Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.
References
[1]
Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, et al. Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target. Science. 2009;326: 285–289. doi: 10.1126/science.1178746. pmid:19729618
[2]
Walker LM, Simek MD, Priddy F, Gach JS, Wagner D, Zwick MB, et al. A Limited Number of Antibody Specificities Mediate Broad and Potent Serum Neutralization in Selected HIV-1 Infected Individuals. Trkola A, editor. PLoS Pathog. 2010;6: e1001028. doi: 10.1371/journal.ppat.1001028.g009. pmid:20700449
[3]
Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, et al. Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science. 2010;329: 856–861. doi: 10.1126/science.1187659. pmid:20616233
[4]
Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, Olivera TYK, et al. Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science. 2011. doi: 10.1126/science.1207227.
[5]
Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012;491: 406–412. doi: 10.1038/nature11544. pmid:23151583
[6]
Falkowska E, Le KM, Ramos A, Doores KJ, Lee JH, Blattner C, et al. Broadly Neutralizing HIV Antibodies Definea Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers. Immunity. Elsevier Inc; 2014;: 1–12. doi: 10.1016/j.immuni.2014.04.009.
[7]
Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med. 2000;6: 207–210. doi: 10.1038/72318. pmid:10655111
[8]
Hessell AJ, Poignard P, Hunter M, Hangartner L, Tehrani DM, Bleeker WK, et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nature Publishing Group. Nature Publishing Group; 2009;: 1–5. doi: 10.1038/nm.1974.
[9]
Moldt B, Rakasz EG, Schultz N, Chan-Hui PY, Swiderek K, Weisgrau KL, et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proceedings of the National Academy of Sciences. 2012. doi: 10.1073/pnas.1214785109.
[10]
Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, Nabel GJ, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. Journal of Experimental Medicine. 2014;211: 2061–2074. doi: 10.1084/jem.20132494. pmid:25155019
Fauci AS, Marston HD. Ending AIDS—is an HIV vaccine necessary? N Engl J Med. 2014;370: 495–498. doi: 10.1056/NEJMp1313771. pmid:24499210
[13]
Gray ES, Moore PL, Choge IA, Decker JM, Bibollet-Ruche F, Li H, et al. Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection. JOURNAL OF VIROLOGY. 2007;81: 6187–6196. doi: 10.1128/JVI.00239-07. pmid:17409164
[14]
Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, et al. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. JOURNAL OF VIROLOGY. 2008;82: 11651–11668. doi: 10.1128/JVI.01762-08. pmid:18815292
[15]
Sather DN, Armann J, Ching LK, Mavrantoni A, Sellhorn G, Caldwell Z, et al. Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection. JOURNAL OF VIROLOGY. 2008;83: 757–769. doi: 10.1128/JVI.02036-08. pmid:18987148
[16]
Simek MD, Rida W, Priddy FH, Pung P, Carrow E, Laufer DS, et al. 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. JOURNAL OF VIROLOGY. 2009;83: 7337–7348. doi: 10.1128/JVI.00110-09. pmid:19439467
[17]
Doria-Rose NA, Klein RM, Daniels MG, O'Dell S, Nason M, Lapedes A, et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. JOURNAL OF VIROLOGY. 2010;84: 1631–1636. doi: 10.1128/JVI.01482-09. pmid:19923174
[18]
Euler Z, van Gils MJ, Bunnik EM, Phung P, Schweighardt B, Wrin T, et al. Cross-reactive neutralizing humoral immunity does not protect from HIV type 1 disease progression. J Infect Dis. 2010;201: 1045–1053. doi: 10.1086/651144. pmid:20170371
[19]
Mikell I, Sather DN, Kalams SA, Altfeld M, Alter G, Stamatatos L. Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog. 2011;7: e1001251. doi: 10.1371/journal.ppat.1001251. pmid:21249232
[20]
Gray ES, Madiga MC, Hermanus T, Moore PL, Wibmer CK, Tumba NL, et al. 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. JOURNAL OF VIROLOGY. 2011;85: 4828–4840. doi: 10.1128/JVI.00198-11. pmid:21389135
van Gils MJ, Euler Z, Schweighardt B, Wrin T, Schuitemaker H. Prevalence of cross-reactive HIV-1-neutralizing activity in HIV-1-infected patients with rapid or slow disease progression. AIDS. 2009;23: 2405–2414. doi: 10.1097/QAD.0b013e32833243e7. pmid:19770692
[23]
Piantadosi A, Panteleeff D, Blish CA, Baeten JM, Jaoko W, McClelland RS, et al. Breadth of neutralizing antibody response to human immunodeficiency virus type 1 is affected by factors early in infection but does not influence disease progression. JOURNAL OF VIROLOGY. 2009;83: 10269–10274. doi: 10.1128/JVI.01149-09. pmid:19640996
[24]
van den Kerkhof TLGM, Feenstra K, Euler Z, van Gils MJ, Rijsdijk LWE, Boeser-Nunnink BD, et al. HIV-1 envelope glycoprotein signatures that correlate with the development of cross-reactive neutralizing activity. Retrovirology. 2013;10: 102. doi: 10.1186/1742-4690-10-102. pmid:24059682
[25]
Euler Z, van Gils MJ, Schuitemaker H. Cross-reactive neutralizing activity in HIV-1 infected injecting drug users. Retrovirology. BioMed Central; 2012;9: P56. doi: 10.1186/1742-4690-9-S2-P56.
[26]
Burton DR, Ahmed R, Barouch DH, Butera ST, Crotty S, Godzik A, et al. A Blueprint for HIV Vaccine Discovery. Cell Host and Microbe. Elsevier Inc; 2012;12: 396–407. doi: 10.1016/j.chom.2012.09.008. pmid:23084910
[27]
Burton DR, Mascola JR. Antibody responses to envelope glycoproteins in HIV-1 infection. Nat Immunol. 2015;16: 571–576. doi: 10.1038/ni.3158. pmid:25988889
[28]
Amornkul PN, Karita E, Kamali A, Rida WN, Sanders EJ, Lakhi S, et al. Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa. AIDS. 2013;27: 2775–2786. doi: 10.1097/QAD.0000000000000012. pmid:24113395
[29]
Prentice HA, Price MA, Porter TR, Cormier E, Mugavero MJ, Kamali A, et al. Dynamics of viremia in primary HIV-1 infection in Africans: Insights from analyses of host and viral correlates. Virology. 2014;449: 254–262. doi: 10.1016/j.virol.2013.11.024. pmid:24418560
[30]
Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien J-P, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature. Nature Publishing Group; 2011;: 1–6. doi: 10.1038/nature10373.
[31]
Seaman MS, Janes H, Hawkins N, Grandpre LE, Devoy C, Giri A, et al. Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies. JOURNAL OF VIROLOGY. 2010;84: 1439–1452. doi: 10.1128/JVI.02108-09. pmid:19939925
[32]
Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. Human Circulating PD-1. Immunity. Elsevier Inc; 2013;: 1–12. doi: 10.1016/j.immuni.2013.08.031.
[33]
Binley JM, Klasse PJ, Cao Y, Jones I, Markowitz M, Ho DD, et al. Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. JOURNAL OF VIROLOGY. 1997;71: 2799–2809. pmid:9060635
[34]
Lynch RM, Tran L, Louder MK, Schmidt SD, Cohen M, CHAVI 001 Clinical Team Members, et al. The development of CD4 binding site antibodies during HIV-1 infection. JOURNAL OF VIROLOGY. 2012;86: 7588–7595. doi: 10.1128/JVI.00734-12. pmid:22573869
[35]
Feng Y, McKee K, Tran K, O'Dell S, Schmidt SD, Phogat A, et al. Biochemically defined HIV-1 Env variant immunogens display differential binding and neutralizing specificities to the CD4 binding site. Journal of Biological Chemistry. 2011. doi: 10.1074/jbc.M111.317776.
[36]
Jardine J, Julien J-P, Menis S, Ota T, Kalyuzhniy O, McGuire A, et al. Rational HIV immunogen design to target specific germline B cell receptors. Science. 2013;340: 711–716. doi: 10.1126/science.1234150. pmid:23539181
[37]
Doores KJ, Burton DR. Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. JOURNAL OF VIROLOGY. 2010;84: 10510–10521. doi: 10.1128/JVI.00552-10. pmid:20686044
[38]
Bonsignori M, Hwang K-K, Chen X, Tsao C-Y, Morris L, Gray E, et al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. JOURNAL OF VIROLOGY. 2011;85: 9998–10009. doi: 10.1128/JVI.05045-11. pmid:21795340
[39]
Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN, Dekosky BJ, et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature. 2014;509: 55–62. doi: 10.1038/nature13036. pmid:24590074
[40]
Scharf L, Scheid JF, Lee JH, West AP Jr, Chen C, Gao H, et al. Antibody 8ANC195 Reveals a Site of Broad Vulnerability on the HIV-1 Envelope Spike. CellReports. The Authors; 2014;7: 785–795. doi: 10.1016/j.celrep.2014.04.001.
[41]
Huang J, Kang BH, Pancera M, Lee JH, Tong T, Feng Y, et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface. Nature. Nature Publishing Group; 2014;: 1–17. doi: 10.1038/nature13601.
[42]
Lavine CL, Lao S, Montefiori DC, Haynes BF, Sodroski JG, Yang X, et al. High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Infection of Human Immunodeficiency Virus Type 1. JOURNAL OF VIROLOGY. 2011. doi: 10.1128/JVI.06201-11.
[43]
Mouquet H, Klein F, Scheid JF, Warncke M, Pietzsch J, Oliveira TYK, et al. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses. PLoS ONE. 2011;6: e24078. doi: 10.1371/journal.pone.0024078. pmid:21931643
[44]
Doores KJ, Kong L, Krumm SA, Le KM, Sok D, Laserson U, et al. Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope. Doms RW, editor. JOURNAL OF VIROLOGY. 2015;89: 1105–1118. doi: 10.1128/JVI.02905-14. pmid:25378488
[45]
Goo L, Chohan V, Nduati R, Overbaugh J. Early development of broadly neutralizing antibodies in HIV-1–infected infants. Nature Publishing Group. Nature Publishing Group; 2014;: 1–6. doi: 10.1038/nm.3565.
[46]
Kroon FP, van Dissel JT, de Jong JC, van Furth R. Antibody response to influenza, tetanus and pneumococcal vaccines in HIV-seropositive individuals in relation to the number of CD4+ lymphocytes. AIDS. 1994;8: 469–476. pmid:7912086 doi: 10.1097/00002030-199404000-00008
[47]
Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine. 2005;23: 2902–2908. doi: 10.1016/j.vaccine.2004.11.057. pmid:15780739
[48]
Euler Z, van den Kerkhof TLGM, van Gils MJ, Burger JA, Edo-Matas D, Phung P, et al. Longitudinal Analysis of Early HIV-1-Specific Neutralizing Activity in an Elite Neutralizer and in Five Patients Who Developed Cross-Reactive Neutralizing Activity. JOURNAL OF VIROLOGY. 2012;86: 2045–2055. doi: 10.1128/JVI.06091-11. pmid:22156522
[49]
Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. JOURNAL OF VIROLOGY. 1994;68: 6103–6110. pmid:8057491
[50]
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999;283: 857–860. pmid:9933172 doi: 10.1126/science.283.5403.857
[51]
Kaslow RA, Rivers C, Tang J, Bender TJ, Goepfert PA, Habib El R, et al. Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines. JOURNAL OF VIROLOGY. 2001;75: 8681–8689. pmid:11507213 doi: 10.1128/jvi.75.18.8681-8689.2001
[52]
Carrington M, O'Brien SJ. The influence of HLA genotype on AIDS. Annu Rev Med. 2003;54: 535–551. doi: 10.1146/annurev.med.54.101601.152346. pmid:12525683
[53]
Brumme ZL, Brumme ZL, Poon AFY, Poon AFY, Carlson JM, Carlson JM, et al. Identifying HLA-Associated Polymorphisms in HIV-1. HIV Molecular Immunology 2010. 2011;: 1–14.
[54]
Carrington M, Carrington M, Walker BD, Walker BD. Immunogenetics of spontaneous control of HIV. Annu Rev Med. 2012;63: 131–145. doi: 10.1146/annurev-med-062909-130018. pmid:22248321
[55]
Ranasinghe S, Ranasinghe S, Cutler S, Cutler S, Davis I, Davis I, et al. Association of HLA-DRB1-restricted CD4(+) T cell responses with HIV immune control. Nat Med. 2013;19: 930–933. doi: 10.1038/nm.3229. pmid:23793098
[56]
Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, Carlson JM, et al. Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. Journal of Experimental Medicine. 2008;205: 1009–1017. doi: 10.1084/jem.20072457. pmid:18426987
[57]
Yue L, Prentice HA, Farmer P, Song W, He D, Lakhi S, et al. Cumulative impact of host and viral factors on HIV-1 viral-load control during early infection. JOURNAL OF VIROLOGY. 2013;87: 708–715. doi: 10.1128/JVI.02118-12. pmid:23115285
[58]
Fraser C, Mugo PM, McCoy LE, Jaafoura S, Payne RP, Mann JK, et al. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science. 2014;343: 1243727. doi: 10.1126/science.1243727. pmid:24653038
[59]
Claiborne DT, Prince JL, Scully E, Macharia G, Micci L, Lawson B, et al. Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 +T cells, and disease progression. Proceedings of the National Academy of Sciences. 2015;: 201421607. doi: 10.1073/pnas.1421607112.
[60]
Li X, Price MA, He D, Kamali A, Karita E, Lakhi S, et al. Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions. Hum Genet. 2014;133: 1187–1197. doi: 10.1007/s00439-014-1465-x. pmid:24969460
[61]
Rademeyer C, Moore PL, Taylor N, Martin DP, Choge IA, Gray ES, et al. Genetic characteristics of HIV-1 subtype C envelopes inducing cross-neutralizing antibodies. Virology. 2007;368: 172–181. doi: 10.1016/j.virol.2007.06.013. pmid:17632196
[62]
Baalwa J, Wang S, Parrish NF, Decker JM, Keele BF, Learn GH, et al. Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones. Virology. Elsevier; 2012;: 1–16. doi: 10.1016/j.virol.2012.10.009.
[63]
Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, Parrish EH, et al. Phenotypic properties of transmitted founder HIV-1. Proceedings of the National Academy of Sciences. 2013. doi: 10.1073/pnas.1304288110.
[64]
Derdeyn CA, Sok D, Valdez KPR, Gardner MR, Hunter E, Sok D, et al. Viral characteristics of transmitted HIV. Curr Opin HIV AIDS. 2008;3: 16–21. doi: 10.1097/COH.0b013e3282f2982c. pmid:19372939
[65]
Piantadosi A, Chohan B, Chohan V, McClelland RS, Overbaugh J. Chronic HIV-1 infection frequently fails to protect against superinfection. PLoS Pathog. 2007;3: e177. doi: 10.1371/journal.ppat.0030177. pmid:18020705
[66]
Cohen K, Altfeld M, Alter G, Stamatatos L. Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection. JOURNAL OF VIROLOGY. 2014;88: 13310–13321. doi: 10.1128/JVI.02186-14. pmid:25210168
[67]
Boliar S, Murphy MK, Tran TC, Carnathan DG, Armstrong WS, Silvestri G, et al. B-lymphocyte dysfunction in chronic HIV-1 infection does not prevent cross-clade neutralization breadth. JOURNAL OF VIROLOGY. 2012;86: 8031–8040. doi: 10.1128/JVI.00771-12. pmid:22623771
[68]
Gao F, Bonsignori M, Liao H- X, Kumar A, Xia S-M, Lu X, et al. Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies. Cell. Elsevier Inc; 2014;: 1–11. doi: 10.1016/j.cell.2014.06.022. pmid:25065977
[69]
Wibmer CK, Bhiman JN, Gray ES, Tumba N, Abdool Karim SS, Williamson C, et al. Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes. PLoS Pathog. 2013;9: e1003738. doi: 10.1371/journal.ppat.1003738. pmid:24204277
[70]
Liao HX, Tsao CY, Alam SM, Muldoon M, Vandergrift N, Ma BJ, et al. Antigenicity and Immunogenicity of Transmitted/Founder, Consensus and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1. JOURNAL OF VIROLOGY. 2013. doi: 10.1128/JVI.02297-12.
[71]
Moore PL, Gray ES, Wibmer CK, Bhiman JN, Nonyane M, Sheward DJ, et al. Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nature Publishing Group. 2012;18: 1688–1692. doi: 10.1038/nm.2985.
[72]
Moore PL, Williamson C, Morris L. Virological features associated with the development of broadly neutralizing antibodies to HIV-1. Trends Microbiol. 2015. doi: 10.1016/j.tim.2014.12.007.
[73]
Moore PL, Ranchobe N, Lambson BE, Gray ES, Cave E, Abrahams M-R, et al. Limited neutralizing antibody specificities drive neutralization escape in early HIV-1 subtype C infection. PLoS Pathog. 2009;5: e1000598. doi: 10.1371/journal.ppat.1000598. pmid:19763271
[74]
Tomaras GD, Binley JM, Gray ES, Crooks ET, Osawa K, Moore PL, et al. Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals. JOURNAL OF VIROLOGY. 2011;85: 11502–11519. doi: 10.1128/JVI.05363-11. pmid:21849452
[75]
Bonsignori M, Montefiori DC, Wu X, Chen X, Hwang K-K, Tsao C-Y, et al. Two distinct broadly neutralizing antibody specificities of different clonal lineages in a single HIV-1-infected donor: implications for vaccine design. JOURNAL OF VIROLOGY. 2012;86: 4688–4692. doi: 10.1128/JVI.07163-11. pmid:22301150
[76]
Klein F, Gaebler C, Mouquet H, Sather DN, Lehmann C, Scheid JF, et al. Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. Journal of Experimental Medicine. 2012;209: 1469–1479. doi: 10.1084/jem.20120423. pmid:22826297
[77]
Gray ES, Madiga MC, Moore PL, Mlisana K, Abdool Karim SS, Binley JM, et al. Broad Neutralization of Human Immunodeficiency Virus Type 1 Mediated by Plasma Antibodies against the gp41 Membrane Proximal External Region. JOURNAL OF VIROLOGY. 2009;83: 11265–11274. doi: 10.1128/JVI.01359-09. pmid:19692477
[78]
Moore PL, Gray ES, Sheward D, Madiga M, Ranchobe N, Lai Z, et al. Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop. JOURNAL OF VIROLOGY. 2011;85: 3128–3141. doi: 10.1128/JVI.02658-10. pmid:21270156
[79]
Euler Z, van Gils MJ, Schuitemaker H. Cross-Reactive Neutralizing Activity in HIV-1 Infected Injection Drug Users. AIDS Vaccine Conference, Boston 2012; 2012.
[80]
Liao Hua-Xin, Lynch R, Zhou T, Gao Feng, Alam S Munir, Boyd SD, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. Nature Publishing Group; 2013;: 1–11. doi: 10.1038/nature12053.
[81]
Haynes BF, Verkoczy L. AIDS/HIV. Host controls of HIV neutralizing antibodies. Science. 2014;344: 588–589. doi: 10.1126/science.1254990. pmid:24812389
[82]
Sanders RW, Derking R, Cupo A, Julien J- P, Yasmeen A, de Val N, et al. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog. 2013;9: e1003618. doi: 10.1371/journal.ppat.1003618. pmid:24068931
[83]
Sharma SK, de Val N, Bale S, Guenaga J, Tran K, Feng Y, et al. Cleavage-Independent HIV-1 Env Trimers Engineered as Soluble Native Spike Mimetics for Vaccine Design. CellReports. The Authors; 2015;: 1–13. doi: 10.1016/j.celrep.2015.03.047.
[84]
Kong L, Lee JH, Doores KJ, Murin CD, Julien J-P, McBride R, et al. Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120. Nat Struct Mol Biol. Nature Publishing Group; 2013;: 1–10. doi: 10.1038/nsmb.2594. pmid:23708606
[85]
Sok D, Doores KJ, Briney B, Le KM, Saye-Francisco KL, Ramos A, et al. Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV. Science Translational Medicine. 2014;6: 236ra63–236ra63. doi: 10.1126/scitranslmed.3008104. pmid:24828077
[86]
Li M, Gao F, Mascola JR, Stamatatos L, Polonis VR, Koutsoukos M, et al. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. JOURNAL OF VIROLOGY. 2005;79: 10108–10125. doi: 10.1128/JVI.79.16.10108–10125.2005. pmid:16051804
[87]
Doores KJ, Fulton Z, Huber M, Wilson IA, Burton DR. Antibody 2G12 Recognizes Di-Mannose Equivalently in Domain- and Nondomain-Exchanged Forms but Only Binds the HIV-1 Glycan Shield if Domain Exchanged. JOURNAL OF VIROLOGY. 2010;84: 10690–10699. doi: 10.1128/JVI.01110-10. pmid:20702629
[88]
Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med. 2007;13: 1032–1034. doi: 10.1038/nm1624. pmid:17721546
