A vital part of the renewed hope for a vaccine against the human immunodeficiency virus (HIV-1) is based on recent studies that have highlighted major sites of HIV-1 vulnerability that could be effectively targeted by a preventive vaccine. One of these potential vulnerabilities includes the dense cluster of carbohydrates surrounding HIV-1's envelope glycoproteins gp120 and gp41, typically referred to as the “glycan shield.” Recent data from several laboratories have shown that glycans on the HIV-1 envelope form key epitopes for broadly neutralizing antibodies (bNAb). Moreover, HIV-1 envelope glycans play an important role in viral transmission, antigenicity, and immunogenicity. The recent availability of novel tools and technologies has now allowed investigators to leverage glycomic structure–function relationships in the design of candidate HIV-1 vaccines. Additionally, glycans modulate the immune response, playing an essential role in Fc receptor and complement activity. To promote cross-disciplinary collaboration and promote synergistic HIV-1- glycomics research, the National Institutes of Health (NIH) cosponsored and convened a 1.5-day workshop entitled “Functional Glycomics in HIV-1 Vaccine Design.” The meeting focused on the role of glycan interactions with neutralizing antibodies, the influence of immunoglobulin G (IgG) Fc receptor glycosylation, newly available glycomics technologies, and how new information on the role of glycans could be applied in HIV-1 immunogen design strategies. This report summarizes the discussions of this workshop.
Get full access to this article
View all access options for this article.
References
1.
Committee on Assessing the Importance and Impact of Glycomics and Glycosciences. Transforming Glycoscience: A Roadmap for the Future. The National Academies Press: Washington, DC, 2012.
2.
VarkiA. Evolutionary forces shaping the Golgi glycosylation machinery: Why cell surface glycans are universal to living cells. Cold Spring Harb Perspect Biol, 2011; 3,6:a005462.
3.
VarkiAet al.Essentials of Glycobiology, 2nd784. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2009.
4.
PejchalRet al.A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science, 2011; 334,6059:1097–1103.
5.
SongXet al.Shotgun glycomics: A microarray strategy for functional glycomics. Nat Methods, 2011; 8,1:85–90.
6.
WangYet al.Platelet biogenesis and functions require correct protein O-glycosylation. Proc Natl Acad Sci USA, 2012; 109,40:16143–16148.
7.
MacnaughtanMAet al.NMR structural characterization of substrates bound to N-acetylglucosaminyltransferase V. J Mol Biol, 2007; 366,4:1266–1281.
8.
Van Den BergLM, GeijtenbeekTB. Antiviral immune responses by human Langerhans cells and dendritic cells in HIV-1 infection. Adv Exp Med Biol, 2013; 762:45–70.
9.
BarbAWet al.NMR characterization of immunoglobulin G Fc glycan motion on enzymatic sialylation. Biochemistry, 2012; 51,22:4618–4626.
10.
NorthSJet al.Mass spectrometry in the analysis of N-linked and O-linked glycans. Curr Opin Struct Biol, 2009; 19,5:498–506.
11.
GoEPet al.Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry. J Virol, 2011; 85,16:8270–8284.
12.
GoEPet al.Characterization of host-cell line specific glycosylation profiles of early transmitted/founder HIV-1 gp120 envelope proteins. J Proteome Res, 2013; 12,3:1223–1234.
13.
PlotkinSA. Correlates of protection induced by vaccination. Clin Vaccine Immunol, 2010; 17,7:1055–1065.
14.
AmannaIJ, SlifkaMK. Contributions of humoral and cellular immunity to vaccine-induced protection in humans. Virology, 2011; 411,2:206–215.
15.
KorberBet al.Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull, 2001; 58:19–42.
16.
ScheidJFet al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science, 2011; 333,6049:1633–1637.
17.
WuXet al.Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science, 2011; 333,6049:1593–1602.
18.
WalkerLMet al.Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science, 2009; 326,5950:285–289.
19.
WalkerLMet al.Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature, 2011; 477,7365:466–470.
20.
CortiDet al.Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One, 2010; 5,1:e8805.
21.
BonsignoriMet al.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, 2011; 85,19:9998–10009.
22.
FalkowskaEet al.PGV04, an HIV-1 gp120 CD4 binding site antibody, is broad and potent in neutralization but does not induce conformational changes characteristic of CD4. J Virol, 2012; 86,8:4394–4403.
23.
KleinFet al.Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J Exp Med, 2012; 209,8:1469–1479.
24.
ZhouTet al.Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science, 2010; 329,5993:811–817.
25.
HuangJet al.Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature, 2012; 491,7424:406–412.
26.
KwongPD, MascolaJR, NabelGJ. Rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1. Cold Spring Harb Perspect Med, 2011; 1,1:a007278.
27.
McLellanJSet al.Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature, 2011; 480,7377:336–343.
28.
MoorePLet al.Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop. J Virol, 2011; 85,7:3128–3141.
29.
Zolla-PaznerS, CardozoT. Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat Rev Immunol, 2010; 10,7:527–535.
30.
GornyMKet al.Human anti-V3 HIV-1 monoclonal antibodies encoded by the VH5-51/VL lambda genes define a conserved antigenic structure. PLoS One, 2011; 6,12:e27780.
31.
CalareseDAet al.Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science, 2003; 300,5628:2065–2071.
32.
KwongPD, MascolaJR. Human antibodies that neutralize HIV-1: Identification, structures, and B cell ontogenies. Immunity, 2012; 37,3:412–425.
33.
MoorePLet al.Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat Med, 2012; 18,11:1688–1692.
34.
MaoYet al.Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol, 2012; 19,9:893–899.
35.
PanceraMet al.Crystal structure of PG16 and chimeric dissection with somatically related PG9: Structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1. J Virol, 2010; 84,16:8098–8110.
36.
PejchalRet al.Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc Natl Acad Sci USA, 2010; 107,25:11483–11488.
37.
PanceraMet al.Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16. Nat Struct Mol Biol, 2013; 20,7:804–813.
38.
ZhuJet al.Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains. Proc Natl Acad Sci USA, 2013; 110,16:6470–6475.
39.
YuBet al.Glycoform and net charge heterogeneity in gp120 immunogens used in HIV vaccine trials. PLoS One, 2012; 7,8:e43903.
40.
GregoryTet al.Structure and function in recombinant HIV-1 gp120 and speculation about the disulfide bonding in the gp120 homologs of HIV-2 and SIV. Adv Exp Med Biol, 1991; 303:1–14.
41.
DooresKJet al.Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens. Proc Natl Acad Sci USA, 2010; 107,31:13800–13805.
42.
BonomelliCet al.The glycan shield of HIV is predominantly oligomannose independently of production system or viral clade. PLoS One, 2011; 6,8:e23521.
TrkolaAet al.Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J Virol, 1996; 70,2:1100–1108.
47.
CalareseDAet al.Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12. Proc Natl Acad Sci USA, 2005; 102,38:13372–13377.
48.
AstronomoRDet al.A glycoconjugate antigen based on the recognition motif of a broadly neutralizing human immunodeficiency virus antibody, 2G12, is immunogenic but elicits antibodies unable to bind to the self glycans of gp120. J Virol, 2008; 82,13:6359–6368.
49.
WangSKet al.Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN. Proc Natl Acad Sci USA, 2008; 105,10:3690–3695.
50.
LuallenRJet al.A yeast glycoprotein shows high-affinity binding to the broadly neutralizing human immunodeficiency virus antibody 2G12 and inhibits gp120 interactions with 2G12 and DC-SIGN. J Virol, 2009; 83,10:4861–4870.
51.
LuallenRJet al.Antibodies against Manalpha1,2-Manalpha1,2-Man oligosaccharide structures recognize envelope glycoproteins from HIV-1 and SIV strains. Glycobiology, 2010; 20,3:280–286.
52.
AstronomoRDet al.Defining criteria for oligomannose immunogens for HIV using icosahedral virus capsid scaffolds. Chem Biol, 2010; 17,4:357–370.
53.
DunlopDCet al.Polysaccharide mimicry of the epitope of the broadly neutralizing anti-HIV antibody, 2G12, induces enhanced antibody responses to self oligomannose glycans. Glycobiology, 2010; 20,7:812–823.
54.
HuberMet al.Very few substitutions in a germ line antibody are required to initiate significant domain exchange. J Virol, 2010; 84,20:10700–10707.
55.
DooresKJet al.Antibody 2G12 recognizes di-mannose equivalently in domain- and nondomain-exchanged forms but only binds the HIV-1 glycan shield if domain exchanged. J Virol, 2010; 84,20:10690–10699.
56.
WoodsRJ, TessierMB. Computational glycoscience: Characterizing the spatial and temporal properties of glycans and glycan-protein complexes. Curr Opin Struct Biol, 2010; 20,5:575–583.
57.
ErnstB, MagnaniJL. From carbohydrate leads to glycomimetic drugs. Nat Rev Drug Discov, 2009; 8,8:661–677.
58.
LiYet al.Removal of a single N-linked glycan in human immunodeficiency virus type 1 gp120 results in an enhanced ability to induce neutralizing antibody responses. J Virol, 2008; 82,2:638–651.
59.
AnthonyRM, NimmerjahnF. The role of differential IgG glycosylation in the interaction of antibodies with FcgammaRs in vivo. Curr Opin Organ Transplant, 2011; 16,1:7–14.
60.
LuxA, NimmerjahnF. Impact of differential glycosylation on IgG activity. Adv Exp Med Biol, 2011; 780:113–124.
61.
ShieldsRLet al.Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem, 2002; 277,30:26733–26740.
62.
ShinkawaTet al.The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem, 2003; 278,5:3466–3473.
63.
NiwaRet al.Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res, 2004; 64,6:2127–2133.
64.
NiwaRet al.IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J Immunol Methods, 2005; 306,1–2:151–160.
65.
MoldtBet al.A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcgammaRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. J Virol, 2012; 86,11:6189–6196.
66.
KanekoY, NimmerjahnF, RavetchJV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science, 2006; 313,5787:670–673.
67.
ForthalDNet al.Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J Immunol, 2007; 178,10:6596–6603.
68.
ForthalDN, MoogC. Fc receptor-mediated antiviral antibodies. Curr Opin HIV AIDS, 2009; 4,5:388–393.
69.
ForthalDNet al.IgG2 inhibits HIV-1 internalization by monocytes, and IgG subclass binding is affected by gp120 glycosylation. AIDS, 2011; 25,17:2099–2104.
70.
AckermanME, DugastAS, AlterG. Emerging concepts on the role of innate immunity in the prevention and control of HIV infection. Annu Rev Med, 2012; 63:113–130.
71.
AlterG, AltfeldM. NK cells in HIV-1 infection: Evidence for their role in the control of HIV-1 infection. J Intern Med, 2009; 265,1:29–42.
72.
IsitmanG, StratovI, KentSJ. Antibody-dependent cellular cytotoxicity and NK cell-driven immune escape in HIV infection: Implications for HIV vaccine development. Adv Virol, 2012; 2012:637208.
73.
AckermanMEet al.Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J Clin Invest, 2013; 123,5:2183–2192.
74.
DerdeynCAet al.Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science, 2004; 303,5666:2019–2022.
75.
ChohanBet al.Evidence for frequent reinfection with human immunodeficiency virus type 1 of a different subtype. J Virol, 2005; 79,16:10701–10708.
76.
KeeleBFet al.Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA, 2008; 105,21:7552–7557.
77.
ZhangMet al.Tracking global patterns of N-linked glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza hemagglutinin. Glycobiology, 2004; 14,12:1229–1246.
78.
FrostSDet al.Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. Proc Natl Acad Sci USA, 2005; 102,51:18514–18519.
79.
GrayESet al.N-linked glycan modifications in gp120 of human immunodeficiency virus type 1 subtype C render partial sensitivity to 2G12 antibody neutralization. J Virol, 2007; 81,19:10769–10776.
80.
AsmalMet al.A signature in HIV-1 envelope leader peptide associated with transition from acute to chronic infection impacts envelope processing and infectivity. PLoS One, 2011; 6,8:e23673.
81.
PinterAet al.The C108g epitope in the V2 domain of gp120 functions as a potent neutralization target when introduced into envelope proteins derived from human immunodeficiency virus type 1 primary isolates. J Virol, 2005; 79,11:6909–6917.
82.
KrachmarovCet al.Characterization of structural features and diversity of variable-region determinants of related quaternary epitopes recognized by human and rhesus macaque monoclonal antibodies possessing unusually potent neutralizing activities. J Virol, 2011; 85,20:10730–10740.
83.
TongTet al.HIV-1 virus-like particles bearing pure env trimers expose neutralizing epitopes but occlude nonneutralizing epitopes. J Virol, 2012; 86,7:3574–3587.
84.
KreismanLS, CobbBA. Infection, inflammation and host carbohydrates: A glyco-evasion hypothesis. Glycobiology, 2012; 22,8:1019–1030.
85.
van KooykY, RabinovichGA. Protein-glycan interactions in the control of innate and adaptive immune responses. Nat Immunol, 2008; 9,6:593–601.
86.
ParkerRB, KohlerJJ. Regulation of intracellular signaling by extracellular glycan remodeling. ACS Chem Biol, 2010; 5,1:35–46.
87.
RabinovichGA, van KooykY, CobbBA. Glycobiology of immune responses. Ann NY Acad Sci, 2012; 1253:1–15.
88.
SelmanMHet al.Changes in antigen-specific IgG1 Fc N-glycosylation upon influenza and tetanus vaccination. Mol Cell Proteomics, 2012; 11,4:M111014563.
89.
GuoNet al.Repeated immunization induces the increase in fucose content on antigen-specific IgG N-linked oligosaccharides. Clin Biochem, 2005; 38,2:149–153.
90.
LastraGCet al.Changes in the galactose content of IgG during humoral immune responses. Autoimmunity, 1998; 28,1:25–30.
91.
ForthalDNet al.Fc-glycosylation influences Fcgamma receptor binding and cell-mediated anti-HIV activity of monoclonal antibody 2G12. J Immunol, 2010; 185,11:6876–6882.
LilleyBN, PloeghHL. Viral modulation of antigen presentation: Manipulation of cellular targets in the ER and beyond. Immunol Rev, 2005; 207:126–144.
94.
HansenTH, BouvierM. MHC class I antigen presentation: Learning from viral evasion strategies. Nat Rev Immunol, 2009; 9,7:503–513.
95.
LiHet al.Proximal glycans outside of the epitopes regulate the presentation of HIV-1 envelope gp120 helper epitopes. J Immunol, 2009; 182,10:6369–6378.
