Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans

Garcés, Fernando; Lee, Jeong Hyun; Val, Natalia de; Peña, Alba Torrents de la; Kong, Leopold; Puchades, Cristina; Hua, Yuanzi; Stanfield, Robyn L.; Burton, Dennis R.; Moore, John P.; Sanders, Rogier W.; Ward, Andrew B.; Wilson, Ian A.

doi:10.1016/j.immuni.2015.11.007

Cited by 196 publications

(320 citation statements)

References 36 publications

(74 reference statements)

Supporting

Mentioning

308

Contrasting

Unclassified

Order By: Relevance

“…While the V3-glycan epitope centers on the glycan at N332, high-mannose glycans at other positions can variably be involved in the bnAb epitope (46–49). Such diversity is reflected in crystal and electron microscopy structures by different angles of approaches of individual V3-glycan bnAbs (24, 28,45,46,48–50) (Wilson and Ward, this volume).…”

Section: Characteristics Of Broadly Neutralizing Antibodiesmentioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

164

150

View full text Add to dashboard Cite

Summary Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody “arms race” occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

show abstract

Section: Characteristics Of Broadly Neutralizing Antibodiesmentioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

164

150

View full text Add to dashboard Cite

show abstract

“…Single-particle electron microscopy (EM) structures of recombinant native-like soluble Env gp140 trimers (SOSIPs) confirmed that they can adopt the same closed and open architectures as virion-bound Env trimers (5-7), thus the SOSIP substitutions (introduction of a disulfide bond linking gp120 to gp41 and an Ile→Pro mutation in gp41; ref. The closed conformation of HIV-1 Env is stabilized by interactions at the trimer apex mediated by the gp120 V1V2 loop (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In the closed state, the V1V2 region shields the binding site for the coreceptor on the V3 loop (11, 16), but V1V2 interactions with V3 cannot be maintained when the gp120 protomers rotate and separate to create the CD4-bound open conformation.…”

mentioning

confidence: 99%

Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Wang

Cohen

Galimidi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

143

200

View full text Add to dashboard Cite

The HIV-1 envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, relies on conformational flexibility to function in fusing the viral and host membranes. Fusion is achieved after gp120 binds to CD4, the HIV-1 receptor, and a coreceptor, capturing an open conformational state in which the fusion machinery on gp41 gains access to the target cell membrane. In the well-characterized closed Env conformation, the gp120 V1V2 loops interact at the apex of the Env trimer. Less is known about the structure of the open CD4-bound state, in which the V1V2 loops must rearrange and separate to allow access to the coreceptor binding site. We identified two anti-HIV-1 antibodies, the coreceptor mimicking antibody 17b and the gp120-gp41 interface-spanning antibody 8ANC195, that can be added as Fabs to a soluble native-like Env trimer to stabilize it in a CD4-bound conformation. Here, we present an 8.9-Å cryo-electron microscopy structure of a BG505 Env-sCD4-17b-8ANC195 complex, which reveals large structural rearrangements in gp120, but small changes in gp41, compared with closed Env structures. The gp120 protomers are rotated and separated in the CD4-bound structure, and the three V1V2 loops are displaced by ∼40 Å from their positions at the trimer apex in closed Env to the sides of the trimer in positions adjacent to, and interacting with, the three bound CD4s. These results are relevant to understanding CD4-induced conformational changes leading to coreceptor binding and fusion, and HIV-1 Env conformational dynamics, and describe a target structure relevant to drug design and vaccine efforts.T he HIV-1 envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, mediates recognition of host receptors and fusion of the viral and target cell membranes (1). Structural flexibility of HIV-1 Env is required for its function in membrane fusion; thus, Env exists in multiple conformational states on the surface of virions (2). Fusion involves several steps: The gp120 portion of Env trimer first binds to the host receptor CD4 to capture a conformational state of Env that exposes the binding site for an HIV-1 coreceptor (CCR5 or CXCR4), which, in turn, leads to gp41-mediated fusion of the viral and host cell membranes. CD4-induced conformational changes within the Env trimer are incompletely understood. The binding of soluble CD4 (sCD4) produces little to no changes in the structures of gp120 cores (gp120 monomers with truncations in the N and C termini and variable V1V2 and V3 loops) (3), but results in rotation of the gp120 protomers within virion-bound Env trimers to create an open conformation distinct from the closed conformation of unliganded virion-bound trimers (4). Single-particle electron microscopy (EM) structures of recombinant native-like soluble Env gp140 trimers (SOSIPs) confirmed that they can adopt the same closed and open architectures as virion-bound Env trimers (5-7), thus the SOSIP substitutions (introduction of a disulfide bond linking gp120 to gp41 and an Ile→Pro mutation in gp41; ref. The closed co...

show abstract

“…The HIV-1 Env trimer was regarded as a difficult target for crystallization, as depending on the viral strain it contains 30 AE 3 PNGSs per subunit. Thus, the first crystal structures of the HIV-1 Env trimer were derived from proteins produced in high-mannoseonly forms that were usually further deglycosylated (Julien et al, 2013;Pancera et al, 2014;Scharf et al, 2015;Garces et al, 2015;Stewart-Jones et al, 2016). However, we recently showed that it is possible to obtain crystal structures of fully and natively glycosylated HIV-1 Env trimers despite using trimers containing both complex-type and high-mannose glycans .…”

Section: Discussionmentioning

confidence: 99%

“…Apart from two exceptions (Scharf et al, 2015;Stewart-Jones et al, 2016), previous HIV Env trimer crystal structures used proteins produced in cells that attached only high-mannosetype N-glycans (Julien et al, 2013;Pancera et al, 2014;Scharf et al, 2015;Garces et al, 2015;Stewart-Jones et al, 2016) that were then further enzymatically trimmed to reduce the glycans to single N-acetylglucosamines (GlcNAcs) at accessible PNGSs. Our crystals were obtained from a natively glycosylated Env trimer (BG505 SOSIP.664; Sanders et al, 2013) that was prepared from human embryonic kidney cells (HEK 293 6E cells) that attached both complex-type and high-mannose N-glycans.…”

Section: Crystal Structures Of Natively Glycosylated Env Trimer-fab Cmentioning

confidence: 99%

“…Structural studies of bNAbs bound to HIV Env trimers revealed mechanisms by which bNAbs targeting various epitopes penetrate the glycan shield to either accommodate or include N-glycans in their epitopes (Julien et al, 2013;Pancera et al, 2014;Scharf et al, 2015;Garces et al, 2015;Lee et al, 2015Lee et al, , 2016Stewart-Jones et al, 2016). However, because heterogeneous glycosylation generally prevents the formation of well ordered crystals, all HIV Env crystal structures had been solved using glycoproteins produced in exclusively high-mannose forms (Diskin et al, 2011(Diskin et al, , 2013Kwon et al, 2015;Garces et al, 2015;Julien et al, 2013;Pancera et al, 2014;Scharf et al, 2014Scharf et al, , 2015StewartJones et al, 2016;Zhou et al, 2010Zhou et al, , 2013Zhou et al, , 2015Kwong et al, 1998). Therefore, little was known about the structure of the native HIV-1 Env glycan shield that includes both complextype and oligomannose N-glycans, and the natively glycosylated epitopes of important HIV-1 bNAb classes, such as Asn332 gp120 glycan/V3 loop and CD4bs bNAbs, remained research papers Acta Cryst.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

X-ray and EM structures of a natively glycosylated HIV-1 envelope trimer

Gristick

Wang

Björkman

2017

Acta Crystallogr D Struct Biol

View full text Add to dashboard Cite

The structural and biochemical characterization of broadly neutralizing anti-HIV-1 antibodies (bNAbs) has been essential in guiding the design of potential vaccines to prevent infection by HIV-1. While these studies have revealed critical mechanisms by which bNAbs recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env), they have been limited to the visualization of high-mannose glycan forms only, since heterogeneity introduced from the presence of complex glycans makes it difficult to obtain high-resolution structures. 3.5 and 3.9 Å resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation were solved, revealing a glycan shield of high-mannose and complex-type N-glycans that were used to define the complete epitopes of two bNAbs. Here, the refinement of the N-glycans in the crystal structures is discussed and comparisons are made with glycan densities in glycosylated Env structures derived by single-particle cryo-electron microscopy.

show abstract

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans

Cited by 196 publications

References 36 publications

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

X-ray and EM structures of a natively glycosylated HIV-1 envelope trimer

Contact Info

Product

Resources

About