Characterization of a Novel Human Immunodeficiency Virus Type 1 Neutralizable Epitope within the Immunodominant Region of gp41

Viveros, Monica; Dickey, Chad A.; Cotropia, Joseph; Gevorkian, Gohar; Larralde, Carlos; Broliden, Kristina; Levi, Mikael; Burgess, Andrew W. O.; Cao, Chuanhai; Weiner, David B.; Agadjanyan, Michael G.; Ugen, Kenneth E.

doi:10.1006/viro.2000.0269

Cited by 10 publications

(8 citation statements)

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“…Since it is extremely difficult to maintain the monomer form of any single cysteine containing peptide, we may also suppose that a discrepancy in all previous studies was related to this phenomena. On the other hand, there is at least one human neutralizing monoclonal anti-HIV-1 gp41 antibody that recognized the immunodominant region loop comprising peptide only in the presence of ␤-mercaptoethanol indicating that some individuals have antibodies recognizing linear peptide [24,25]. In addition, in agreement with these reports, we found here a correlation between the presence of anti-linear peptide antibodies and endurance of infection.…”

Section: Discussionsupporting

confidence: 92%

Antigenic properties of phage displayed peptides comprising disulfide-bonded loop of the immunodominant region of HIV-1 gp41

et al. 2004

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Section: Discussionsupporting

confidence: 92%

Antigenic properties of phage displayed peptides comprising disulfide-bonded loop of the immunodominant region of HIV-1 gp41

et al. 2004

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“…Less is known about how this antibody inhibits infection, but the mechanism may be related to the one used by D5 since both target the heptad repeats that form six-helix coiled-coiled fusion intermediates in vitro. Clone 3 is specific for the immunodominant region and shows neutralizing activity against a diverse group of laboratory-adapted HIV-1 strains (10,51). This antibody was produced by EBV-transformed PBMCs from an asymptomatic HIV-1-positive donor (10).…”

Section: Vol 84 2010 Gp41 Epitope Mapping In Hiv-1 5037mentioning

confidence: 99%

Anti-gp41 Antibodies Cloned from HIV-Infected Patients with Broadly Neutralizing Serologic Activity

Pietzsch

Scheid

Mouquet

et al. 2010

J Virol

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Most HIV-infected individuals develop antibodies to the gp120 and gp41 components of the viral spike; however, only a fraction of these individuals mount a broadly neutralizing serum response against HIV. We have cloned anti-HIV antibodies from the memory B-cell compartment of six individuals with variable viral loads and high titers of broadly neutralizing antibodies. Here, we report on the features of the anti-gp41 response in these patients. Competition experiments with previously characterized antibodies targeting defined epitopes on the gp41 ectodomain showed antibodies directed against the "immunodominant region" (cluster I), the carboxy-terminal heptad repeat (cluster II), and the membrane-proximal external region (cluster IV). On the other hand, antibodies directed against the amino-terminal part of the molecule, including the fusion peptide, polar region, and the N-terminal heptad repeat, were not detected. When all patients' data were combined, unique B-cell clones targeting cluster I, II, and IV accounted for 32%, 49%, and 53% of all anti-gp41-reactive B cells, respectively; therefore, no single region was truly immunodominant. Finally, although we found no new neutralizing epitopes or HIV-1-neutralizing activity by any of the gp41 antibodies at concentrations of up to 50 g/ml, high concentrations of 7 out of 15 anti-cluster I antibodies neutralized tier 2 viruses.The trimeric envelope spike of the human immunodeficiency virus (HIV) consists of three heterodimers of the transmembrane glycoprotein (gp41) and the surface glycoprotein (gp120) (59). Whereas gp120 carries the CD4 and chemokine receptor binding sites, gp41 is crucial for fusion between the viral particle and the cell membrane (Fig. 1a). The glycine-rich fusion peptide, located at the amino-terminal region of gp41, is normally covered by gp120 but is transiently exposed for interaction with the target cell membrane when gp120 binds to its receptors (14). The fusion peptide is followed by a serine/ threonine-rich polar region and heptad repeats, which form leucine zippers that mediate assembly of the coiled-coiled form of gp41 in response to gp120 engagement (8,22,24,52). Finally, the membrane-proximal external region (MPER) also plays a role in virus-host membrane fusion (38); however, the mechanism by which it enhances fusion is not known.Some regions of gp41 are accessible to antibodies on the native gp140 trimer; however, others are exposed to the immune system only after gp120 shedding (40). In addition, otherwise cryptic gp41 epitopes are uncovered during viral fusion with the cell membrane (13). Consistent with gp41 exposure to the immune system, serologic studies of infected individuals indicate that there is a strong humoral response to gp41 during HIV infection (35) which precedes the response against gp120 (26).Antibodies to gp41 have been isolated from phage display libraries, as have Epstein-Barr virus (EBV) immortalized B cells from infected individuals (4, 53). Some of these anti-gp41 antibodies can neutralize HIV infection in ...

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“…However, only a limited number of antibodies have been developed for potential use as passive immunotherapies. To date, the human anti-HIV-1 antibodies that have been characterized as potential candidates for expanded testing in primates in passive immunotherapy protocols are 2F5 (Stiegler et al, 2002), 4E10, 2G12 (Stiegler et al, 2002), b12 Roben et al, 1994;D'Souza et al, 1997), F105 , and clone 3 (Cotropia et al, 1992;Cotropia et al, 1996;Viveros et al, 2000;Ferrantelli et al, 2004). 2F5, 4E10 and clone 3 are directed against gp41, and these human monoclonal anti-HIV antibodies have been demonstrated to neutralize across different clades of HIV-1 (Cotropia et al, 1992;Cotropia et al, 1996;Li et al, 1997;Stiegler et al, 2002;Ferrantelli et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In this report, we have characterized a novel human IgM anti-HIV antibody, which binds to a novel epitope of gp41. C37 was isolated from the same nondisease progressing HIV-1-positive donor as was used for the generation and characterization of Clone 3 previously (Cotropia et al, 1996;Viveros et al, 2000;Ferrantelli et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Human Anti-HIV-1 gp41 IgM Monoclonal Antibody Designated Clone 37

Cao¹,

Bai²,

Holloway³

et al. 2004

dna cell biol

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Human monoclonal antibodies (HuMAbs) demonstrate great potential for passive immunotherapy against HIV-1. The gp41 transmembrane envelope glycoprotein of HIV has an important role in the pathogenicity of AIDS and importantly displays considerably less hypervariability than the gp120 surface envelope HIV glycoprotein, which makes it particularly a better candidate for the development of passive and active immunotherapies. The general aim of this study was to develop HuMAbs to HIV surface glycoproteins and particularly gp41. Peripheral blood mononuclear cells (PBMCs) were isolated from an HIV-seropositive long-term nondisease progressing patient. B-cells from this individual were then immortalized by Epstein-Barr virus (EBV) transformation, and antibody production was stabilized by fusion of transformed cells with a heteromyeloma. Subsets of the human heterohybridomas so generated were analyzed by ELISA. The hybridoma with the highest binding by immunoassay against gp160 was further analyzed. This hybridoma, designated as clone 37 (C37), was determined to be an IgM Kappa antibody and overlapping peptides of HIV envelope proteins (derived from the MN tissue culture line adapted HIV isolate) were used to map the specific binding domain of this HuMAb. Overlapping peptides designated 2026 (SWSNKSLDDIWNN, AA614-626), and 2027 (DDIWNNMTWMQWEREIDNYT, AA621-640) within the HIV-1 gp41 transmembrane glycoprotein were demonstrated to bind to C37 indicating that the specific binding domain for the antibody was DDIWNN. High affinity binding of C37 by ELISA to recombinant gp41 was demonstrated as well. Few IgM HuMAbs against HIV have been generated and characterized. Theoretically, because of the pentameric binding nature of IgM antibodies as well as their very efficient ability to activate complement, such reagents could have potential as anti-HIV agents. 836

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Characterization of a Novel Human Immunodeficiency Virus Type 1 Neutralizable Epitope within the Immunodominant Region of gp41

Cited by 10 publications

References 51 publications

Antigenic properties of phage displayed peptides comprising disulfide-bonded loop of the immunodominant region of HIV-1 gp41

Antigenic properties of phage displayed peptides comprising disulfide-bonded loop of the immunodominant region of HIV-1 gp41

Anti-gp41 Antibodies Cloned from HIV-Infected Patients with Broadly Neutralizing Serologic Activity

Characterization of a Novel Human Anti-HIV-1 gp41 IgM Monoclonal Antibody Designated Clone 37

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