Characterization of the variable regions of a chimpanzee monoclonal antibody with potent neutralizing activity against HIV-1

Vijh-Warrier, Sujata; Murphy, Ellen; Yokoyama, Izumi; Tilley, Shermaine A.

doi:10.1016/0161-5890(95)00081-x

Cited by 11 publications

(11 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ␥1 heavy chains had high degrees of identity (89.4% for HEV#4 and 88.5% for HEV#31) at the nucleotide level with two different ␥1 heavy chains from the human VH3 gene family. The degree of identity between the chimpanzee and human ␥-chain genes was similar to that of the only other chimpanzee antibody characterized to date, an anti-HIV gp160 MAb having 92% identity with its nearest human germ line equivalent (59).…”

Section: Discussionmentioning

confidence: 60%

Identification by Phage Display and Characterization of Two Neutralizing Chimpanzee Monoclonal Antibodies to the Hepatitis E Virus Capsid Protein

Schofield

Glamann

Emerson³

et al. 2000

J Virol

155

109

View full text Add to dashboard Cite

Two monoclonal antibodies (MAbs) against the ORF2 protein of the SAR-55 strain of hepatitis E virus (HEV) were isolated by phage display from a cDNA library of chimpanzee (Pan troglodytes) ␥1/ antibody genes. Both MAbs, HEV#4 and HEV#31, bound to reduced, denatured open reading frame 2 (ORF2) protein in a Western blot, suggesting that they recognize linear epitopes. The affinities (equilibrium dissociation constants, K d ) for the SAR-55 ORF2 protein were 1.7 nM for HEV#4 and 5.4 nM for HEV#31. The two MAbs also reacted in an enzyme-linked immunosorbent assay with recombinant ORF2 protein from a heterologous HEV, the Meng strain. Each MAb blocked the subsequent binding of the other MAb to homologous ORF2 protein in indirect competition assays, suggesting that they recognize the same or overlapping epitopes. Radioimmunoprecipitation assays suggested that at least part of the linear epitope(s) recognized by the two MAbs is located between amino acids 578 and 607. MAbs were mixed with homologous HEV in vitro and then inoculated into rhesus monkeys (Macaca mulatta) to determine their neutralizing ability. Whereas all control animals developed hepatitis (elevated liver enzyme levels in serum) and seroconverted to HEV, those receiving an inoculum incubated with either HEV#4 or HEV#31 were not infected. Therefore, each MAb neutralized the SAR-55 strain of HEV in vitro.Hepatitis E is an acute disease endemic in many countries throughout developing parts of the world, in particular on the continents of Africa and Asia, where epidemics have also occurred. The causative agent, hepatitis E virus (HEV), is transmitted via the fecal-oral route, predominantly through contaminated water (45). HEV is an RNA virus with a positive-sense genome approximately 7.5 kb in length. The genome contains three open reading frames (ORFs); ORF2 encodes the putative capsid protein (45). Hepatitis E has a low mortality rate in young adults (38). However, mortality rates can reach 20% in women in the third trimester of pregnancy (32, 58). Surprisingly, in industrialized countries such as the United States, where hepatitis E is not endemic, a significant proportion of healthy individuals within the general population are seropositive (over 20% in some areas; 39, 50). However, clinical hepatitis E is rare in these countries and usually is seen in individuals who acquired the infection during travel to a region in which HEV is endemic or epidemic.It has been suggested that animals serve as reservoirs for HEV and that human infections may, in part, be zoonoses. There have been several reports of HEV-specific (anti-HEV) antibody in animals (1, 9, 28, 29). Furthermore, an HEV-like virus was recently isolated from naturally infected swine in the United States (40). Although four genotypes of HEV have been identified, to date, only one serotype of HEV has been recognized. Therefore, it may be possible to produce a broadly protective vaccine. Passively transferred anti-HEV serum significantly reduced virus shedding in feces and abrogated disease in nonhu...

show abstract

Section: Discussionmentioning

confidence: 60%

Identification by Phage Display and Characterization of Two Neutralizing Chimpanzee Monoclonal Antibodies to the Hepatitis E Virus Capsid Protein

Schofield

Glamann

Emerson³

et al. 2000

J Virol

155

109

View full text Add to dashboard Cite

show abstract

“…Requirements for expression of C108g and 10/76b epitopes in YU2. Previous studies showed that the presence of residues G167 and V169 in the V2 domain allows expression of the C108g and 10/76b epitopes in several different Env backbones (36,40). YU2 Env contains D and V at these positions, suggesting that the only element of the C108g and 10/76b epitopes missing from this Env was G167.…”

Section: Resultsmentioning

confidence: 99%

“…The characteristics of chimpanzee MAb C108g and its epitope were previously described (27,36,38,40). 10/76b was isolated from a rat immunized with soluble HXB10 gp120 (23), and characteristics of its epitope have also been described previously (32).…”

Section: Methodsmentioning

confidence: 99%

“…However, several anti-V2 MAbs possess unusually potent type-specific neutralizing activities. These include C108g, directed against a complex epitope localized in the V2 domain (36,40), and 2909, the first anti-HIV MAb that reacts specifically with a quaternary epitope restricted to native Env oligomers present on the surface of intact virion particles (14). The epitopes recognized by these MAbs have not been…”

mentioning

confidence: 99%

See 1 more Smart Citation

Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence

Honnen

Krachmarov

Kayman³

et al. 2007

J Virol

View full text Add to dashboard Cite

Only a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HIV-1 neutralization.A major factor thwarting the development of a successful human immunodeficiency virus type 1 (HIV-1) vaccine is the resistance of primary isolates to neutralization by classes of antibodies commonly induced after infection or immunization (1, 45). Sequence variability at major neutralization sites contributes to this effect, but recent evidence argues that the major factor in this resistance is conformational shielding of susceptible epitopes in the native oligomeric complex (18,28). Nlinked glycans located in various regions of Env play a general role in epitope masking (6,7,22,39), and increasing evidence documents a dominant role for the V1/V2 domain in such masking (6,12,18,28,34,44). One approach being investigated to overcome the effects of this masking is to delete the V2 domain from Env-based immunogens. Oligomeric V2-deleted forms of gp140 have been reported to possess enhanced immunogenicity over the wild-type molecule and to produce increased titers of neutralizing antibodies (8,21,33,43). However, these effects are only modest, and recent studies indicate that this approach involves the induction of type-specific neutralizing antibodies directed mostly toward highly variable epitopes in V1 that possess limited neutralizing activities for heterologous isolates (10, 42).The critical role of conformational masking in neutralization resistance poses a major conundrum fo...

show abstract

“…Broad cross-neutralization of heterologous viruses may be explained by multiple responses to isolate-specific epitopes that accumulate over time or by responses against highly conserved epitopes, including those recognized by the human monoclonal antibodies 2G12, IgG1b12 and 2F5 (25). BCN antibodies in the sera of these infected patients indicate that HIV-1 strains share cross-reactive neutralization epitopes and that humans have the capacity to respond to these epitopes (8)(9)(10)(26)(27)(28).…”

Section: Hiv-1 Primary Isolatementioning

confidence: 99%

Identification and characterization of broadly cross-reactive neutralizing antibodies in patients infected with HIV-1 B'/C recombinant (CRF07_BC)

et al. 2012

View full text Add to dashboard Cite

Abstract. The identification of broadly cross-reactive neutralizing (BCN) antibodies is essential for the development of a more universally effective vaccine for human immunodeficiency virus (HIV). In this study, CRF07_BC serum was analyzed for cross-clade antibody reactivity and neutralization. A total of 117 HIV-1 sera (CRF07_BC) were screened for their capacity to neutralize three primary HIV-1 isolates. A total of 18 out of 117 sera cross-neutralized all three viruses, and were tested along with eight randomly selected non-BCN sera against seven primary HIV-1 isolates and two laboratory strains that represented different clades and tropisms. BCN sera neutralized eight or all nine of these primary isolates. Non-BCN sera did not display any broadly cross-reactive neutralizing responses. BCN sera neutralized with higher frequency and geometric mean titers compared to non-BCN sera. Sera from asymptomatic individuals on average neutralized a significantly greater number of the three key isolates than sera from symptomatic individuals. Our data indicate that the three HIV-1 isolated strains are sufficient to screen broad cross-neutralizing sera, and that BCN responses may contribute to protection from infection and disease progression. The neutralizing antibody response demonstrated extensive cross-neutralization, suggesting that neutralizing antibodies induced by vaccines will have a relatively low epitope diversity to overcome in patients infected with HIV-1 B'/C recombinant (CRF07_BC).

show abstract

Characterization of the variable regions of a chimpanzee monoclonal antibody with potent neutralizing activity against HIV-1

Cited by 11 publications

References 52 publications

Identification by Phage Display and Characterization of Two Neutralizing Chimpanzee Monoclonal Antibodies to the Hepatitis E Virus Capsid Protein

Identification by Phage Display and Characterization of Two Neutralizing Chimpanzee Monoclonal Antibodies to the Hepatitis E Virus Capsid Protein

Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence

Identification and characterization of broadly cross-reactive neutralizing antibodies in patients infected with HIV-1 B'/C recombinant (CRF07_BC)

Contact Info

Product

Resources

About