elongation by recruiting P-TEFb and TAT to the LTR promoter. PLoS Pathog. 2013;9(10):e1003712. doi:10.1371/journal.ppat.1003712.
  • Yokoyama A, Lin M, Naresh A, et al. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17(2):198–212. doi:10.1016/j.ccr.2009.12.040.
  • He N, Liu M, Hsu J, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38(3):428–438. doi:10.1016/j.molcel.2010.04.013.
  • Herrera-Carrillo E, Berkhout B. Potential mechanisms for cell-based gene therapy to treat HIV/AIDS. Expert Opin Ther Targets. 2015;19(2):245–263. doi:10.1517/14728222.2014.980236.
  • Berkhout B, Liu YP. Towards improved shRNA and miRNA reagents as inhibitors of HIV-1 replication. Future Microbiol. 2014;9(4):561–571. doi:10.2217/fmb.14.5.
  • Green VA, Arbuthnot P, Weinberg MS. Impact of sustained RNAi-mediated suppression of cellular cofactor Tat-SF1 on HIV-1 replication in CD4+ T cells. Virol J. 2012;9:272. doi:10.1186/1743-422X-9-272.
  • Verschure PJ, Visser AE, Rots MG. Step out of the groove: epigenetic gene control systems and engineered transcription factors. Adv Genet. 2006;56:163–204.
  • Eberhardy SR, Goncalves J, Coelho S, et al. Inhibition of human immunodeficiency virus type 1 replication with artificial transcription factors targeting the highly conserved primer-binding site. J Virol. 2006;80(6):2873–2883.
  • Qureshi A, Thakur N, Kumar M. HIPdb: a database of experimentally validated HIV inhibiting peptides. PLoS one. 2013;8(1):e54908. doi:10.1371/journal.pone.0054908.
  • Ammosova T, Platonov M, Ivanov A, et al. 1E7-03, a small molecule targeting host protein phosphatase-1, inhibits HIV-1 transcription. Br J Pharmacol. 2014. doi:10.1111/bph.12863.
  • Geluykens P, Van Acker K, Vingerhoets J, et al. A fluorescence-based high-throughput screening assay to identify HIV-1 inhibitors. Methods Mol Biol. 2013;1030:3–9. doi:10.1007/978-1-62703-484-5_1.
  • Laird GM, Eisele EE, Rabi SA, et al. A novel cell-based high-throughput screen for inhibitors of HIV-1 gene expression and budding identifies the cardiac glycosides. J Antimicrob Chemother. 2014;69(4):988–994. doi:10.1093/jac/dkt471.
  • Kumar SP, Jasrai YT, Mehta VP, et al. Development of pharmacophore similarity-based quantitative activity hypothesis and its applicability domain: applied on a diverse data-set of HIV-1 integrase inhibitors. J Biomol Struct Dyn. 2015;33(4):706–722. doi:10.1080/07391102.2014.908142.
  • Wang J, Wang Y, Li Z, et al. Design, synthesis and biological evaluation of substituted guanidine indole derivatives as potential inhibitors of HIV-1 Tat-TAR interaction. Med Chem. 2014;10(7):738–746.
  • Veselovsky AV, Zharkova MS, Poroikov VV, et al. Computer-aided design and discovery of protein-protein interaction inhibitors as agents for anti-HIV therapy. SAR QSAR Environ Res. 2014;25(6):457–471. doi:10.1080/1062936X.2014.898689.
  • Sancineto L, Iraci N, Barreca ML, et al. Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands. Bioorg Med Chem. 2014;22(17):4658–4666. doi:10.1016/j.bmc.2014.07.018.
  • Harvey AL. Natural products in drug discovery. Drug Discov Today. 2008;13(19–20):894–901. doi:10.1016/j.drudis.2008.07.004.
  • Clark RL, Johnston BF, Mackay SP, et al. The drug discovery portal: a resource to enhance drug discovery from academia. Drug Discov Today. 2010;15(15–16):679–683. doi:10.1016/j.drudis.2010.06.003.
  • Chaplin B, Eisen G, Idoko J, et al. Impact of HIV type 1 subtype on drug resistance mutations in Nigerian patients failing first-line therapy. AIDS Res Hum Retroviruses. 2011;27(1):71–80. doi:10.1089/aid.2010.0050.
  • Lessells RJ, Katzenstein DK, de Oliveira T. Are subtype differences important in HIV drug resistance? Curr Opin Virol. 2012;2(5):636–643. doi:10.1016/j.coviro.2012.08.006.
  • Herrera-Carrillo E, Paxton WA, Berkhout B. The search for a T cell line for testing novel antiviral strategies against HIV-1 isolates of diverse receptor tropism and subtype origin. J Virol Methods. 2014;203:88–96. doi:10.1016/j.jviromet.2014.03.021.
  • Hatziioannou T, Evans DT. Animal models for HIV/AIDS research. Nat Rev Microbiol. 2012;10(12):852–867. doi:10.1038/nrmicro2911.
  • Gosling J, Monteclaro FS, Atchison RE, et al. Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proc Natl Acad Sci U S A. 1997;94(10):5061–5066.
  • Landau NR, Warton M, Littman DR. The envelope glycoprotein of the human immunodeficiency virus binds to the immunoglobulin-like domain of CD4. Nature. 1988;334(6178):159–162. doi:10.1038/334159a0.
  • Mariani R, Rutter G, Harris ME, et al. A block to human immunodeficiency virus type 1 assembly in murine cells. J Virol. 2000;74(8):3859–3870.
  • Alonso A, Derse D, Peterlin BM. Human chromosome 12 is required for optimal interactions between Tat and TAR of human immunodeficiency virus type 1 in rodent cells. J Virol. 1992;66(7):4617–4621.
  • Brehm MA, Wiles MV, Greiner DL, et al. Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods. 2014;410:3–17. doi:10.1016/j.jim.2014.02.011.
  • Garcia S, Freitas AA. Humanized mice: current states and perspectives. Immunol Lett. 2012;146(1–2):1–7. doi:10.1016/j.imlet.2012.03.009.
  • Karpel ME, Boutwell CL, Allen TM. BLT humanized mice as a small animal model of HIV infection. Curr Opin Virol. 2015;13:75–80. doi:10.1016/j.coviro.2015.05.002.
  • Marsden MD, Zack JA. Studies of retroviral infection in humanized mice. Virology. 2015;479-480:297–309. doi:10.1016/j.virol.2015.01.017.
  • Iordanskiy S, Van Duyne R, Sampey GC, et al. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology. 2015;485:1–15. doi:10.1016/j.virol.2015.06.021.
  • Gorantla S, Gendelman HE, Poluektova LY. Can humanized mice reflect the complex pathobiology of HIV-associated neurocognitive disorders? J Neuroimmune Pharmacol. 2012;7(2):352–362. doi:10.1007/s11481-011-9335-y.
  • Akkina R, Allam A, Balazs AB, et al. Improvements and limitations of humanized mouse models for HIV research: NIH/NIAID ‘meet the experts’ 2015 workshop summary. AIDS Res Hum Retroviruses. 2016;32(2):109–119. doi:10.1089/AID.2015.0258.
  • Seay K, Qi X, Zheng JH, et al. Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS One. 2013;8(5):e63537. doi:10.1371/journal.pone.0063537.
  • Jang S, Hyun S, Kim S, et al. Cell-penetrating, dimeric α-helical peptides: nanomolar inhibitors of HIV-1 transcription. Angew Chem Int Ed Engl. 2014;53(38):10086–10089. doi:10.1002/anie.201404684.
  • Kim PS, Read SW. Nanotechnology and HIV: potential applications for treatment and prevention. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(6):693–702.
  • Mamo T, Moseman EA, Kolishetti N, et al. Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine (Lond). 2010;5(2):269–285.
  • Vyas TK, Shah L, Amiji MM. Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv. 2006;3(5):613–628. doi:10.1517/17425247.3.5.613.
  • das Neves J, Amiji MM, Bahia MF, et al. Nanotechnology-based systems for the treatment and prevention of HIV/AIDS. Adv Drug Deliv Rev. 2010;62(4–5):458–477.
  • Sharma P, Garg S. Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs. Adv Drug Deliv Rev. 2010;62(4–5):491–502.
  • Sagar V, Pilakka-Kanthikeel S, Pottathil R, et al. Towards nanomedicines for neuroAIDS. Rev Med Virol. 2014;24(2):103–124. doi:10.1002/rmv.1778.
  • Gomes MJ, das Neves J, Sarmento B. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system. Int J Nanomedicine. 2014;9:1757–1769. doi:10.2147/IJN.S45886.
  • Vyas TK, Shahiwala A, Amiji MM. Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations. Int J Pharm. 2008;347(1–2):93–101. doi:10.1016/j.ijpharm.2007.06.016.
  • Lanao JM, Briones E, Colino CI. Recent advances in delivery systems for anti-HIV1 therapy. J Drug Target. 2007;15(1):21–36. doi:10.1080/10611860600942178.
  • Lenjisa JL, Woldu MA, Satessa GD. New hope for eradication of HIV from the body: the role of polymeric nanomedicines in HIV/AIDS pharmacotherapy. J Nanobiotechnol. 2014;12:9. doi:10.1186/1477-3155-12-9.
  • Ojewole E, Mackraj I, Naidoo P, et al. Exploring the use of novel drug delivery systems for antiretroviral drugs. Eur J Pharm Biopharm. 2008;70(3):697–710. doi:10.1016/j.ejpb.2008.06.020.
  • Mahajan SD, Aalinkeel R, Law W-C, et al. Anti-HIV-1 nanotherapeutics: promises and challenges for the future. Int J Nanomedicine. 2012;7:5301–5314. doi:10.2147/IJN.S25871.
  • Wang J, Hou T. Advances in computationally modeling human oral bioavailability. Adv Drug Deliv Rev. 2015;86:11–16. doi:10.1016/j.addr.2015.01.001.
  • Moreno S, Lopez Aldeguer J, Arribas JR, et al. The future of antiretroviral therapy: challenges and needs. J Antimicrob Chemother. 2010;65(5):827–835.
  • Taiwo B, Hicks C, Eron J. Unmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1. J Antimicrob Chemother. 2010;65(6):1100–1107.
  • Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12:309. doi:10.1038/nrneurol.2016.27.
  • Nath A, Clements JE. Eradication of HIV from the brain: reasons for pause. AIDS (London, England). 2011;25(5):577–580. doi:10.1097/QAD.0b013e3283437d2f.
  • Li JW-H, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science (New York, N.Y.). 2009;325(5937):161–165. doi:10.1126/science.1168243.

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