1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Antibodies Targeting the Envelope of HIV-1

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • XML
    114.24 Kb
  • HTML
    117.68 Kb
  • PDF
    248.62 Kb
  • Authors: Luzia M. Mayr1, Susan Zolla-Pazner3
  • Editors: James E. Crowe Jr.5, Diana Boraschi6, Rino Rappuoli7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: New York Veterans Affairs Harbor Healthcare System, New York, NY 10010; 2: New York University School of Medicine, New York, NY 10016; 3: New York Veterans Affairs Harbor Healthcare System, New York, NY 10010; 4: New York University School of Medicine, New York, NY 10016; 5: Vanderbilt University School of Medicine, Nashville, TN; 6: National Research Council, Pisa, Italy; 7: Novartis Vaccines, Siena, Italy
  • Source: microbiolspec January 2015 vol. 3 no. 1 doi:10.1128/microbiolspec.AID-0025-2014
  • Received 10 November 2014 Accepted 15 November 2014 Published 16 January 2015
  • Susan Zolla-Pazner, zollas01@med.nyu.edu
image of Antibodies Targeting the Envelope of HIV-1
    Preview this microbiology spectrum article:
    Zoom in
    Zoomout

    Antibodies Targeting the Envelope of HIV-1, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/3/1/AID-0025-2014-1.gif /docserver/preview/fulltext/microbiolspec/3/1/AID-0025-2014-2.gif
  • Abstract:

    Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, “conventional Abs” are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, “exceptional Abs” require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs.

  • Citation: Mayr L, Zolla-Pazner S. 2015. Antibodies Targeting the Envelope of HIV-1. Microbiol Spectrum 3(1):AID-0025-2014. doi:10.1128/microbiolspec.AID-0025-2014.

References

2. Mascola JR, Montefiori DC. 2003. HIV-1: nature's master of disguise. Nat Med 9:393–394.[PubMed][CrossRef]
3. Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, Komarova NL, Nowak MA, Hahn BH, Kwong PD, Shaw GM. 2003. Antibody neutralization and escape by HIV-1. Nature 422:307–312.[PubMed][CrossRef]
4. Kumar R, Tuen M, Liu J, Nadas A, Pan R, Kong X, Hioe CE. 2013. Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines. Vaccine 31:5413–5421. [PubMed][CrossRef]
5. Hioe CE, Kumar R, Hu S-L. 2014. The influence of HIV envelope glycosylation on adaptive immune response, p. 59–83. In Pantophlet R (ed), HIV Glycans in Infection and Immunity. Springer Science + Business Media, New York, NY. [CrossRef]
6. Robertson DL, Sharp PM, McCutchan FE, Hahn BH. 1995. Recombination in HIV-1. Nature 374:124–126. [PubMed][CrossRef]
7. Richman DD, Wrin T, Little SJ, Petropoulos CJ. 2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci USA 100:4144–4149. [PubMed][CrossRef]
8. Moore PL, Ranchobe N, Lambson BE, Gray ES, Cave E, Abrahams MR, Bandawe G, Mlisana K, Abdool Karim SS, Williamson C, Morris L. 2009. Limited neutralizing antibody specificities drive neutralization escape in early HIV-1 subtype C infection. PLoS Pathog 5:e1000598. doi:10.1371/journal.ppat.1000598. [PubMed][CrossRef]
9. Liao HX, Lynch R, Zhou T, Gao F, Alam SM, Boyd SD, Fire AZ, Roskin KM, Schramm CA, Zhang Z, Zhu J, Shapiro L, Mullikin JC, Gnanakaran S, Hraber P, Wiehe K, Kelsoe G, Yang G, Xia SM, Montefiori DC, Parks R, Lloyd KE, Scearce RM, Soderberg KA, Cohen M, Kamanga G, Louder MK, Tran LM, Chen Y, Cai F, Chen S, Moquin S, Du X, Joyce MG, Srivatsan S, Zhang B, Zheng A, Shaw GM, Hahn BH, Kepler TB, Korber BT, Kwong PD, Mascola JR, Haynes BF. 2013. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496:469–476. [PubMed][CrossRef]
10. Hemelaar J. 2012. Implications of HIV diversity for the HIV-1 pandemic. J Infect 66:391–400. [PubMed][CrossRef]
11. Rusert P, Krarup A, Magnus C, Brandenberg OF, Weber J, Ehlert AK, Regoes RR, Gunthard HF, Trkola A. 2011. Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies. J Exp Med 208:1419–1433. [PubMed][CrossRef]
12. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD. 2010. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329:811–817. [PubMed][CrossRef]
13. Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O'Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR. 2011. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333:1593–1602. [PubMed][CrossRef]
14. Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA, Majeed S, Steenbeke TD, Venturi M, Chaiken I, Fung M, Katinger H, Parren PW, Robinson J, Van Ryk D, Wang L, Burton DR, Freire E, Wyatt R, Sodroski J, Hendrickson WA, Arthos J. 2002. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420:678–682. [PubMed][CrossRef]
15. Korkut A, Hendrickson WA. 2012. Structural plasticity and conformational transitions of HIV envelope glycoprotein gp120. PloS One 7:e52170. doi:10.1371/journal.pone.0052170. [PubMed][CrossRef]
16. Shrivastava IH, Wendel K, LaLonde JM. 2012. Spontaneous rearrangement of the beta20/beta21 strands in simulations of unliganded HIV-1 glycoprotein, gp120. Biochemistry 51:7783–7793. [PubMed][CrossRef]
17. Zolla-Pazner S. 2014. A critical question for HIV vaccine development: which antibodies to induce? Science 345:167–168. [PubMed][CrossRef]
18. Gorny MK, Pan R, Williams C, Wang XH, Volsky B, O'Neal T, Spurrier B, Sampson JM, Li L, Seaman MS, Kong XP, Zolla-Pazner S. 2012. Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals. Virology 427:198–207. [PubMed][CrossRef]
19. Prince AM, Reesink H, Pascual D, Horowitz B, Hewlett I, Murthy KK, Cobb KE, Eichberg JW. 1991. Prevention of HIV infection by passive immunization with HIV immunoglobulin. AIDS Res Hum Retroviruses 7:971–973. [PubMed][CrossRef]
20. Bar KJ, Tsao CY, Iyer SS, Decker JM, Yang Y, Bonsignori M, Chen X, Hwang KK, Montefiori DC, Liao HX, Hraber P, Fischer W, Li H, Wang S, Sterrett S, Keele BF, Ganusov VV, Perelson AS, Korber BT, Georgiev I, McLellan JS, Pavlicek JW, Gao F, Haynes BF, Hahn BH, Kwong PD, Shaw GM. 2012. Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. PLoS Pathog 8:e1002721. doi:10.1371/journal.ppat.1002721. [PubMed][CrossRef]
21. Hioe CE, Wrin T, Seaman MS, Yu X, Wood B, Self S, Williams C, Gorny MK, Zolla-Pazner S. 2010. Anti-V3 monoclonal antibodies display broad neutralizing activities against multiple HIV-1 subtypes. PloS One 5:e10254. doi:10.1371/journal.pone.0010254. [PubMed][CrossRef]
22. Li L, Wang XH, Banerjee S, Volsky B, Williams C, Virland D, Nadas A, Seaman MS, Chen X, Spearman P, Zolla-Pazner S, Gorny MK. 2012. Different pattern of immunoglobulin gene usage by HIV-1 compared to non-HIV-1 antibodies derived from the same infected subject. PloS One 7:e39534. doi:10.1371/journal.pone.0039534. [PubMed][CrossRef]
23. Karasavvas N, Billings E, Rao M, Williams C, Zolla-Pazner S, Bailer RT, Koup RA, Madnote S, Arworn D, Shen X, Tomaras GD, Currier JR, Jiang M, Magaret C, Andrews C, Gottardo R, Gilbert P, Cardozo TJ, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Paris R, Greene K, Gao H, Gurunathan S, Tartaglia J, Sinangil F, Korber BT, Montefiori DC, Mascola JR, Robb ML, Haynes BF, Ngauy V, Michael NL, Kim JH, de Souza MS. 2012. The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses 28:1444–1457. [PubMed][CrossRef]
24. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH. 2012. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 366:1275–1286. [PubMed][CrossRef]
25. Zolla-Pazner S, deCamp AC, Cardozo T, Karasavvas N, Gottardo R, Williams C, Morris DE, Tomaras G, Rao M, Billings E, Berman P, Shen X, Andrews C, O'Connell RJ, Ngauy V, Nitayaphan S, de Souza M, Korber B, Koup R, Bailer RT, Mascola JR, Pinter A, Montefiori D, Haynes BF, Robb ML, Rerks-Ngarm S, Michael NL, Gilbert PB, Kim JH. 2013. Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PloS One 8:e53629. doi:10.1371/journal.pone.0053629. [PubMed][CrossRef]
26. Zolla-Pazner S, deCamp A, Gilbert PB, Williams C, Yates NL, Williams WT, Howington R, Fong Y, Morris DE, Soderberg KA, Irene C, Reichman C, Pinter A, Parks R, Pitisuttithum P, Kaewkungwal J, Rerks-Ngarm S, Nitayaphan S, Andrews C, O'Connell RJ, Yang ZY, Nabel GJ, Kim JH, Michael NL, Montefiori DC, Liao HX, Haynes BF, Tomaras GD. 2014. Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PloS One 9:e87572. doi:10.1371/journal.pone.0087572. [PubMed][CrossRef]
27. Yates NL, Liao HX, Fong Y, deCamp A, Vandergrift NA, Williams WT, Alam SM, Ferrari G, Yang ZY, Seaton KE, Berman PW, Alpert MD, Evans DT, O'Connell RJ, Francis D, Sinangil F, Lee C, Nitayaphan S, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, Pinter A, Zolla-Pazner S, Gilbert PB, Nabel GJ, Michael NL, Kim JH, Montefiori DC, Haynes BF, Tomaras GD. 2014. Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Science Trans Med 6:228–239. [PubMed][CrossRef]
28. Gottardo R, Bailer RT, Korber BT, Gnanakaran S, Phillips J, Shen X, Tomaras GD, Turk E, Imholte G, Eckler L, Wenschuh H, Zerweck J, Greene K, Gao H, Berman PW, Francis D, Sinangil F, Lee C, Nitayaphan S, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, Robb ML, Michael NL, Kim JH, Zolla-Pazner S, Haynes BF, Mascola JR, Self S, Gilbert P, Montefiori DC. 2013. Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial. PloS One 8:e75665. doi:10.1371/journal.pone.0075665. [PubMed][CrossRef]
29. Montefiori DC, Karnasuta C, Huang Y, Ahmed H, Gilbert P, de Souza MS, McLinden R, Tovanabutra S, Laurence-Chenine A, Sanders-Buell E, Moody MA, Bonsignori M, Ochsenbauer C, Kappes J, Tang H, Greene K, Gao H, LaBranche CC, Andrews C, Polonis VR, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Self SG, Berman PW, Francis D, Sinangil F, Lee C, Tartaglia J, Robb ML, Haynes BF, Michael NL, Kim JH. 2012. Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials. J Infect Dis 206:431–441. [PubMed][CrossRef]
30. Liao HX, Bonsignori M, Alam SM, McLellan JS, Tomaras GD, Moody MA, Kozink DM, Hwang KK, Chen X, Tsao CY, Liu P, Lu X, Parks RJ, Montefiori DC, Ferrari G, Pollara J, Rao M, Peachman KK, Santra S, Letvin NL, Karasavvas N, Yang ZY, Dai K, Pancera M, Gorman J, Wiehe K, Nicely NI, Rerks-Ngarm S, Nitayaphan S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, Sinangil F, Kim JH, Michael NL, Kepler TB, Kwong PD, Mascola JR, Nabel GJ, Pinter A, Zolla-Pazner S, Haynes BF. 2013. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 38:176–186. [PubMed][CrossRef]
31. Moody MA, Zhang R, Walter EB, Woods CW, Ginsburg GS, McClain MT, Denny TN, Chen X, Munshaw S, Marshall DJ, Whitesides JF, Drinker MS, Amos JD, Gurley TC, Eudailey JA, Foulger A, DeRosa KR, Parks R, Meyerhoff RR, Yu JS, Kozink DM, Barefoot BE, Ramsburg EA, Khurana S, Golding H, Vandergrift NA, Alam SM, Tomaras GD, Kepler TB, Kelsoe G, Liao HX, Haynes BF. 2011. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PloS One 6:e25797. doi:10.1371/journal.pone.0025797. [PubMed][CrossRef]
32. Seaman MS, Janes H, Hawkins N, Grandpre LE, Devoy C, Giri A, Coffey RT, Harris L, Wood B, Daniels MG, Bhattacharya T, Lapedes A, Polonis VR, McCutchan FE, Gilbert PB, Self SG, Korber BT, Montefiori DC, Mascola JR. 2010. Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J Virol 84:1439–1452. [PubMed][CrossRef]
33. Zolla-Pazner S, Kong XP, Jiang X, Cardozo T, Nadas A, Cohen S, Totrov M, Seaman MS, Wang S, Lu S. 2011. Cross-clade HIV-1 neutralizing antibodies induced with V3-scaffold protein immunogens following priming with gp120 DNA. J Virol 85:9887–9898. [PubMed][CrossRef]
34. Cardozo T, Wang S, Jiang X, Kong XP, Hioe C, Krachmarov C. 2014. Vaccine focusing to cross-subtype HIV-1 gp120 variable loop epitopes. Vaccine 32:4916–4924. [PubMed][CrossRef]
35. Sather DN, Armann J, Ching LK, Mavrantoni A, Sellhorn G, Caldwell Z, Yu X, Wood B, Self S, Kalams S, Stamatatos L. 2009. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J Virol 83:757–769. [PubMed][CrossRef]
36. Simek MD, Rida W, Priddy FH, Pung P, Carrow E, Laufer DS, Lehrman JK, Boaz M, Tarragona-Fiol T, Miiro G, Birungi J, Pozniak A, McPhee DA, Manigart O, Karita E, Inwoley A, Jaoko W, Dehovitz J, Bekker LG, Pitisuttithum P, Paris R, Walker LM, Poignard P, Wrin T, Fast PE, Burton DR, Koff WC. 2009. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J Virol 83:7337–7348. [PubMed][CrossRef]
37. Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW, Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DR. 2009. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326:285–289. [PubMed][CrossRef]
38. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD, Koff WC, Wilson IA, Burton DR, Poignard P. 2011. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477:466–470. [PubMed][CrossRef]
39. Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O'Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR. 2010. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329:856–861. [PubMed][CrossRef]
40. Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, Imamichi H, Bailer RT, Chakrabarti B, Sharma SK, Alam SM, Wang T, Yang Y, Zhang B, Migueles SA, Wyatt R, Haynes BF, Kwong PD, Mascola JR, Connors M. 2012. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491:406–412. [PubMed][CrossRef]
41. Morris L, Chen X, Alam M, Tomaras G, Zhang R, Marshall DJ, Chen B, Parks R, Foulger A, Jaeger F, Donathan M, Bilska M, Gray ES, Abdool Karim SS, Kepler TB, Whitesides J, Montefiori D, Moody MA, Liao HX, Haynes BF. 2011. Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting. PloS One 6:e23532. doi:10.1371/journal.pone.0023532. [CrossRef]
42. Klein F, Diskin R, Scheid JF, Gaebler C, Mouquet H, Georgiev IS, Pancera M, Zhou T, Incesu RB, Fu BZ, Gnanapragasam PN, Oliveira TY, Seaman MS, Kwong PD, Bjorkman PJ, Nussenzweig MC. 2013. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153:126–138. [PubMed][CrossRef]
43. Sok D, Laserson U, Laserson J, Liu Y, Vigneault F, Julien JP, Briney B, Ramos A, Saye KF, Le K, Mahan A, Wang S, Kardar M, Yaari G, Walker LM, Simen BB, St John EP, Chan-Hui PY, Swiderek K, Kleinstein SH, Alter G, Seaman MS, Chakraborty AK, Koller D, Wilson IA, Church GM, Burton DR, Poignard P. 2013. The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. PLoS Pathog 9:e1003754. doi:10.1371/journal.ppat.1003754. [PubMed][CrossRef]
44. Mascola JR, Haynes BF. 2013. HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol Rev 254:225–244. [PubMed][CrossRef]
45. Yu L, Guan Y. 2014. Immunologic basis for long HCDR3s in broadly neutralizing antibodies against HIV-1. Front Immunol 5:250. [PubMed][CrossRef]
46. Verkoczy L, Diaz M. 2014. Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination. Curr Opin HIV AIDS 9:224–234. [PubMed][CrossRef]
47. Haynes BF, Fleming J, St Clair EW, Katinger H, Stiegler G, Kunert R, Robinson J, Scearce RM, Plonk K, Staats HF, Ortel TL, Liao HX, Alam SM. 2005. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308:1906–1908. [PubMed][CrossRef]
48. Moldt B, Rakasz EG, Schultz N, Chan-Hui PY, Swiderek K, Weisgrau KL, Piaskowski SM, Bergman Z, Watkins DI, Poignard P, Burton DR. 2012. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc Natl Acad Sci USA 109:18921–18925. [PubMed][CrossRef]
49. Parren PW, Marx PA, Hessell AJ, Luckay A, Harouse J, Cheng-Mayer C, Moore JP, Burton DR. 2001. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol 75:8340–8347. [PubMed][CrossRef]
50. Hessell AJ, Rakasz EG, Poignard P, Hangartner L, Landucci G, Forthal DN, Koff WC, Watkins DI, Burton DR. 2009. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog 5:e1000433. doi:10.1371/journal.ppat.1000433. [PubMed][CrossRef]
51. Hessell AJ, Rakasz EG, Tehrani DM, Huber M, Weisgrau KL, Landucci G, Forthal DN, Koff WC, Poignard P, Watkins DI, Burton DR. 2010. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol 84:1302–1313. [PubMed][CrossRef]
52. Haynes BF, Verkoczy L. 2014. AIDS/HIV. Host controls of HIV neutralizing antibodies. Science 344:588–589. [PubMed][CrossRef]
53. Pegu A, Yang ZY, Boyington JC, Wu L, Ko SY, Schmidt SD, McKee K, Kong WP, Shi W, Chen X, Todd JP, Letvin NL, Huang J, Nason MC, Hoxie JA, Kwong PD, Connors M, Rao SS, Mascola JR, Nabel GJ. 2014. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci Trans Med 6:243–288. [PubMed][CrossRef]
54. Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, Nabel GJ, Nason MC, Montefiori D, Moldt B, Poignard P, Diskin R, Bjorkman PJ, Eckhaus MA, Klein F, Mouquet H, Cetrulo Lorenzi JC, Gazumyan A, Burton DR, Nussenzweig MC, Martin MA, Nishimura Y. 2014. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med 211:2061–2074. [PubMed][CrossRef]
55. Watkins JD, Siddappa NB, Lakhashe SK, Humbert M, Sholukh A, Hemashettar G, Wong YL, Yoon JK, Wang W, Novembre FJ, Villinger F, Ibegbu C, Patel K, Corti D, Agatic G, Vanzetta F, Bianchi S, Heeney JL, Sallusto F, Lanzavecchia A, Ruprecht RM. 2011. An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV. PloS One 6:e18207. doi:10.1371/journal.pone.0018207. [PubMed][CrossRef]
56. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, Nogueira L, Eisenreich TR, Liu C, Gazumyan A, Schaefer U, Furze RC, Seaman MS, Prinjha R, Tarakhovsky A, Ravetch JV, Nussenzweig MC. 2014. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989–999. [PubMed][CrossRef]
57. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, Stephenson KE, Chang HW, Shekhar K, Gupta S, Nkolola JP, Seaman MS, Smith KM, Borducchi EN, Cabral C, Smith JY, Blackmore S, Sanisetty S, Perry JR, Beck M, Lewis MG, Rinaldi W, Chakraborty AK, Poignard P, Nussenzweig MC, Burton DR. 2013. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503:224–228. [PubMed]
58. Klein F, Nogueira L, Nishimura Y, Phad G, West AP, Jr, Halper-Stromberg A, Horwitz JA, Gazumyan A, Liu C, Eisenreich TR, Lehmann C, Fatkenheuer G, Shingai M, Martin M, Bjorkman PJ, Seaman MS, Zolla-Pazner S, Hedestam G, Nussenzweig MC. 2014. Enhanced HIV-1 immunotherapy by naturally arising antibodies targeting resistant variants. J Exp Med 211:2361–2372. [PubMed][CrossRef]
59. Wu X, Parast AB, Richardson BA, Nduati R, John-Stewart G, Mbori-Ngacha D, Rainwater SM, Overbaugh J. 2006. Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant. J Virol 80:835–844. [PubMed][CrossRef]
60. Mabuka J, Goo L, Omenda MM, Nduati R, Overbaugh J. 2013. HIV-1 maternal and infant variants show similar sensitivity to broadly neutralizing antibodies, but sensitivity varies by subtype. AIDS 27:1535–1544. [PubMed][CrossRef]
61. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. 2005. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 191:654–665. [PubMed][CrossRef]
62. Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K. 2006. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 194:1661–1671. [PubMed][CrossRef]
63. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH. 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 361:2209–2220. [PubMed][CrossRef]
64. Burton DR, Desrosiers RC, Doms RW, Koff WC, Kwong PD, Moore JP, Nabel GJ, Sodroski J, Wilson IA, Wyatt RT. 2004. HIV vaccine design and the neutralizing antibody problem. Nat Immunol 5:233–236. [PubMed][CrossRef]
65. Sanders RW, Vesanen M, Schuelke N, Master A, Schiffner L, Kalyanaraman R, Paluch M, Berkhout B, Maddon PJ, Olson WC, Lu M, Moore JP. 2002. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol 76:8875–8889. [PubMed][CrossRef]
66. Binley JM, Sanders RW, Clas B, Schuelke N, Master A, Guo Y, Kajumo F, Anselma DJ, Maddon PJ, Olson WC, Moore JP. 2000. A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J Virol 74:627–643. [PubMed][CrossRef]
67. Yang X, Lee J, Mahony EM, Kwong PD, Wyatt R, Sodroski J. 2002. Highly stable trimers formed by human immunodeficiency virus type 1 envelope glycoproteins fused with the trimeric motif of T4 bacteriophage fibritin. J Virol 76:4634–4642. [PubMed][CrossRef]
68. Spearman P, Lally MA, Elizaga M, Montefiori D, Tomaras GD, McElrath MJ, Hural J, De Rosa SC, Sato A, Huang Y, Frey SE, Sato P, Donnelly J, Barnett S, Corey LJ. 2011. A trimeric, V2-deleted HIV-1 envelope glycoprotein vaccine elicits potent neutralizing antibodies but limited breadth of neutralization in human volunteers. J Infect Dis 203:1165–1173. [PubMed][CrossRef]
69. Forsell MN, Schief WR, Wyatt RT. 2009. Immunogenicity of HIV-1 envelope glycoprotein oligomers. Curr Opin HIV AIDS 4:380–387. [PubMed][CrossRef]
70. Sather DN, Carbonetti S, Malherbe D, Pissani F, Stuart AB, Hessell AJ, Gray MD, Mikell I, Kalams SA, Haigwood NL, Stamatatos L. 2014. Emergence of broadly neutralizing antibodies and viral co-evolution in two subjects during the early stages of infection with the human immunodeficiency virus type 1. J Virol 88:12968–12981. [PubMed][CrossRef]
71. Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN, DeKosky BJ, Ernandes MJ, Georgiev IS, Kim HJ, Pancera M, Staupe RP, Altae-Tran HR, Bailer RT, Crooks ET, Cupo A, Druz A, Garrett NJ, Hoi KH, Kong R, Louder MK, Longo NS, McKee K, Nonyane M, O'Dell S, Roark RS, Rudicell RS, Schmidt SD, Sheward DJ, Soto C, Wibmer CK, Yang Y, Zhang Z, Mullikin JC, Binley JM, Sanders RW, Wilson IA, Moore JP, Ward AB, Georgiou G, Williamson C, Abdool Karim SS, Morris L, Kwong PD, Shapiro L, Mascola JR. 2014. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509:55–62. [PubMed][CrossRef]
72. Correia BE, Bates JT, Loomis RJ, Baneyx G, Carrico C, Jardine JG, Rupert P, Correnti C, Kalyuzhniy O, Vittal V, Connell MJ, Stevens E, Schroeter A, Chen M, Macpherson S, Serra AM, Adachi Y, Holmes MA, Li Y, Klevit RE, Graham BS, Wyatt RT, Baker D, Strong RK, Crowe JE, Jr, Johnson PR, Schief WR. 2014. Proof of principle for epitope-focused vaccine design. Nature 507:201–206. [PubMed][CrossRef]
73. Delany I, Rappuoli R, Seib KL. 2013. Vaccines, reverse vaccinology, and bacterial pathogenesis. Cold Spring Harbor Perspect Med 3:a012476. [PubMed][CrossRef]
74. Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. 2007. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445:732–737. [PubMed][CrossRef]
75. Cimbro R, Gallant TR, Dolan MA, Guzzo C, Zhang P, Lin Y, Miao H, Van Ryk D, Arthos J, Gorshkova I, Brown PH, Hurt DE, Lusso P. 2014. Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2-V3 interaction and modulates neutralization sensitivity. Proc Natl Acad Sci USA 111:3152–3157. [PubMed][CrossRef]
76. White TA, Bartesaghi A, Borgnia MJ, Meyerson JR, de la Cruz MJ, Bess JW, Nandwani R, Hoxie JA, Lifson JD, Milne JL, Subramaniam S. 2010. Molecular architectures of trimeric SIV and HIV-1 envelope glycoproteins on intact viruses: strain-dependent variation in quaternary structure. PLoS Pathog 6:e1001249. doi:10.1371/journal.ppat.1001249. [PubMed][CrossRef]
77. Zolla-Pazner S, Cardozo T. 2011. Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat Rev 10:527–535.
78. McLellan JS, Pancera M, Carrico C, Gorman J, Julien JP, Khayat R, Louder R, Pejchal R, Sastry M, Dai K, O'Dell S, Patel N, Shahzad-ul-Hussan S, Yang Y, Zhang B, Zhou T, Zhu J, Boyington JC, Chuang GY, Diwanji D, Georgiev I, Kwon YD, Lee D, Louder MK, Moquin S, Schmidt SD, Yang ZY, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Burton DR, Koff WC, Walker LM, Phogat S, Wyatt R, Orwenyo J, Wang LX, Arthos J, Bewley CA, Mascola JR, Nabel GJ, Schief WR, Ward AB, Wilson IA, Kwong PD. 2011. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480:336–343. [PubMed][CrossRef]
79. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz CC, Censoplano N, Chung E, Reitano KN, Kottilil S, Goode DJ, Fauci AS. 2008. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 9:301–309. [PubMed][CrossRef]
80. Gorny MK, Moore JP, Conley AJ, Karwowska S, Sodroski J, Williams C, Burda S, Boots LJ, Zolla-Pazner S. 1994. Human anti-V2 monoclonal antibody that neutralizes primary but not laboratory isolates of human immunodeficiency virus type 1. J Virol 68:8312–8320. [PubMed]
81. Mayr LM, Cohen S, Spurrier B, Kong XP, Zolla-Pazner S. 2013. Epitope mapping of conformational V2-specific anti-HIV human monoclonal antibodies reveals an immunodominant site in V2. PloS One 8:e70859. doi:10.1371/journal.pone.0070859. [PubMed][CrossRef]
82. Bonsignori M, Pollara J, Moody MA, Alpert MD, Chen X, Hwang KK, Gilbert PB, Huang Y, Gurley TC, Kozink DM, Marshall DJ, Whitesides JF, Tsao CY, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Kim JH, Michael NL, Tomaras GD, Montefiori DC, Lewis GK, DeVico A, Evans DT, Ferrari G, Liao HX, Haynes BF. 2012. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol 86:11521–11532. [PubMed][CrossRef]
83. Gorny MK, Stamatatos L, Volsky B, Revesz K, Williams C, Wang XH, Cohen S, Staudinger R, Zolla-Pazner S. 2005. Identification of a new quaternary neutralizing epitope on human immunodeficiency virus type 1 virus particles. J Virol 79:5232–5237. [PubMed][CrossRef]
84. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O'Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori DC, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF. 2011. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol 85:9998–10009. [PubMed][CrossRef]
85. Julien JP, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse PJ, Burton DR, Sanders RW, Moore JP, Ward AB, Wilson IA. 2013. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342:1477–1483. [PubMed][CrossRef]
86. Ivanoff LA, Dubay JW, Morris JF, Roberts SJ, Gutshall L, Sternberg EJ, Hunter E, Matthews TJ, Petteway SR, Jr. 1992. V3 loop region of the HIV-1 gp120 envelope protein is essential for virus infectivity. Virology 187:423–432. [PubMed][CrossRef]
87. Zolla-Pazner S. 2004. Identifying epitopes of HIV-1 that induce protective antibodies. Nat Rev 4:199–210. [PubMed]
88. Zolla-Pazner S, Cardozo T. 2010. Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat Rev 10:527–535. [PubMed]
89. Jiang X, Burke V, Totrov M, Williams C, Cardozo T, Gorny MK, Zolla-Pazner S, Kong XP. 2010. Conserved structural elements in the V3 crown of HIV-1 gp120. Nat Struct Mol Biol 17:955–961. [PubMed][CrossRef]
90. Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA, Wyatt R, Kwong PD. 2005. Structure of a V3-containing HIV-1 gp120 core. Science 310:1025–1028. [PubMed][CrossRef]
91. Zolla-Pazner S. 2005. Improving on nature: focusing the immune response on the V3 loop. Hum Antibodies 14:69–72. [PubMed]
92. Crooks ET, Moore PL, Franti M, Cayanan CS, Zhu P, Jiang P, de Vries RP, Wiley C, Zharkikh I, Schulke N, Roux KH, Montefiori DC, Burton DR, Binley JM. 2007. A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120. Virology 366:245–262. [PubMed][CrossRef]
93. Visciano ML, Tagliamonte M, Stewart-Jones G, Heyndrickx L, Vanham G, Jansson M, Fomsgaard A, Grevstad B, Ramaswamy M, Buonaguro FM, Tornesello ML, Biswas P, Scarlatti G, Buonaguro L. 2013. Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate. J Transl Med 11:165. [PubMed][CrossRef]
94. Totrov M, Jiang X, Kong XP, Cohen S, Krachmarov C, Salomon A, Williams C, Seaman MS, Abagyan R, Cardozo T, Gorny MK, Wang S, Lu S, Pinter A, Zolla-Pazner S. 2010. Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold. Virology 405:513–523. [PubMed][CrossRef]
95. Zolla-Pazner S, Cohen S, Pinter A, Krachmarov C, Wrin T, Wang S, Lu S. 2009. Cross-clade neutralizing antibodies against HIV-1 induced in rabbits by focusing the immune response on a neutralizing epitope. Virology 392:82–93. [PubMed][CrossRef]
96. Pan R, Sampson JM, Chen Y, Vaine M, Wang S, Lu S, Kong XP. 2013. Rabbit anti-HIV-1 monoclonal antibodies raised by immunization can mimic the antigen-binding modes of antibodies derived from HIV-1-infected humans. J Virol 87:10221–10231. [PubMed][CrossRef]
97. Burke V, Williams C, Sukumaran M, Kim SS, Li H, Wang XH, Gorny MK, Zolla-Pazner S, Kong XP. 2009. Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens. Structure 17:1538–1546. [PubMed][CrossRef]
98. Mouquet H, Klein F, Scheid JF, Warncke M, Pietzsch J, Oliveira TY, Velinzon K, Seaman MS, Nussenzweig MC. 2011. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade Aand B viruses. PloS One 6:e24078. doi:10.1371/journal.pone.0024078. [PubMed][CrossRef]
99. Corti D, Langedijk JP, Hinz A, Seaman MS, Vanzetta F, Fernandez-Rodriguez BM, Silacci C, Pinna D, Jarrossay D, Balla-Jhagjhoorsingh S, Willems B, Zekveld MJ, Dreja H, O'Sullivan E, Pade C, Orkin C, Jeffs SA, Montefiori DC, Davis D, Weissenhorn W, McKnight A, Heeney JL, Sallusto F, Sattentau QJ, Weiss RA, Lanzavecchia A. 2010. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PloS One 5:e8805. doi:10.1371/journal.pone.0008805. [CrossRef]
100. McCaffrey RA, Saunders C, Hensel M, Stamatatos L. 2004. N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J Virol 78:3279–3295. [PubMed][CrossRef]
101. Wyatt R, Moore J, Accola M, Desjardin E, Robinson J, Sodroski J. 1995. Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. J Virol 69:5723–5733. [PubMed]
102. Gzyl J, Bolesta E, Wierzbicki A, Kmieciak D, Naito T, Honda M, Komuro K, Kaneko Y, Kozbor D. 2004. Effect of partial and complete variable loop deletions of the human immunodeficiency virus type 1 envelope glycoprotein on the breadth of gp160-specific immune responses. Virology 318:493–506. [PubMed][CrossRef]
103. Upadhyay C, Mayr LM, Zhang J, Kumar R, Gorny MK, Nadas A, Zolla-Pazner S, Hioe CE. 2014. Distinct mechanisms regulate exposure of neutralizing epitopes in the V2 and V3 loops of HIV-1 envelope. J Virol 88:12853–12865. [PubMed][CrossRef]
104. Pejchal R, Doores KJ, Walker LM, Khayat R, Huang PS, Wang SK, Stanfield RL, Julien JP, Ramos A, Crispin M, Depetris R, Katpally U, Marozsan A, Cupo A, Maloveste S, Liu Y, McBride R, Ito Y, Sanders RW, Ogohara C, Paulson JC, Feizi T, Scanlan CN, Wong CH, Moore JP, Olson WC, Ward AB, Poignard P, Schief WR, Burton DR, Wilson IA. 2011. A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 334:1097–1103. [PubMed][CrossRef]
105. Julien JP, Sok D, Khayat R, Lee JH, Doores KJ, Walker LM, Ramos A, Diwanji DC, Pejchal R, Cupo A, Katpally U, Depetris RS, Stanfield RL, McBride R, Marozsan AJ, Paulson JC, Sanders RW, Moore JP, Burton DR, Poignard P, Ward AB, Wilson IA. 2013. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog 9:e1003342. doi:10.1371/journal.ppat.1003342. [PubMed][CrossRef]
106. Wu X, Zhou T, O'Dell S, Wyatt RT, Kwong PD, Mascola JR. 2009. Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment. J Virol 83:10892–10907. [PubMed][CrossRef]
107. Chen L, Kwon YD, Zhou T, Wu X, O'Dell S, Cavacini L, Hessell AJ, Pancera M, Tang M, Xu L, Yang ZY, Zhang MY, Arthos J, Burton DR, Dimitrov DS, Nabel GJ, Posner MR, Sodroski J, Wyatt R, Mascola JR, Kwong PD. 2009. Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science 326:1123–1127. [PubMed][CrossRef]
108. Selvarajah S, Puffer B, Pantophlet R, Law M, Doms RW, Burton DR. 2005. Comparing antigenicity and immunogenicity of engineered gp120. J Virol 79:12148–12163. [PubMed][CrossRef]
109. Ahmed FK, Clark BE, Burton DR, Pantophlet R. 2012. An engineered mutant of HIV-1 gp120 formulated with adjuvant Quil A promotes elicitation of antibody responses overlapping the CD4-binding site. Vaccine 30:922–930. [PubMed][CrossRef]
110. Yasmeen A, Ringe R, Derking R, Cupo A, Julien JP, Burton DR, Ward AB, Wilson IA, Sanders RW, Moore JP, Klasse PJ. 2014. Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits. Retrovirology 11:41. [PubMed][CrossRef]
111. Bhattacharyya S, Singh P, Rathore U, Purwar M, Wagner D, Arendt H, DeStefano J, LaBranche CC, Montefiori DC, Phogat S, Varadarajan R. 2013. Design of an Escherichia coli expressed HIV-1 gp120 fragment immunogen that binds to b12 and induces broad and potent neutralizing antibodies. J Biol Chem 288:9815–9825. [PubMed][CrossRef]
112. Montero M, van Houten NE, Wang X, Scott JK. 2008. The membrane-proximal external region of the human immunodeficiency virus type 1 envelope: dominant site of antibody neutralization and target for vaccine design. Microbiol Mol Biol Rev 72:54–84. [PubMed][CrossRef]
113. Kim M, Sun ZY, Rand KD, Shi X, Song L, Cheng Y, Fahmy AF, Majumdar S, Ofek G, Yang Y, Kwong PD, Wang JH, Engen JR, Wagner G, Reinherz EL. 2011. Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization. Nat Struct Mol Biol 18:1235–1243. [PubMed][CrossRef]
114. Song L, Sun ZY, Coleman KE, Zwick MB, Gach JS, Wang JH, Reinherz EL, Wagner G, Kim M. 2009. Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface. Proc Natl Acad Sci USA 106:9057–9062. [PubMed][CrossRef]
115. Dennison SM, Sutherland LL, Jaeger FH, Anasti KM, Parks R, Stewart S, Bowman C, Xia SM, Zhang R, Shen X, Scearce RM, Ofek G, Yang Y, Kwong PD, Santra S, Liao HX, Tomaras G, Letvin NL, Chen B, Alam SM, Haynes BF. 2011. Induction of antibodies in rhesus macaques that recognize a fusion-intermediate conformation of HIV-1 gp41. PloS One 6:e27824. doi:10.1371/journal.pone.0027824. [PubMed][CrossRef]
116. Shen X, Parks RJ, Montefiori DC, Kirchherr JL, Keele BF, Decker JM, Blattner WA, Gao F, Weinhold KJ, Hicks CB, Greenberg ML, Hahn BH, Shaw GM, Haynes BF, Tomaras GD. 2009. In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth. J Virol 83:3617–3625. [PubMed][CrossRef]
microbiolspec.AID-0025-2014.citations
cm/3/1
content/journal/microbiolspec/10.1128/microbiolspec.AID-0025-2014
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.AID-0025-2014
2015-01-16
2017-11-20

Abstract:

Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, “conventional Abs” are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, “exceptional Abs” require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

/deliver/fulltext/microbiolspec/3/1/AID-0025-2014.html?itemId=/content/journal/microbiolspec/10.1128/microbiolspec.AID-0025-2014&mimeType=html&fmt=ahah

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error