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Although newly identified glycan-targeting mAbs are potent inhibitors of HIV entry, 79 their neutralization breadth seems to be lower than that of mAbs targeting the Bj rn falkenhagen site. Replication and neutralization of human immunodeficiency virus type 1 lacking the V1 and Onion booty on zshare variable loops of the Bn envelope glycoprotein. Your email address will never be sold or distributed to a third party for any reason. DOI: Boyd M. AAV-delivered antibody mediates significant protective effects against SIVmac challenge in Bj rn falkenhagen absence of neutralizing activity. Multiple studies have shown that antibodies and antibody-based antiviral proteins are secreted in significant quantities from gene-modified muscle cells in macaques and can result in partial protection of animals from infection.

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Namespaces Article Talk. Adam Falckenhagen Bj rn falkenhagen April — 6 October was a German lutenist and composer of the Baroque period. Traffic Analysis Compare it to He wrote tuneful music which is still played today on lute and guitar. Traffic Analysis Compare it to Views Read Edit View history. Falckenhagen held this position until his death in In other projects Wikimedia Commons. Mname: ns. Countable Data Brief. Subdomains Traffic Shares.

HIV entry is a highly specific and time-sensitive process that can be divided into receptor binding, coreceptor binding, and membrane fusion.

  • Adam Falckenhagen 26 April — 6 October was a German lutenist and composer of the Baroque period.
  • Over the time it has been ranked as high as 8 in the world.

HIV entry is a highly specific and time-sensitive process that can be divided into receptor binding, coreceptor binding, and membrane fusion. Bifunctional antiviral proteins bAVPs exploit the multi-step nature of the HIV entry process by binding to two different extracellular targets. They are generated by expressing a fusion protein containing two entry inhibitors with a flexible linker.

The resulting fusion proteins exhibit exceptional neutralization potency and broad cross-clade inhibition. In this review, we summarize the HIV entry process and provide an overview of the design, antiviral potency, and methods of delivery of bAVPs.

Passive infusion of broadly neutralizing antibodies bnAbs is extensively being investigated for HIV treatment and prevention. Indeed, clinical trials based on the infusion of single antibodies have shown that pre-existing as well as emerging resistance are obstacles to bnAb-based approaches.

Bifunctional antiviral proteins bAVPs consist of two protein-based entry inhibitors that target different steps of the HIV entry process. They exploit the multi-step nature of HIV entry to overcome the limitations of single inhibitors and exhibit exceptional antiviral effects. In this review, we summarize the HIV entry process and provide an overview of the design and antiviral potency of the currently identified bAVPs.

Bispecific T-cell-engaging antibodies are also covered elsewhere. HIV entry represents the first step in the virus life cycle and is an attractive target for controlling HIV replication. The extracellular domains of gp41 are followed by the transmembrane domain TMD and the cytoplasmic tail CT. Although some of these regions are highly immunogenic, their variable nature eventually leads to the evasion of antibody-mediated responses that are directed against them.

A Schematic representation of gp and gp CXCR4 is ubiquitously expressed on all blood cells 30 and interacts with the CXC chemokine stromal cell-derived factor-1 SDF-1 , 31 which functions as a chemoattractant and regulates hematopoiesis. Receptor and coreceptor binding is mediated by gp, and membrane fusion is mediated by gp The first step in the viral entry process is binding of gp to CD4.

CD4 binding induces extensive conformational changes in HIV Env that cause the trimeric complex to assume an open or activated state. Specifically, gp41 forms a pre-hairpin intermediate, in which the HR1 and HR2 form extended helices and the FP is inserted into the host cell membrane.

Receptor binding induces conformational changes in gp that result in the exposure of the coreceptor-binding site on gp and the HR1 light green and HR2 dark green of gp Coreceptor binding induces additional changes that result in the release of the FP of gp41 yellow and cause the HR1 and HR2 of gp41 to assume an extended conformation pre-fusion intermediate. Insertion of the FP into the host cell membrane initiates the formation of the 6-helix bundle and lipid mixing between the viral and cellular membranes, leading to the formation of a fusion pore and content mixing.

Entry inhibitors interfere with the first step in the HIV replication cycle and can prevent cells from becoming infected. Small-molecule inhibitors, peptides, and proteins have been described against each step of HIV entry.

This section focuses on peptides and proteins that interfere with individual steps of HIV entry by targeting viral or cellular proteins.

It is a truncated version of the CD4 receptor that contains the gpbinding site but lacks the transmembrane domain. Remarkably, three out of four patients in the highest dose group became aviremic. The gpbinding site is located in D1 of CD4, which is unstable when expressed on its own.

Screening a large library of D1 mutants has recently revealed two stable residue D1 proteins mD1. It remains to be seen to what extent resistance to these modified sCD4 variants develops. The mAb b12 was one of the first well-characterized CD4-binding site antibodies with broad specificity. The mAb 2G12 binds to a distinct gp epitope that is formed by multiple glycans. These epitopes are formed by the N glycan and the V3 loop, the N glycan and V1 and V2 loops, or the N-linked glycans near the interface between gp and gp Although newly identified glycan-targeting mAbs are potent inhibitors of HIV entry, 79 their neutralization breadth seems to be lower than that of mAbs targeting the CD4-binding site.

Therefore, antibodies targeting the coreceptor-binding site are generally not considered as bnAbs. HIV gp41 MPER-targeting antibodies bind to a fusion-intermediate of gp41 and prevent conformational changes in gp41 that are necessary for fusion. The field of bnAb research for HIV treatment and prevention is developing rapidly, and many new bnAbs within the above-mentioned classes have been described in recent years. These novel bnAbs were either isolated from patients or were engineered by rational design.

When latently infected cells become active, they start to express HIV Env. In turn, cells that express the Fc receptor CD16 on their surface, mainly natural killer cells, recognize infected cells that are coated with antibodies and mediate ADCC. Therefore, bnAbs have the potential to reduce the viral reservoir in patients.

Reduction of the viral reservoir can be accelerated when bnAbs are used in combination latency-reversing agents. Lectins are proteins that bind complex carbohydrate structures. The complementary determining region 2 CDR2 -like domain of the D1 of CD4 contains residues critical for interaction with gp but is unstable when expressed on its own.

CD4-mimicking peptides were designed by inserting critical residues from the CDR2-like region of CD4 into the CDR2-like region of stable but inactive scorpion toxin derivatives.

Fusion inhibitors FIs are short peptides based on the HR2 of gp FIs bind to the HR1 of gp41 and prevent the formation of the six-helix bundle that is necessary for the fusion of viral and cellular membranes. To overcome this limitation, bAVPs are designed that simultaneously bind two different targets. A summary of bAVPs and their antiviral potency is provided in Table 1. A bAVPs targeting receptor binding. B bAVPs targeting receptor binding and coreceptor binding.

C bAVP targeting coreceptor binding. D bAVPs targeting receptor and membrane fusion. E bAVPs targeting coreceptor binding and membrane fusion. The targeted entry steps and molecular targets of different bAVPs are shown.

The mean geometric IC 50 s and number of isolates that were tested in single-round infection assays are indicated for each bAVP. Dendritic cell-specific intercellular adhesion moleculegrabbing non-integrin DC-SIGN is a C-type lectin receptor expressed on the surface of dendritic cells that binds to high mannose glycans on gp Interestingly, changing the serine at position 60 of the D1 of sCD4 to cysteine S60C was previously shown to enhance the affinity of sCD4 to gp by enabling the formation of a disulfide bond between the S60C of sCD4 and the cysteine at position of gp However, further characterization of the fusion protein, e.

In another study, bispecific antibodies were designed that resembled normal mAbs in their structure. The bispecific antibodies are generated by combining the CrossMap technology, which involves C H 1 and C L domain swapping, with the knob-into-hole technology, which introduces a point mutation in the C H 3 domain for heavy chain heterodimerization. Alternatively, several genetic strategies may be used to deliver genes encoding bAVPs. Virus-derived vectors, such as AAV vectors, have been used to deliver genes to non-hematopoietic cells by direct injection into the target site.

Probiotic bacteria of the genital tract can be engineered to secrete bAVPs for prevention. Autologous hematopoietic cells can be modified to secrete bAVPs with viral and non-viral vectors.

In a different study, bispecific antibodies were found to be less effective in comparison to their parental antibodies. The structure of the individual Env spikes also impedes binding of both antibody arms to the same Env spike. In order to allow bispecific antibodies to engage one Env spike with both arms, variants based on IgG3 were designed. In order to measure the distance between two antibody arms that allows binding to the same Env spike, two antibody fragments were linked using variable-length double-stranded DNA.

Instead, ibalizumab interferes with coreceptor engagement of CD4-bound virions. Resistance to ibalizumab is readily acquired by mutations in HIV Env that allow coreceptor engagement despite binding of ibalizumab to CD4. In order to overcome this limitation, the C terminus of each ibalizumab heavy chain was linked using a four-repeat GGGGS linker to a stable antibody fragment that binds to a conserved CD4-induced epitope of gp, m Detailed IC 50 values for each strain and inhibitor were not provided.

Screening a phage library of diversified human antibody heavy-chain variable domains resulted in the identification of m36, the aforementioned stable antibody fragment that binds to a conserved CD4-induced epitope of gp In another study, sCD4 was fused to modified versions of the mAb E51, which also targets the coreceptor-binding site.

Introducing three mutations present in D1. Overall, fusing sCD4 to coreceptor binding-site-targeting moieties seems to be a highly promising approach. The high potency of eCD4-Ig in comparison to the other bAVPs based on the same concept is probably related to use of the small coreceptor-mimicking peptide as opposed to antibody fragments, which may have problems reaching the coreceptor-binding site due to steric hindrance or improper folding.

Nevertheless, eCD4-Ig has a high potential for HIV prophylaxis and therapy and can be expected to advance to testing in clinical trials.

The remarkable antiviral effect was likely due to bringing the scFv moiety close to its site of action, the CD4 receptor on the surface of HIV target cells.

Antiviral activity was optimal when a residue flexible linker was used as shorter and longer linkers decreased the potency. In a follow-up study, bispecific antibodies were designed in which one arm was derived from ibalizumab or PRO, and the other arm was derived from bnAbs targeting HIV Env. Therefore, combining FIs with sCD4 addresses one of the major drawbacks of FIs, namely their inability to bind to virus particles in the absence of target cell binding.

Both sCD4 and FIs have been tested in clinical trials and were found to be safe. The bAVPs could be used to augment the effect of existing therapies in individuals on ART who fail to suppress viremia.

For example, the 2DLT worked synergistically with antiretroviral drugs, including nucleoside and non-nucleoside reverse-transcriptase inhibitors as well as protease inhibitors. Therefore, it might be necessary to adapt an antibody-based design, e. Additionally, GRFT originates from algae and may therefore induce immune responses. The antiviral activity of 5Plinker-C37 was similar to that observed for 5Plinker-C This was likely due to the lack of synergy between the scFv 17b moiety and the FI T45 moiety as linking FI T45 to scFv 17b alone also did not increase the potency of scFv 17b.

However, the trifunctional antibody was not compared to mixtures of the single moieties. Despite this unnatural design, the trispecific antibody had a similar plasma half-life to VRC01 in macaques. The trifunctional antibody could be a good candidate for HIV prevention, as it was effective against HIV isolates that were resistant to the individual antibodies.

Further studies are necessary to evaluate the capability of the trispecific antibody to bind to HIV Env on the surface of infected cells and induce ADCC. E8 is The broad neutralization activity of bAVPs is likely due to their unique mechanism of action.

Because HIV needs to maintain its ability to interact with surface CD4 on target cells, mutations that affect binding to sCD4 inevitably reduce viral fitness. The sCD4-induced conformational state of HIV Env is transient and is followed by the permanent loss of infectivity of the virus.

It has been suggested that Falckenhagen also studied with Johann Jakob Graf , a pupil of Sylvius Leopold Weiss , and later with Weiss himself. Please help improve this article by adding citations to reliable sources. Safety Compare it to It seems that traffic on this site is too low to be displayed, sorry. Domain Registration Data Compare it to Subdomains Traffic Shares.

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