Peptide Triazole Inhibitors of HIV-1: Hijackers of Env Metastability

Erik      P. Carter; Charles      G. Ang; Irwin      M. Chaiken
Abstract

With 1.5 million new infections and 690,000 AIDS-related deaths globally each year, HIV- 1 remains a pathogen of significant public health concern. Although a wide array of effective antiretroviral drugs have been discovered, these largely target intracellular stages of the viral infectious cycle, and inhibitors that act at or before the point of viral entry still require further advancement. A unique class of HIV-1 entry inhibitors, called peptide triazoles (PTs), has been developed, which irreversibly inactivates Env trimers by exploiting the protein structure’s innate metastable nature. PTs, and a related group of inhibitors called peptide triazole thiols (PTTs), are peptide compounds that dually engage the CD4 receptor and coreceptor binding sites of Env’s gp120 subunit. This triggers dramatic conformational rearrangements of Env, including the shedding of gp120 (PTs and PTTs) and lytic transformation of the gp41 subunit to a post-fusion-like arrangement (PTTs). Due to the nature of their dual receptor site engagement, PT/PTT-induced conformational changes may elucidate mechanisms behind the native fusion program of Env trimers following receptor and coreceptor engagement, including the role of thiols in fusion. In addition to inactivating Env, PTT-induced structural transformation enhances the exposure of important and conserved neutralizable regions of gp41, such as the membrane proximal external region (MPER). PTT-transformed Env could present an intriguing potential vaccine immunogen prototype. In this review, we discuss the origins of the PT class of peptide inhibitors, our current understanding of PT/PTT-induced structural perturbations and viral inhibition, and prospects for using these antagonists for investigating Env structural mechanisms and for vaccine development.
Keywords: HIV-1, peptide triazoles, peptide triazole thiols, peptide antagonists, gp120, gp41, metastability, HIV vaccines, MPER
Graphical Abstract

[1]
Pau, A.K.; George, J.M. Antiretroviral therapy: Current drugs. Infect. Dis. Clin. North Am.,  2014, 28(3), 371-402.
 [http://dx.doi.org/10.1016/j.idc.2014.06.001] [PMID:  25151562]

[2]
Esté, J.A.; Cihlar, T. Current status and challenges of antiretroviral research and therapy. Antiviral Res.,  2010, 85(1), 25-33.
 [http://dx.doi.org/10.1016/j.antiviral.2009.10.007] [PMID:  20018390]

[3]
Ng’uni, T.; Chasara, C.; Ndhlovu, Z.M. Major scientific hurdles in HIV vaccine development: Historical perspective and future directions. Front. Immunol.,  2020, 11, 590780.
 [http://dx.doi.org/10.3389/fimmu.2020.590780] [PMID:  33193428]

[4]
Ensoli, B.; Cafaro, A.; Monini, P.; Marcotullio, S.; Ensoli, F. Challenges in HIV vaccine research for treatment and prevention. Front. Immunol.,  2014, 5(AUG), 417.
 [http://dx.doi.org/10.3389/fimmu.2014.00417] [PMID:  25250026]

[5]
Pace, M.; Frater, J. A cure for HIV: Is it in sight? Expert Rev. Anti Infect. Ther.,  2014, 12(7), 783-791.
 [http://dx.doi.org/10.1586/14787210.2014.910112] [PMID:  24745361]

[6]
Jilg, N.; Li, J.Z. On the road to a HIV Cure: Moving beyond Berlin and London. Infect. Dis. Clin. North Am.,  2019, 33(3), 857-868.
 [http://dx.doi.org/10.1016/j.idc.2019.04.007] [PMID:  31395147]

[7]
 UNAIDS report shows that people living with HIV face a double jeopardy, HIV and COVID-19, while key populations and children continue to be left behind in access to HIV services. UNAIDS, https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2021/july/20210714_global-aids-update

[8]
Arrildt, K.T.; Joseph, S.B.; Swanstrom, R. The HIV-1 env protein: A coat of many colors. Curr. HIV/AIDS Rep.,  2012, 9(1), 52-63.
 [http://dx.doi.org/10.1007/s11904-011-0107-3] [PMID:  22237899]

[9]
Oxenius, A.; Price, D.A.; Trkola, A.; Edwards, C.; Gostick, E.; Zhang, H-T.; Easterbrook, P.J.; Tun, T.; Johnson, A.; Waters, A.; Holmes, E.C.; Phillips, R.E. Loss of viral control in early HIV-1 infection is temporally associated with sequential escape from CD8+ T cell re-sponses and decrease in HIV-1-specific CD4+ and CD8+ T cell frequencies. J. Infect. Dis.,  2004, 190(4), 713-721.
 [http://dx.doi.org/10.1086/422760] [PMID:  15272399]

[10]
Wyatt, R.; Sodroski, J. The HIV-1 envelope glycoproteins: fFsogens, antigens, and immunogens. Science,  1998, 280(5371), 1884-1888.
 [http://dx.doi.org/10.1126/science.280.5371.1884] [PMID:  9632381]

[11]
Pacheco, B.; Alsahafi, N.; Debbeche, O.; Prévost, J.; Ding, S.; Chapleau, J-P.; Herschhorn, A.; Madani, N.; Princiotto, A.; Melillo, B.; Gu, C.; Zeng, X.; Mao, Y.; Smith, A.B., III; Sodroski, J.; Finzi, A. Residues in the gp41 ectodomain regulate HIV-1 envelope glycoprotein con-formational transitions induced by gp120-directed inhibitors. J. Virol.,  2017, 91(5), e02219-e16.
 [http://dx.doi.org/10.1128/JVI.02219-16] [PMID:  28003492]

[12]
Wilen, C.B.; Tilton, J.C.; Doms, R.W. HIV: Cell binding and entry. Cold Spring Harb. Perspect. Med.,  2012, 2(8), a006866.
 [http://dx.doi.org/10.1101/cshperspect.a006866] [PMID:  22908191]

[13]
Blumenthal, R.; Durell, S.; Viard, M. HIV entry and envelope glycoprotein-mediated fusion. J. Biol. Chem.,  2012, 287(49), 40841-40849.
 [http://dx.doi.org/10.1074/jbc.R112.406272] [PMID:  23043104]

[14]
Chen, B. Molecular mechanism of HIV-1 entry. Trends Microbiol.,  2019, 27(10), 878-891.
 [http://dx.doi.org/10.1016/j.tim.2019.06.002] [PMID:  31262533]

[15]
Wang, Q.; Finzi, A.; Sodroski, J. The conformational states of the HIV-1 envelope glycoproteins. Trends Microbiol.,  2020, 28(8), 655-667.
 [http://dx.doi.org/10.1016/j.tim.2020.03.007] [PMID:  32418859]

[16]
Doms, R.W.; Moore, J.P. HIV-1 membrane fusion: Targets of opportunity. J. Cell Biol.,  2000, 151(2), F9-F14.
 [http://dx.doi.org/10.1083/jcb.151.2.F9] [PMID:  11038194]

[17]
Kwong, P.D.; Wyatt, R.; Robinson, J.; Sweet, R.W.; Sodroski, J.; Hendrickson, W.A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature,  1998, 393(6686), 648-659.
 [http://dx.doi.org/10.1038/31405] [PMID:  9641677]

[18]
McKeating, J.A.; McKnight, A.; Moore, J.P. Differential loss of envelope glycoprotein gp120 from virions of human immunodeficiency virus type 1 isolates: Effects on infectivity and neutralization. J. Virol.,  1991, 65(2), 852-860.
 [http://dx.doi.org/10.1128/jvi.65.2.852-860.1991] [PMID:  1898972]

[19]
Gallo, S.A.; Finnegan, C.M.; Viard, M.; Raviv, Y.; Dimitrov, A.; Rawat, S.S.; Puri, A.; Durell, S.; Blumenthal, R. “The HIV Env-mediated fusion reaction,” Biochimica et Biophysica Acta (BBA) -. Biochim. Biophys. Acta Biomembr.,  2003, 1614(1), 36-50.
 [http://dx.doi.org/10.1016/S0005-2736(03)00161-5]

[20]
Khasnis, M.D.; Halkidis, K.; Bhardwaj, A.; Root, M.J. Receptor activation of HIV-1 env leads to asymmetric exposure of the gp41 trimer. PLoS Pathog.,  2016, 12(12), e1006098.
 [http://dx.doi.org/10.1371/journal.ppat.1006098] [PMID:  27992602]

[21]
Harris, A.; Borgnia, M.J.; Shi, D.; Bartesaghi, A.; He, H.; Pejchal, R.; Kang, Y.K.; Depetris, R.; Marozsan, A.J.; Sanders, R.W.; Klasse, P.J.; Milne, J.L.S.; Wilson, I.A.; Olson, W.C.; Moore, J.P.; Subramaniam, S. Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures. Proc. Natl. Acad. Sci. USA,  2011, 108(28), 11440-11445.
 [http://dx.doi.org/10.1073/pnas.1101414108] [PMID:  21709254]

[22]
Ward, A.B.; Wilson, I.A. The HIV-1 envelope glycoprotein structure: Nailing down a moving target. Immunol. Rev.,  2017, 275(1), 21-32.
 [http://dx.doi.org/10.1111/imr.12507] [PMID:  28133813]

[23]
Wyatt, R.; Kwong, P.D.; Desjardins, E.; Sweet, R.W.; Robinson, J.; Hendrickson, W.A.; Sodroski, J.G. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature,  1998, 393(6686), 705-711.
 [http://dx.doi.org/10.1038/31514] [PMID:  9641684]

[24]
Pantophlet, R.; Burton, D.R. GP120: Target for neutralizing HIV-1 antibodies. Annu. Rev. Immunol.,  2006, 24(1), 739-769.
 [http://dx.doi.org/10.1146/annurev.immunol.24.021605.090557] [PMID:  16551265]

[25]
Wei, X.; Decker, J.M.; Wang, S.; Hui, H.; Kappes, J.C.; Wu, X.; Salazar-Gonzalez, J.F.; Salazar, M.G.; Kilby, J.M.; Saag, M.S.; Komarova, N.L.; Nowak, M.A.; Hahn, B.H.; Kwong, P.D.; Shaw, G.M. Antibody neutralization and escape by HIV-1. Nature,  2003, 422(6929), 307-312.
 [http://dx.doi.org/10.1038/nature01470] [PMID:  12646921]

[26]
Munro, J.B.; Gorman, J.; Ma, X.; Zhou, Z.; Arthos, J.; Burton, D.R.; Koff, W.C.; Courter, J.R.; Smith, A.B., III; Kwong, P.D.; Blanchard, S.C.; Mothes, W. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science,  2014, 346(6210), 759-763.
 [http://dx.doi.org/10.1126/science.1254426] [PMID:  25298114]

[27]
Kumar, Sonu; Sarkar, Anita; Pugach, Pavel; Sanders, Rogier W.; Moore, John P.; Ward, Andrew B.; Wilson, Ian A. Capturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide. Nat. Commun.,  2019, 10, 1-5.
 [http://dx.doi.org/10.1038/s41467-019-08738-5]

[28]
Ghosh, D.K.; Ranjan, A. The metastable states of proteins. Protein Sci.,  2020, 29(7), 1559-1568.
 [http://dx.doi.org/10.1002/pro.3859] [PMID:  32223005]

[29]
Lee, C.; Park, S-H.; Lee, M-Y.; Yu, M-H. Regulation of protein function by native metastability. Proc. Natl. Acad. Sci. USA,  2000, 97(14), 7727-7731.
 [http://dx.doi.org/10.1073/pnas.97.14.7727] [PMID:  10884404]

[30]
Ang, C.G.; Carter, E.; Haftl, A.; Zhang, S.; Rashad, A.A.; Kutzler, M.; Abrams, C.F.; Chaiken, I.M. Peptide triazole thiol irreversibly inacti-vates metastable hiv-1 env by accessing conformational triggers intrinsic to virus–cell entry. Microorganisms,  2021, 9(6), 1286.
 [http://dx.doi.org/10.3390/microorganisms9061286] [PMID:  34204725]

[31]
Ferrer, Marc; Harrison, Stephen C. Peptide ligands to human immunodeficiency virus type 1 gp120 identified from phage display libraries. J. Virol.,  1999, 73, 5795.
 [http://dx.doi.org/10.1128/JVI.73.7.5795-5802.1999]

[32]
Gopi, H.; Umashankara, M.; Pirrone, V.; LaLonde, J.; Madani, N.; Tuzer, F.; Baxter, S.; Zentner, I.; Cocklin, S.; Jawanda, N.; Miller, S.R.; Schön, A.; Klein, J.C.; Freire, E.; Krebs, F.C.; Smith, A.B.; Sodroski, J.; Chaiken, I. Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1. J. Med. Chem.,  2008, 51(9), 2638-2647.
 [http://dx.doi.org/10.1021/jm070814r] [PMID:  18402432]

[33]
Gopi, H.; Cocklin, S.; Pirrone, V.; McFadden, K.; Tuzer, F.; Zentner, I.; Ajith, S.; Baxter, S.; Jawanda, N.; Krebs, F.C.; Chaiken, I.M. In-troducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120. J. Mol. Recognit.,  2009, 22(2), 169-174.
 [http://dx.doi.org/10.1002/jmr.892] [PMID:  18498083]

[34]
Bastian, A.R.; Contarino, M.; Bailey, L.D.; Aneja, R.; Moreira, D.R.M.; Freedman, K.; McFadden, K.; Duffy, C.; Emileh, A.; Leslie, G.; Jacobson, J.M.; Hoxie, J.A.; Chaiken, I. Interactions of peptide triazole thiols with Env gp120 induce irreversible breakdown and inactiva-tion of HIV-1 virions. Retrovirology,  2013, 10(1), 153.
 [http://dx.doi.org/10.1186/1742-4690-10-153] [PMID:  24330857]

[35]
Umashankara, M.; McFadden, K.; Zentner, I.; Schön, A.; Rajagopal, S.; Tuzer, F.; Kuriakose, S.A.; Contarino, M.; Lalonde, J.; Freire, E.; Chaiken, I. The active core in a triazole peptide dual-site antagonist of HIV-1 gp120. ChemMedChem,  2010, 5(11), 1871-1879.
 [http://dx.doi.org/10.1002/cmdc.201000222] [PMID:  20677318]

[36]
Rashad, A.A.; Kalyana Sundaram, R.V.; Aneja, R.; Duffy, C.; Chaiken, I. Macrocyclic envelope glycoprotein antagonists that irreversibly inactivate HIV-1 before host cell encounter. J. Med. Chem.,  2015, 58(18), 7603-7608.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b00935] [PMID:  26331669]

[37]
Zhang, W.; Godillot, A.P.; Wyatt, R.; Sodroski, J.; Chaiken, I. Antibody 17b binding at the coreceptor site weakens the kinetics of the in-teraction of envelope glycoprotein gp120 with CD4. Biochemistry,  2001, 40(6), 1662-1670.
 [http://dx.doi.org/10.1021/bi001397m] [PMID:  11327825]

[38]
Cocklin, S.; Gopi, H.; Querido, B.; Nimmagadda, M.; Kuriakose, S.; Cicala, C.; Ajith, S.; Baxter, S.; Arthos, J.; Martín-García, J.; Chaiken, I.M. Broad-spectrum anti-human immunodeficiency virus (HIV) potential of a peptide HIV type 1 entry inhibitor. J. Virol.,  2007, 81(7), 3645-3648.
 [http://dx.doi.org/10.1128/JVI.01778-06] [PMID:  17251295]

[39]
Gopi, H.N.; Tirupula, K.C.; Baxter, S.; Ajith, S.; Chaiken, I.M. Click chemistry on azidoproline: High-affinity dual antagonist for HIV-1 envelope glycoprotein gp120. ChemMedChem,  2006, 1(1), 54-57.
 [http://dx.doi.org/10.1002/cmdc.200500037] [PMID:  16892335]

[40]
Aneja, R.; Rashad, A.A.; Li, H.; Kalyana Sundaram, R.V.; Duffy, C.; Bailey, L.D.; Chaiken, I. Peptide triazole inactivators of HIV-1 utilize a conserved two-cavity binding site at the junction of the inner and outer domains of env gp120. J. Med. Chem.,  2015, 58(9), 3843-3858.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b00073] [PMID:  25860784]

[41]
Emileh, A.; Tuzer, F.; Yeh, H.; Umashankara, M.; Moreira, D.R.M.; Lalonde, J.M.; Bewley, C.A.; Abrams, C.F.; Chaiken, I.M. A model of peptide triazole entry inhibitor binding to HIV-1 gp120 and the mechanism of bridging sheet disruption. Biochemistry,  2013, 52(13), 2245-2261.
 [http://dx.doi.org/10.1021/bi400166b] [PMID:  23470147]

[42]
Otvos, L., Jr; Wade, J.D. Current challenges in peptide-based drug discovery. Front Chem.,  2014, 2, 62.
 [http://dx.doi.org/10.3389/fchem.2014.00062] [PMID:  25152873]

[43]
Lee, A.C-L.; Harris, J.L.; Khanna, K.K.; Hong, J-H. A comprehensive review on current advances in peptide drug development and de-sign. Int. J. Mol. Sci.,  2019, 20(10), E2383.
 [http://dx.doi.org/10.3390/ijms20102383] [PMID:  31091705]

[44]
Rashad, A.A.; Acharya, K.; Haftl, A.; Aneja, R.; Dick, A.; Holmes, A.P.; Chaiken, I. Chemical optimization of macrocyclic HIV-1 inactiva-tors for improving potency and increasing the structural diversity at the triazole ring. Org. Biomol. Chem.,  2017, 15(37), 7770-7782.
 [http://dx.doi.org/10.1039/C7OB01448A] [PMID:  28770939]

[45]
Bastian, A.R. Kantharaju, ; McFadden, K.; Duffy, C.; Rajagopal, S.; Contarino, M.R.; Papazoglou, E.; Chaiken, I. Cell-free HIV-1 virucidal action by modified peptide triazole inhibitors of Env gp120. ChemMedChem,  2011, 6(8), 1335-1339, 1318.
 [http://dx.doi.org/10.1002/cmdc.201100177] [PMID: 21714095]

[46]
Bailey, L.D.; Kalyana Sundaram, R.V.; Li, H.; Duffy, C.; Aneja, R.; Rosemary Bastian, A.; Holmes, A.P.; Kamanna, K.; Rashad, A.A.; Chaiken, I. Disulfide sensitivity in the env protein underlies lytic inactivation of HIV-1 by peptide triazole thiols. ACS Chem. Biol.,  2015, 10(12), 2861-2873.
 [http://dx.doi.org/10.1021/acschembio.5b00381] [PMID:  26458166]

[47]
Tzanko, S. Stantchev; Mark, Paciga.; Crala R, Lankford.; Franziska, Schwartzkopff Cell-type specific requirements for thiol/disulfide exchange during HIV-1 entry and infection. Retrovirology,  2012, 9(1), 97.
 [http://dx.doi.org/10.1186/1742-4690-9-97]

[48]
van Anken, E.; Sanders, R.W.; Liscaljet, I.M.; Land, A.; Bontjer, I.; Tillemans, S.; Nabatov, A.A.; Paxton, W.A.; Berkhout, B.; Braakman, I. Only five of 10 strictly conserved disulfide bonds are essential for folding and eight for function of the HIV-1 envelope glycoprotein. Mol. Biol. Cell,  2008, 19(10), 4298-4309.
 [http://dx.doi.org/10.1091/mbc.e07-12-1282] [PMID:  18653472]

[49]
Anfinsen, C.B. The formation and stabilization of protein structure. Biochem. J.,  1972, 128(4), 737-749.
 [http://dx.doi.org/10.1042/bj1280737] [PMID:  4565129]

[50]
Givol, D.; Delorenzo, F.; Goldberger, R.F.; Anfinsen, C.B. Disulfide interchange and the three-dimensional structure of proteins. Proc. Natl. Acad. Sci. USA,  1965, 53(3), 676-684.
 [http://dx.doi.org/10.1073/pnas.53.3.676] [PMID:  14338250]

[51]
Hogg, P.J. Disulfide bonds as switches for protein function. Trends Biochem. Sci.,  2003, 28(4), 210-214.
 [http://dx.doi.org/10.1016/S0968-0004(03)00057-4] [PMID:  12713905]

[52]
Mor-Cohen, R. Disulfide bonds as regulators of integrin function in thrombosis and hemostasis. Antioxid. Redox Signal.,  2016, 24(1), 16-31.
 [http://dx.doi.org/10.1089/ars.2014.6149] [PMID:  25314675]

[53]
Passam, F.J.; Chiu, J. Allosteric disulphide bonds as reversible mechano-sensitive switches that control protein functions in the vascula-ture. Biophys. Rev.,  2019, 11(3), 419-430.
 [http://dx.doi.org/10.1007/s12551-019-00543-0] [PMID:  31090016]

[54]
Yang, T.; Yao, Y.; Wang, X.; Li, Y.; Si, Y.; Li, X.; Ayala, G.J.; Wang, Y.; Mayo, K.H.; Tai, G.; Zhou, Y.; Su, J. Galectin-13/placental pro-tein 13: Redox-active disulfides as switches for regulating structure, function and cellular distribution. Glycobiology,  2020, 30(2), 120-129.
 [http://dx.doi.org/10.1093/glycob/cwz081] [PMID:  31584064]

[55]
Messens, J.; Collet, J-F. Thiol-disulfide exchange in signaling: Disulfide bonds as a switch. Antioxid. Redox Signal.,  2013, 18(13), 1594-1596.
 [http://dx.doi.org/10.1089/ars.2012.5156] [PMID:  23330837]

[56]
Ryser, H.J.; Levy, E.M.; Mandel, R.; DiSciullo, G.J. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc. Natl. Acad. Sci. USA,  1994, 91(10), 4559-4563.
 [http://dx.doi.org/10.1073/pnas.91.10.4559] [PMID:  8183947]

[57]
Fenouillet, E.; Barbouche, R.; Courageot, J.; Miquelis, R. The catalytic activity of protein disulfide isomerase is involved in human immu-nodeficiency virus envelope-mediated membrane fusion after CD4 cell binding. J. Infect. Dis.,  2001, 183(5), 744-752.
 [http://dx.doi.org/10.1086/318823] [PMID:  11181151]

[58]
Barbouche, R.; Miquelis, R.; Jones, I.M.; Fenouillet, E. Protein-disulfide isomerase-mediated reduction of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. J. Biol. Chem.,  2003, 278(5), 3131-3136.
 [http://dx.doi.org/10.1074/jbc.M205467200] [PMID:  12218052]

[59]
Gallina, A.; Hanley, T.M.; Mandel, R.; Trahey, M.; Broder, C.C.; Viglianti, G.A.; Ryser, H.J. Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J. Biol. Chem.,  2002, 277(52), 50579-50588.
 [http://dx.doi.org/10.1074/jbc.M204547200] [PMID:  12218051]

[60]
Markovic, I.; Stantchev, T.S.; Fields, K.H.; Tiffany, L.J.; Tomiç, M.; Weiss, C.D.; Broder, C.C.; Strebel, K.; Clouse, K.A. Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1 envelope-mediated T-cell fusion during viral entry. Blood,  2004, 103(5), 1586-1594.
 [http://dx.doi.org/10.1182/blood-2003-05-1390] [PMID:  14592831]

[61]
Barbouche, R.; Lortat-Jacob, H.; Jones, I.M.; Fenouillet, E. Glycosaminoglycans and protein disulfide isomerase-mediated reduction of HIV Env. Mol. Pharmacol.,  2005, 67(4), 1111-1118.
 [http://dx.doi.org/10.1124/mol.104.008276] [PMID:  15644496]

[62]
Wang, Z.; Zhou, Z.; Guo, Z.Y.; Chi, C.W. Snapshot of the interaction between HIV envelope glycoprotein 120 and protein disulfide iso-merase. Acta Biochim. Biophys. Sin. (Shanghai),  2010, 42(5), 358-362.
 [http://dx.doi.org/10.1093/abbs/gmq024] [PMID:  20458450]

[63]
Papandréou, M.J.; Barbouche, R.; Guieu, R.; Rivera, S.; Fantini, J.; Khrestchatisky, M.; Jones, I.M.; Fenouillet, E. Mapping of domains on HIV envelope protein mediating association with calnexin and protein-disulfide isomerase. J. Biol. Chem.,  2010, 285(18), 13788-13796.
 [http://dx.doi.org/10.1074/jbc.M109.066670] [PMID:  20202930]

[64]
Kornbluth, R.S. HIV envelope becomes unhinged by PDI for entry. Blood,  2004, 103(5), 1567-1567.
 [http://dx.doi.org/10.1182/blood-2003-12-4284]

[65]
Turano, C.; Coppari, S.; Altieri, F.; Ferraro, A. Proteins of the PDI family: Unpredicted non-ER locations and functions. J. Cell. Physiol.,  2002, 193(2), 154-163.
 [http://dx.doi.org/10.1002/jcp.10172] [PMID:  12384992]

[66]
Holmgren, A. Thioredoxin. Annu. Rev. Biochem.,  1985, 54(1), 237-271.
 [http://dx.doi.org/10.1146/annurev.bi.54.070185.001321] [PMID:  3896121]

[67]
Lundberg, Mathias; Mattsson, Åse; Reiser, Kathrin; Holmgren, Arne Curbo, Sophie Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells. Scientific Reports,  2019, 9, 1-9.
 [http://dx.doi.org/10.1038/s41598-019-42068-2]

[68]
Bastian, A.R.; Ang, C.G.; Kamanna, K.; Shaheen, F.; Huang, Y.H.; McFadden, K.; Duffy, C.; Bailey, L.D.; Sundaram, R.V.K.; Chaiken, I. Targeting cell surface HIV-1 Env protein to suppress infectious virus formation. Virus Res.,  2017, 235, 33-36.
 [http://dx.doi.org/10.1016/j.virusres.2017.04.003] [PMID:  28390972]

[69]
Jin, L.; Pan, C.; Qi, Z.; Zhou, Z.H.; Jiang, S. Fab crystallization and preliminary X-ray analysis of NC-1, an anti-HIV-1 antibody that rec-ognizes the six-helix bundle core of gp41. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun.,  2010, 66(Pt 7), 854-857.
 [http://dx.doi.org/10.1107/S1744309110019287] [PMID:  20606291]

[70]
Dingens, A.S.; Acharya, P.; Haddox, H.K.; Rawi, R.; Xu, K.; Chuang, G.Y.; Wei, H.; Zhang, B.; Mascola, J.R.; Carragher, B.; Potter, C.S.; Overbaugh, J.; Kwong, P.D.; Bloom, J.D. Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion pep-tide of HIV. PLoS Pathog.,  2018, 14(7), e1007159.
 [http://dx.doi.org/10.1371/journal.ppat.1007159] [PMID:  29975771]

[71]
Freed, E.O.; Delwart, E.L.; Buchschacher, G.L., Jr; Panganiban, A.T. A mutation in the human immunodeficiency virus type 1 transmem-brane glycoprotein gp41 dominantly interferes with fusion and infectivity. Proc. Natl. Acad. Sci. USA,  1992, 89(1), 70-74.
 [http://dx.doi.org/10.1073/pnas.89.1.70] [PMID:  1729720]

[72]
Yang, X.; Kurteva, S.; Ren, X.; Lee, S.; Sodroski, J. Stoichiometry of envelope glycoprotein trimers in the entry of human immunodefi-ciency virus type 1. J. Virol.,  2005, 79(19), 12132-12147.
 [http://dx.doi.org/10.1128/JVI.79.19.12132-12147.2005] [PMID:  16160141]

[73]
Fung, H.B.; Guo, Y. Enfuvirtide: A fusion inhibitor for the treatment of HIV infection. Clin. Ther.,  2004, 26(3), 352-378.
 [http://dx.doi.org/10.1016/S0149-2918(04)90032-X] [PMID:  15110129]

[74]
Qiu, S.; Yi, H.; Hu, J.; Cao, Z.; Wu, Y.; Li, W. The binding mode of fusion inhibitor T20 onto HIV-1 gp41 and relevant T20-resistant mechanisms explored by computational study. Curr. HIV Res.,  2012, 10(2), 182-194.
 [http://dx.doi.org/10.2174/157016212799937191] [PMID:  22339124]

[75]
Antanasijevic, A.; Ueda, G.; Brouwer, P.J.M.; Copps, J.; Huang, D.; Allen, J.D.; Cottrell, C.A.; Yasmeen, A.; Sewall, L.M.; Bontjer, I.; Ket-as, T.J.; Turner, H.L.; Berndsen, Z.T.; Montefiori, D.C.; Klasse, P.J.; Crispin, M.; Nemazee, D.; Moore, J.P.; Sanders, R.W.; King, N.P.; Baker, D.; Ward, A.B. Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens. PLoS Pathog.,  2020, 16(8), e1008665.
 [http://dx.doi.org/10.1371/journal.ppat.1008665] [PMID:  32780770]

[76]
Piai, Alessandro; Fu, Qingshan; Cai, Yongfei; Ghantous, Fadi; Xiao, Tianshu; Shaik, Md Munan; Peng, Hanqin; Rits-Volloch, Sophia; Chen, Wen; Seaman, Michael S.; Chen, Bing; Chou, James J. Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein. Nat. Commun.,  2020, 11, 1-12.
 [http://dx.doi.org/10.1038/s41467-020-16165-0]

[77]
Zhang, Shiyu; Holmes, Andrew P.; Dick, Alexej; Rashad, Adel A.; Rodríguez, L.Eucía Enríquez; Canziani, Gabriela A.; Root, Michael J.; Chaiken, Irwin M. Altered Env conformational dynamics as a mechanism of resistance to peptide-triazole HIV-1 inactivators. Retrovirology,  2021, 18, 1-18.
 [http://dx.doi.org/10.1186/s12977-021-00575-z]

[78]
Wu, X.; Wang, C.; O’Dell, S.; Li, Y.; Keele, B.F.; Yang, Z.; Imamichi, H.; Doria-Rose, N.; Hoxie, J.A.; Connors, M.; Shaw, G.M.; Wyatt, R.T.; Mascola, J.R. Selection pressure on HIV-1 envelope by broadly neutralizing antibodies to the conserved CD4-binding site. J. Virol.,  2012, 86(10), 5844-5856.
 [http://dx.doi.org/10.1128/JVI.07139-11] [PMID:  22419808]

[79]
Reeves, J.D.; Miamidian, J.L.; Biscone, M.J.; Lee, F-H.; Ahmad, N.; Pierson, T.C.; Doms, R.W. Impact of mutations in the coreceptor binding site on human immunodeficiency virus type 1 fusion, infection, and entry inhibitor sensitivity. J. Virol.,  2004, 78(10), 5476-5485.
 [http://dx.doi.org/10.1128/JVI.78.10.5476-5485.2004] [PMID:  15113926]

[80]
Gall, A.; Kaye, S.; Hué, S.; Bonsall, D.; Rance, R. Restriction of V3 region sequence divergence in the HIV-1 envelope gene during an-tiretroviral treatment in a cohort of recent seroconverters. Retrovirology,  2013, 10, 1-15.
 [http://dx.doi.org/10.1186/1742-4690-10-8]

[81]
Geller, R.; Domingo-Calap, P.; Cuevas, J.M.; Rossolillo, P.; Negroni, M.; Sanjuán, R. The external domains of the HIV-1 envelope are a mutational cold spot. Nat. Commun.,  2015, 6, 1-9.
 [http://dx.doi.org/10.1038/ncomms9571]

[82]
Lai, Y.T. Small molecule HIV-1 attachment inhibitors: Discovery, mode of action and structural basis of inhibition. Viruses,  2021, 13(5), 843.
 [http://dx.doi.org/10.3390/v13050843] [PMID:  34066522]

[83]
Woollard, S.M.; Kanmogne, G.D. Maraviroc: A review of its use in HIV infection and beyond. Drug Des. Devel. Ther.,  2015, 9, 5447-5468.
 [http://dx.doi.org/10.2147/DDDT.S90580] [PMID:  26491256]

[84]
Rowe, I.A.; Tully, D.C.; Armstrong, M.J.; Parker, R.; Guo, K.; Barton, D.; Morse, G.D.; Venuto, C.S.; Ogilvie, C.B.; Hedegaard, D.L.; McKelvy, J.F.; Wong-Staal, F.; Allen, T.M.; Balfe, P.; McKeating, J.A.; Mutimer, D.J. Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation. Liver Transpl.,  2016, 22(3), 287-297.
 [http://dx.doi.org/10.1002/lt.24349] [PMID:  26437376]

[85]
White, J.M.; Delos, S.E.; Brecher, M.; Schornberg, K. Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit. Rev. Biochem. Mol. Biol.,  2008, 43(3), 189-219.
 [http://dx.doi.org/10.1080/10409230802058320] [PMID:  18568847]

[86]
Barrett, C.T.; Dutch, R.E. Viral membrane fusion and the transmembrane domain. Viruses,  2020, 12(7), E693.
 [http://dx.doi.org/10.3390/v12070693] [PMID:  32604992]

[87]
Benhaim, M.A.; Lee, K.K. New biophysical approaches reveal the dynamics and mechanics of type I viral fusion machinery and their interplay with membranes. Viruses,  2020, 12(4), E413.
 [http://dx.doi.org/10.3390/v12040413] [PMID:  32276357]

[88]
Maginnis, M.S. Virus-receptor interactions: The key to cellular invasion. J. Mol. Biol.,  2018, 430(17), 2590-2611.
 [http://dx.doi.org/10.1016/j.jmb.2018.06.024] [PMID:  29924965]

[89]
Castagna, A.; Biswas, P.; Beretta, A.; Lazzarin, A. The appealing story of HIV entry inhibitors. Drugs,  2012, 65, 879-904.
 [http://dx.doi.org/10.2165/00003495-200565070-00001]

[90]
Caffrey, M. HIV envelope: Challenges and opportunities for development of entry inhibitors. Trends Microbiol.,  2011, 19(4), 191-197.
 [http://dx.doi.org/10.1016/j.tim.2011.02.001] [PMID:  21377881]

[91]
Molinos-Albert, L.M.; Carrillo, J.; Curriu, M.; Rodriguez de la Concepción, M.L.; Marfil, S.; García, E.; Clotet, B.; Blanco, J. Anti-MPER antibodies with heterogeneous neutralization capacity are detectable in most untreated HIV-1 infected individuals. Retrovirology,  2014, 11(1), 44.
 [http://dx.doi.org/10.1186/1742-4690-11-44] [PMID:  24909946]

[92]
González, N.; McKee, K.; Lynch, R.M.; Georgiev, I.S.; Jimenez, L.; Grau, E.; Yuste, E.; Kwong, P.D.; Mascola, J.R.; Alcamí, J. Characteri-zation of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors. PLoS One,  2018, 13(3), e0193773.
 [http://dx.doi.org/10.1371/journal.pone.0193773] [PMID:  29558468]

[93]
Luque, F.J.; Camarasa, M.J. HIV-1 envelope spike MPER: From a vaccine target to a new druggable pocket for novel and effective fusion inhibitors. ChemMedChem,  2021, 16(1), 105-107.
 [http://dx.doi.org/10.1002/cmdc.202000411] [PMID:  33428329]

[94]
Xiao, T.; Frey, G.; Fu, Q.; Lavine, C.L.; Scott, D.A.; Seaman, M.S.; Chou, J.J.; Chen, B. HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes. Nat. Chem. Biol.,  2020, 16(5), 529-537.
 [http://dx.doi.org/10.1038/s41589-020-0496-y] [PMID:  32152540]

[95]
Cai, L.; Gochin, M.; Liu, K. Biochemistry and biophysics of HIV-1 gp41 - membrane interactions and implications for HIV-1 envelope protein mediated viral-cell fusion and fusion inhibitor design. Curr. Top. Med. Chem.,  2011, 11(24), 2959-2984.
 [http://dx.doi.org/10.2174/156802611798808497] [PMID:  22044229]

[96]
Salzwedel, K.; John, T.W.; Eric, H. A conserved tryptophan-rich motif in the membrane-proximal region of the human immunodeficiency virus type 1 gp41 ectodomain is important for env-mediated fusion and virus infectivity. J. Virol.,  1999, 73(3), 2469-2480.

[97]
Gossert, S.T.; Parajuli, B.; Chaiken, I.; Abrams, C.F. Roles of conserved tryptophans in trimerization of HIV-1 membrane-proximal exter-nal regions: Implications for virucidal design via alchemical free-energy molecular simulations. Proteins,  2018, 86(7), 707-711.
 [http://dx.doi.org/10.1002/prot.25504] [PMID:  29633345]

[98]
Binley, J.M.; Wrin, T.; Korber, B.; Zwick, M.B.; Wang, M.; Chappey, C.; Stiegler, G.; Kunert, R.; Zolla-Pazner, S.; Katinger, H.; Petropou-los, C.J.; Burton, D.R. Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 mono-clonal antibodies. J. Virol.,  2004, 78(23), 13232-13252.
 [http://dx.doi.org/10.1128/JVI.78.23.13232-13252.2004] [PMID:  15542675]

[99]
Mascola, J.R.; Stiegler, G.; VanCott, T.C.; Katinger, H.; Carpenter, C.B.; Hanson, C.E.; Beary, H.; Hayes, D.; Frankel, S.S.; Birx, D.L.; Lew-is, M.G. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutraliz-ing antibodies. Nat. Med.,  2000, 6, 207-210.
 [http://dx.doi.org/10.1038/72318]

[100]
Ajamian, L.; Melnychuk, L.; Jean-Pierre, P.; Zaharatos, G.J. DNA vaccine-encoded flagellin can be used as an adjuvant scaffold to aug-ment HIV-1 gp41 membrane proximal external region immunogenicity. Viruses,  2018, 10(3), E100.
 [http://dx.doi.org/10.3390/v10030100] [PMID:  29495537]

[101]
Melnychuk, L.; Ajamian, L.; Jean-Pierre, P.; Liang, J.; Gheorghe, R.; Wainberg, M.A.; Zaharatos, G.J. Development of a DNA vaccine expressing a secreted HIV-1 gp41 ectodomain that includes the membrane-proximal external region. Vaccine,  2017, 35(20), 2736-2744.
 [http://dx.doi.org/10.1016/j.vaccine.2017.03.039] [PMID:  28392143]

[102]
Elbahnasawy, M.A.; Donius, L.R.; Reinherz, E.L.; Kim, M. Co-delivery of a CD4 T cell helper epitope via covalent liposome attachment with a surface-arrayed B cell target antigen fosters higher affinity antibody responses. Vaccine,  2018, 36(41), 6191-6201.
 [http://dx.doi.org/10.1016/j.vaccine.2018.08.014] [PMID:  30197285]

[103]
Zhang, Z.; Wei, X.; Lin, Y.; Huang, F.; Shao, J.; Qi, J.; Deng, T.; Li, Z.; Gao, S.; Li, S.; Yu, H.; Zhao, Q.; Li, S.; Gu, Y.; Xia, N. HIV-1 membrane-proximal external region fused to diphtheria toxin domain-A elicits 4E10-like antibodies in mice. Immunol. Lett.,  2019, 213, 30-38.
 [http://dx.doi.org/10.1016/j.imlet.2019.07.004] [PMID:  31356841]

[104]
Oakes, V.; Torralba, J.; Rujas, E.; Nieva, J.L.; Domene, C.; Apellaniz, B. Exposure of the HIV-1 broadly neutralizing antibody 10E8 MPER epitope on the membrane surface by gp41 transmembrane domain scaffolds. Biochim. Biophys. Acta Biomembr.,  2018, 1860(6), 1259-1271.
 [http://dx.doi.org/10.1016/j.bbamem.2018.02.019] [PMID:  29477358]

[105]
Irimia, A.; Sarkar, A.; Stanfield, R.L.; Wilson, I.A. Crystallographic identification of lipid as an integral component of the epitope of HIV broadly neutralizing antibody 4E10. Immunity,  2016, 44(1), 21-31.
 [http://dx.doi.org/10.1016/j.immuni.2015.12.001] [PMID:  26777395]

[106]
Irimia, A.; Serra, A.M.; Sarkar, A.; Jacak, R.; Kalyuzhniy, O.; Sok, D.; Saye-Francisco, K.L.; Schiffner, T.; Tingle, R.; Kubitz, M.; Adachi, Y.; Stanfield, R.L.; Deller, M.C.; Burton, D.R.; Schief, W.R.; Wilson, I.A. Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design. PLoS Pathog.,  2017, 13(2), e1006212.
 [http://dx.doi.org/10.1371/journal.ppat.1006212] [PMID:  28225819]

[107]
Fu, Q.; Shaik, M.M.; Cai, Y.; Ghantous, F.; Piai, A.; Peng, H.; Rits-Volloch, S.; Liu, Z.; Harrison, S.C.; Seaman, M.S.; Chen, B.; Chou, J.J. Structure of the membrane proximal external region of HIV-1 envelope glycoprotein. Proc. Natl. Acad. Sci. USA,  2018, 115(38), E8892-E8899.
 [http://dx.doi.org/10.1073/pnas.1807259115] [PMID:  30185554]

[108]
Chen, J.; Frey, G.; Peng, H.; Rits-Volloch, S.; Garrity, J.; Seaman, M.S.; Chen, B. Mechanism of HIV-1 neutralization by antibodies target-ing a membrane-proximal region of gp41. J. Virol.,  2014, 88(2), 1249-1258.
 [http://dx.doi.org/10.1128/JVI.02664-13] [PMID:  24227838]

[109]
Julien, J.P.; Bryson, S.; Nieva, J.L.; Pai, E.F. Structural details of HIV-1 recognition by the broadly neutralizing monoclonal antibody 2F5: Epitope conformation, antigen-recognition loop mobility, and anion-binding site. J. Mol. Biol.,  2008, 384(2), 377-392.
 [http://dx.doi.org/10.1016/j.jmb.2008.09.024] [PMID:  18824005]

[110]
Pejchal, R.; Gach, J.S.; Brunel, F.M.; Cardoso, R.M.; Stanfield, R.L.; Dawson, P.E.; Burton, D.R.; Zwick, M.B.; Wilson, I.A. A conforma-tional switch in human immunodeficiency virus gp41 revealed by the structures of overlapping epitopes recognized by neutralizing anti-bodies. J. Virol.,  2009, 83(17), 8451-8462.
 [http://dx.doi.org/10.1128/JVI.00685-09] [PMID:  19515770]

[111]
Kim, M.; Song, L.; Moon, J.; Sun, Z-Y.J.; Bershteyn, A.; Hanson, M.; Cain, D.; Goka, S.; Kelsoe, G.; Wagner, G.; Irvine, D.; Reinherz, E.L. Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry. J. Biol. Chem.,  2013, 288(44), 31888-31901.
 [http://dx.doi.org/10.1074/jbc.M113.494609] [PMID:  24047898]

[112]
Treanor, B. B-cell receptor: From resting state to activate. Immunology,  2012, 136(1), 21-27.
 [http://dx.doi.org/10.1111/j.1365-2567.2012.03564.x] [PMID:  22269039]

[113]
Rantalainen, K.; Berndsen, Z.T.; Antanasijevic, A.; Schiffner, T.; Zhang, X.; Lee, W-H.; Torres, J.L.; Zhang, L.; Irimia, A.; Copps, J.; Zhou, K.H.; Kwon, Y.D.; Law, W.H.; Schramm, C.A.; Verardi, R.; Krebs, S.J.; Kwong, P.D.; Doria-Rose, N.A.; Wilson, I.A.; Zwick, M.B.; Yates, J.R., III; Schief, W.R.; Ward, A.B. HIV-1 envelope and MPER antibody structures in lipid assemblies. Cell Rep.,  2020, 31(4), 107583.
 [http://dx.doi.org/10.1016/j.celrep.2020.107583] [PMID:  32348769]

[114]
Alam, S.M.; McAdams, M.; Boren, D.; Rak, M.; Scearce, R.M.; Gao, F.; Camacho, Z.T.; Gewirth, D.; Kelsoe, G.; Chen, P.; Haynes, B.F. The role of antibody polyspecificity and lipid reactivity in binding of broadly neutralizing anti-HIV-1 envelope human monoclonal anti-bodies 2F5 and 4E10 to glycoprotein 41 membrane proximal envelope epitopes. J. Immunol.,  2007, 178(7), 4424-4435.
 [http://dx.doi.org/10.4049/jimmunol.178.7.4424] [PMID:  17372000]

[115]
Kurupati, P.; Ramachandran, N.P.; Poh, C.L. Protective efficacy of DNA vaccines encoding outer membrane protein A and OmpK36 of Klebsiella pneumoniae in mice. Clin. Vaccine Immunol.,  2011, 18(1), 82-88.
 [http://dx.doi.org/10.1128/CVI.00275-10] [PMID:  21048001]

[116]
Corbett, Kizzmekia S.; Edwards, Darin K.; Leist, Sarah R.; Abiona, Olubukola M.; Boyoglu-Barnum, Seyhan; Gillespie, Rebecca A.; Himansu, Sunny; Schäfer, Alexandra; Ziwawo, Cynthia T.; DiPiazza, Anthony T.; Dinnon, Kenneth H.; Elbashir, Sayda M.; Shaw, Christine A.; Woods, Angela; Fritch, Ethan J.; Martinez, David R.; Bock, Kevin W.; Minai, Mahnaz; Nagata, Bianca M.; Hutchinson, Geoffrey B.; Wu, Kai; Henry, Carole; Bahl, Kapil; Garcia- Dominguez, Dario; Ma, LingZhi; Renzi, Isabella; Kong, Wing-Pui; Schmidt, Stephen D.; Wang, Lingshu; Zhang, Yi; Phung, Emily; Chang, Lauren A.; Loomis, Rebecca J.; Altaras, Nedim Emil; Narayanan, Elisabeth; Metkar, Mihir; Presnyak, Vlad; Liu, Cuiping; Louder, Mark K.; Shi, Wei; Leung, Kwanyee; Yang, Eun Sung; West, Ande; Gully, Kendra L.; Stevens, Laura J.; Wang, Nianshuang; Wrapp, Daniel; Doria-Rose, Nicole A.; Stewart-Jones, Guillaume; Bennett, Hamilton; Alvarado, Gabriela S.; Nason, Martha C.; Ruckwardt, Tracy J.; McLellan, Jason S.; Denison, Mark R.; Chappell, James D.; Moore, Ian N.; Morabito, Kaitlyn M.; Mascola, John R.; Baric, Ralph S.; Carfi, Andrea; Graham, Barney S. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature,  2020, 586, 567-571.
 [http://dx.doi.org/10.1038/s41586-020-2622-0]

[117]
Nakatani-Webster, E.; Hu, S-L.; Atkins, W.M.; Catalano, C.E. Assembly and characterization of gp160-nanodiscs: A new platform for biochemical characterization of HIV envelope spikes. J. Virol. Methods,  2015, 226, 15-24.
 [http://dx.doi.org/10.1016/j.jviromet.2015.09.011] [PMID:  26424619]

[118]
Rouck, J.E.; Krapf, J.E.; Roy, J.; Huff, H.C.; Das, A. Recent advances in nanodisc technology for membrane protein studies (2012-2017). FEBS Lett.,  2017, 591(14), 2057-2088.
 [http://dx.doi.org/10.1002/1873-3468.12706] [PMID:  28581067]

[119]
Bibow, S. Exploring lipid and membrane protein dynamics using lipid-bilayer nanodiscs and solution-state NMR spectroscopy. Methods Mol. Biol.,  2020, 2127, 397-419.
 [http://dx.doi.org/10.1007/978-1-0716-0373-4_25] [PMID:  32112335]

[120]
Bayburt, T.H.; Sligar, S.G. Membrane protein assembly into Nanodiscs. FEBS Lett.,  2010, 584(9), 1721-1727.
 [http://dx.doi.org/10.1016/j.febslet.2009.10.024] [PMID:  19836392]

[121]
Efremov, R.G.; Gatsogiannis, C.; Raunser, S. Lipid nanodiscs as a tool for high-resolution structure determination of membrane proteins by single-particle Cryo-EM. Methods Enzymol.,  2017, 594, 1-30.
 [http://dx.doi.org/10.1016/bs.mie.2017.05.007] [PMID:  28779836]

[122]
Witt, K.C.; Castillo-Menendez, L.; Ding, H.; Espy, N.; Zhang, S.; Kappes, J.C.; Sodroski, J. Antigenic characterization of the human immu-nodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs. PLoS One,  2017, 12(2), e0170672.
 [http://dx.doi.org/10.1371/journal.pone.0170672] [PMID:  28151945]

[123]
Bhattacharya, P.; Grimme, S.; Ganesh, B.; Gopisetty, A.; Sheng, J.R.; Martinez, O.; Jayarama, S.; Artinger, M.; Meriggioli, M.; Prabhakar, B.S. Nanodisc-incorporated hemagglutinin provides protective immunity against influenza virus infection. J. Virol.,  2010, 84(1), 361-371.
 [http://dx.doi.org/10.1128/JVI.01355-09] [PMID:  19828606]

[124]
Justesen, B.H.; Günther-Pomorski, T. Chromatographic and electrophoretic methods for nanodisc purification and analysis. Rev. Anal. Chem.,  2014, 33(3), 165-172.
 [http://dx.doi.org/10.1515/revac-2014-0014]

[125]
Soto, C.; Ofek, G.; Joyce, M.G.; Zhang, B.; McKee, K.; Longo, N.S.; Yang, Y.; Huang, J.; Parks, R.; Eudailey, J.; Lloyd, K.E.; Alam, S.M.; Haynes, B.F.; Mullikin, J.C.; Connors, M.; Mascola, J.R.; Shapiro, L.; Kwong, P.D. Developmental pathway of the mper-directed HIV-1-neutralizing antibody 10E8. PLoS One,  2016, 11(6), e0157409.
 [http://dx.doi.org/10.1371/journal.pone.0157409] [PMID:  27299673]

[126]
Burton, D.R.; Stanfield, R.L.; Wilson, I.A. Antibody vs. HIV in a clash of evolutionary titans. Proc. Natl. Acad. Sci. USA,  2005, 102(42), 14943-14948.
 [http://dx.doi.org/10.1073/pnas.0505126102] [PMID:  16219699]

[127]
Gray, E.S.; Madiga, M.C.; Hermanus, T.; Moore, P.L.; Wibmer, C.K.; Tumba, N.L.; Werner, L.; Mlisana, K.; Sibeko, S.; Williamson, C.; Abdool Karim, S.S.; Morris, L. The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection. J. Virol.,  2011, 85(10), 4828-4840.
 [http://dx.doi.org/10.1128/JVI.00198-11] [PMID:  21389135]

[128]
Mikell, I.; Sather, D.N.; Kalams, S.A.; Altfeld, M.; Alter, G.; Stamatatos, L. Characteristics of the earliest cross-neutralizing antibody re-sponse to HIV-1. PLoS Pathog.,  2011, 7(1), e1001251.
 [http://dx.doi.org/10.1371/journal.ppat.1001251] [PMID:  21249232]

[129]
Huang, J.; Ofek, G.; Laub, L.; Louder, M.K.; Doria-Rose, N.A.; Longo, N.S.; Imamichi, H.; Bailer, R.T.; Chakrabarti, B.; Sharma, S.K.; Alam, S.M.; Wang, T.; Yang, Y.; Zhang, B.; Migueles, S.A.; Wyatt, R.; Haynes, B.F.; Kwong, P.D.; Mascola, J.R.; Connors, M. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature,  2012, 491(7424), 406-412.
 [http://dx.doi.org/10.1038/nature11544] [PMID:  23151583]

[130]
Sather, D.N.; Carbonetti, S.; Malherbe, D.C.; Pissani, F.; Stuart, A.B.; Hessell, A.J.; Gray, M.D.; Mikell, I.; Kalams, S.A.; Haigwood, N.L.; Stamatatos, L. Emergence of broadly neutralizing antibodies and viral coevolution in two subjects during the early stages of infection with human immunodeficiency virus type 1. J. Virol.,  2014, 88(22), 12968-12981.
 [http://dx.doi.org/10.1128/JVI.01816-14] [PMID:  25122781]

[131]
Krebs, S.J.; Kwon, Y.D.; Schramm, C.A.; Law, W.H.; Donofrio, G.; Zhou, K.H.; Gift, S.; Dussupt, V.; Georgiev, I.S.; Schätzle, S.; McDan-iel, J.R.; Lai, Y-T.; Sastry, M.; Zhang, B.; Jarosinski, M.C.; Ransier, A.; Chenine, A.L.; Asokan, M.; Bailer, R.T.; Bose, M.; Cagigi, A.; Cale, E.M.; Chuang, G-Y.; Darko, S.; Driscoll, J.I.; Druz, A.; Gorman, J.; Laboune, F.; Louder, M.K.; McKee, K.; Mendez, L.; Moody, M.A.; O’Sullivan, A.M.; Owen, C.; Peng, D.; Rawi, R.; Sanders-Buell, E.; Shen, C-H.; Shiakolas, A.R.; Stephens, T.; Tsybovsky, Y.; Tuck-er, C.; Verardi, R.; Wang, K.; Zhou, J.; Zhou, T.; Georgiou, G.; Alam, S.M.; Haynes, B.F.; Rolland, M.; Matyas, G.R.; Polonis, V.R.; McDermott, A.B.; Douek, D.C.; Shapiro, L.; Tovanabutra, S.; Michael, N.L.; Mascola, J.R.; Robb, M.L.; Kwong, P.D.; Doria-Rose, N.A. Longitudinal analysis reveals early development of three MPER-directed neutralizing antibody lineages from an HIV-1-infected individual. Immunity,  2019, 50(3), 677-691.e13.
 [http://dx.doi.org/10.1016/j.immuni.2019.02.008] [PMID:  30876875]

[132]
Regules, J.A.; Cicatelli, S.B.; Bennett, J.W.; Paolino, K.M.; Twomey, P.S.; Moon, J.E.; Kathcart, A.K.; Hauns, K.D.; Komisar, J.L.; Qabar, A.N.; Davidson, S.A.; Dutta, S.; Griffith, M.E.; Magee, C.D.; Wojnarski, M.; Livezey, J.R.; Kress, A.T.; Waterman, P.E.; Jongert, E.; Wille-Reece, U.; Volkmuth, W.; Emerling, D.; Robinson, W.H.; Lievens, M.; Morelle, D.; Lee, C.K.; Yassin-Rajkumar, B.; Weltzin, R.; Cohen, J.; Paris, R.M.; Waters, N.C.; Birkett, A.J.; Kaslow, D.C.; Ballou, W.R.; Ockenhouse, C.F.; Vekemans, J. Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: A phase 2a controlled human malaria parasite infection and immunogenicity study. J. Infect. Dis.,  2016, 214(5), 762-771.
 [http://dx.doi.org/10.1093/infdis/jiw237] [PMID:  27296848]

[133]
Ockenhouse, C.F.; Regules, J.; Tosh, D.; Cowden, J.; Kathcart, A.; Cummings, J.; Paolino, K.; Moon, J.; Komisar, J.; Kamau, E.; Oliver, T.; Chhoeu, A.; Murphy, J.; Lyke, K.; Laurens, M.; Birkett, A.; Lee, C.; Weltzin, R.; Wille-Reece, U.; Sedegah, M.; Hendriks, J.; Versteege, I.; Pau, M.G.; Sadoff, J.; Vanloubbeeck, Y.; Lievens, M.; Heerwegh, D.; Moris, P.; Guerra Mendoza, Y.; Jongert, E.; Cohen, J.; Voss, G.; Bal-lou, W.R.; Vekemans, J. Ad35.CS.01-RTS,S/AS01 Heterologous prime boost vaccine efficacy against sporozoite challenge in healthy Ma-laria-Naïve adults. PLoS One,  2015, 10(7), e0131571.
 [http://dx.doi.org/10.1371/journal.pone.0131571] [PMID:  26148007]

[134]
Kester, K.E.; Cummings, J.F.; Ofori-Anyinam, O.; Ockenhouse, C.F.; Krzych, U.; Moris, P.; Schwenk, R.; Nielsen, R.A.; Debebe, Z.; Pinelis, E.; Juompan, L.; Williams, J.; Dowler, M.; Stewart, V.A.; Wirtz, R.A.; Dubois, M.C.; Lievens, M.; Cohen, J.; Ballou, W.R.; Hep-pner, D.G. Jr Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J. Infect. Dis.,  2009, 200(3), 337-346.
 [http://dx.doi.org/10.1086/600120] [PMID:  19569965]

[135]
Pallikkuth, S.; Chaudhury, S.; Lu, P.; Pan, L.; Jongert, E.; Wille-Reece, U.; Pahwa, S. A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses. eLife,  2020, 9, e51889.
 [http://dx.doi.org/10.7554/eLife.51889] [PMID:  32342859]

[136]
Kristin, M.S. Schroeder; Amanda, Agazio.; Raul, M. Torres, “Immunological tolerance as a barrier to protective HIV humoral immunity. Curr. Opin. Immunol.,  2017, 47, 26-34.
 [http://dx.doi.org/10.1016/j.coi.2017.06.004]

[137]
Finney, J.; Kelsoe, G. Poly- and autoreactivity of HIV-1 bNAbs: Implications for vaccine design. Retrovirology,  2018, 15(1), 53.
 [http://dx.doi.org/10.1186/s12977-018-0435-0] [PMID:  30055635]

[138]
Bonsignori, M.; Wiehe, K.; Grimm, S.K.; Lynch, R.; Yang, G.; Kozink, D.M.; Perrin, F.; Cooper, A.J.; Hwang, K-K.; Chen, X.; Liu, M.; McKee, K.; Parks, R.J.; Eudailey, J.; Wang, M.; Clowse, M.; Criscione-Schreiber, L.G.; Moody, M.A.; Ackerman, M.E.; Boyd, S.D.; Gao, F.; Kelsoe, G.; Verkoczy, L.; Tomaras, G.D.; Liao, H-X.; Kepler, T.B.; Montefiori, D.C.; Mascola, J.R.; Haynes, B.F. An autoreactive anti-body from an SLE/HIV-1 individual broadly neutralizes HIV-1. J. Clin. Invest.,  2014, 124(4), 1835-1843.
 [http://dx.doi.org/10.1172/JCI73441] [PMID:  24614107]

[139]
Liu, M.; Yang, G.; Wiehe, K.; Nicely, N.I.; Vandergrift, N.A.; Rountree, W.; Bonsignori, M.; Alam, S.M.; Gao, J.; Haynes, B.F.; Kelsoe, G. Polyreactivity and autoreactivity among HIV-1 antibodies. J. Virol.,  2015, 89(1), 784-798.
 [http://dx.doi.org/10.1128/JVI.02378-14] [PMID:  25355869]

[140]
Schroeder, K.M.S.; Agazio, A.; Strauch, P.J.; Jones, S.T.; Thompson, S.B.; Harper, M.S.; Pelanda, R.; Santiago, M.L.; Torres, R.M. Breach-ing peripheral tolerance promotes the production of HIV-1-neutralizing antibodies. J. Exp. Med.,  2017, 214(8), 2283-2302.
 [http://dx.doi.org/10.1084/jem.20161190] [PMID:  28698284]

[141]
Haynes, B.F.; Moody, M.A.; Verkoczy, L.; Kelsoe, G.; Alam, S.M. Antibody polyspecificity and neutralization of HIV-1: A hypothesis. Hum. Antibodies,  2005, 14(3-4), 59-67.
 [http://dx.doi.org/10.3233/HAB-2005-143-402] [PMID:  16720975]

[142]
Verkoczy, L.; Diaz, M. Autoreactivity in HIV-1 broadly neutralizing antibodies: Implications for their function and induction by vaccina-tion. Curr. Opin. HIV AIDS,  2014, 9(3), 224-234.
 [http://dx.doi.org/10.1097/COH.0000000000000049] [PMID:  24714565]

[143]
Reed, J.H.; Jackson, J.; Christ, D.; Goodnow, C.C. Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization. J. Exp. Med.,  2016, 213(7), 1255-1265.
 [http://dx.doi.org/10.1084/jem.20151978] [PMID:  27298445]

[144]
Sabouri, Z.; Schofield, P.; Horikawa, K.; Spierings, E.; Kipling, D.; Randall, K.L.; Langley, D.; Roome, B.; Vazquez-Lombardi, R.; Rouet, R.; Hermes, J.; Chan, T.D.; Brink, R.; Dunn-Walters, D.K.; Christ, D.; Goodnow, C.C. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc. Natl. Acad. Sci. USA,  2014, 111(25), E2567-E2575.
 [http://dx.doi.org/10.1073/pnas.1406974111] [PMID:  24821781]

[145]
Tomasello, G.; Armenia, I.; Molla, G. The Protein Imager: A full-featured online molecular viewer interface with server-side HQ-rendering capabilities. Bioinformatics,  2020, 36(9), 2909-2911.
 [http://dx.doi.org/10.1093/bioinformatics/btaa009] [PMID:  31930403]
Cite As
Current Protein & Peptide Science

Peptide Triazole Inhibitors of HIV-1: Hijackers of Env Metastability

Abstract

Graphical Abstract
