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Characterization of a Novel Dengue Serotype 4 Virus-Specific Neutralizing Epitope on the Envelope Protein Domain III.

Ji GH, Deng YQ, Yu XJ, Jiang T, Wang HJ, Shi X, Zhang DP, Li XF, Zhu SY, Zhao H, Dai JX, Qin CF, Guo YJ - PLoS ONE (2015)

Bottom Line: Furthermore, site-directed mutagenesis assay identified two critical residues (T388 and H390).The epitope is variable among different DENV serotypes but is highly conserved among four DENV4 genotypes.Affinity measurement showed that naturally occurring variations in ED3 outside the epitope region did not alter the binding of mAb 1G6.

View Article: PubMed Central - PubMed

Affiliation: Department of Traditional Chinese Medicine, Navy General Hospital, Beijing, China; International Joint Cancer Institute, Second Military Medical University, Shanghai, China.

ABSTRACT
The dengue virus (DENV) envelope protein domain III (ED3) has been suggested to contain receptor recognition sites and the critical neutralizing epitopes. Up to date, relatively little work has been done on fine mapping of neutralizing epitopes on ED3 for DENV4. In this study, a novel mouse type-specific neutralizing antibody 1G6 against DENV4 was obtained with both prophylactic and therapeutic effects. The epitope was mapped to residues 387-390 of DENV4 envelope protein. Furthermore, site-directed mutagenesis assay identified two critical residues (T388 and H390). The epitope is variable among different DENV serotypes but is highly conserved among four DENV4 genotypes. Affinity measurement showed that naturally occurring variations in ED3 outside the epitope region did not alter the binding of mAb 1G6. These findings expand our understanding of the interactions between neutralizing antibodies and the DENV4 and may be valuable for rational design of DENV vaccines and antiviral drugs.

No MeSH data available.


Related in: MedlinePlus

Prophylactic and therapeutic efficacy of 1G6 in suckling mice.(A) Mice were administered saline or a single 50 μg dose of 1G6 via an IP route one day prior to infection and then infected intracerebrally with 105 PFU/ml of the mouse-adapted DENV–4 virus and monitored for survival for 21 days after infection. (B) Therapeutic efficacy of 1G6 was tested by administering a single 50 μg dose of 1G6 intraperitoneally 4h or 24h after infection with 105 PFU/ml intracerebrally. The number of suckling mice for each group ranged from 10 to 11. Kaplan—Meier survival curves were analyzed by the log-rank test and significant differences are indicated by asterisks (*** p<0.001; * p<0.05).
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pone.0139741.g003: Prophylactic and therapeutic efficacy of 1G6 in suckling mice.(A) Mice were administered saline or a single 50 μg dose of 1G6 via an IP route one day prior to infection and then infected intracerebrally with 105 PFU/ml of the mouse-adapted DENV–4 virus and monitored for survival for 21 days after infection. (B) Therapeutic efficacy of 1G6 was tested by administering a single 50 μg dose of 1G6 intraperitoneally 4h or 24h after infection with 105 PFU/ml intracerebrally. The number of suckling mice for each group ranged from 10 to 11. Kaplan—Meier survival curves were analyzed by the log-rank test and significant differences are indicated by asterisks (*** p<0.001; * p<0.05).

Mentions: Prophylactic and therapeutic efficacy of mAb 1G6 was also investigated in mice by administering a single 50 μg dose of mAb 1G6 or PBS before or after lethal DENV4 challenge. The results showed that prophylactic administration with a single dose of 50 μg 1G6 24 h before lethal DENV4 challenge conferred 50% protection in mice (p<0.001) (Fig 3A). Notably, 90% of mice survived when 1G6 was administered 4 h after challenge (P < 0.001), even 30% of mice survived when given 24 hours after DENV4 challenge (P < 0.05) (Fig 4B). These results strongly indicated the therapeutic potential of 1G6 in antibody based therapy against DENV4 infection.


Characterization of a Novel Dengue Serotype 4 Virus-Specific Neutralizing Epitope on the Envelope Protein Domain III.

Ji GH, Deng YQ, Yu XJ, Jiang T, Wang HJ, Shi X, Zhang DP, Li XF, Zhu SY, Zhao H, Dai JX, Qin CF, Guo YJ - PLoS ONE (2015)

Prophylactic and therapeutic efficacy of 1G6 in suckling mice.(A) Mice were administered saline or a single 50 μg dose of 1G6 via an IP route one day prior to infection and then infected intracerebrally with 105 PFU/ml of the mouse-adapted DENV–4 virus and monitored for survival for 21 days after infection. (B) Therapeutic efficacy of 1G6 was tested by administering a single 50 μg dose of 1G6 intraperitoneally 4h or 24h after infection with 105 PFU/ml intracerebrally. The number of suckling mice for each group ranged from 10 to 11. Kaplan—Meier survival curves were analyzed by the log-rank test and significant differences are indicated by asterisks (*** p<0.001; * p<0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592203&req=5

pone.0139741.g003: Prophylactic and therapeutic efficacy of 1G6 in suckling mice.(A) Mice were administered saline or a single 50 μg dose of 1G6 via an IP route one day prior to infection and then infected intracerebrally with 105 PFU/ml of the mouse-adapted DENV–4 virus and monitored for survival for 21 days after infection. (B) Therapeutic efficacy of 1G6 was tested by administering a single 50 μg dose of 1G6 intraperitoneally 4h or 24h after infection with 105 PFU/ml intracerebrally. The number of suckling mice for each group ranged from 10 to 11. Kaplan—Meier survival curves were analyzed by the log-rank test and significant differences are indicated by asterisks (*** p<0.001; * p<0.05).
Mentions: Prophylactic and therapeutic efficacy of mAb 1G6 was also investigated in mice by administering a single 50 μg dose of mAb 1G6 or PBS before or after lethal DENV4 challenge. The results showed that prophylactic administration with a single dose of 50 μg 1G6 24 h before lethal DENV4 challenge conferred 50% protection in mice (p<0.001) (Fig 3A). Notably, 90% of mice survived when 1G6 was administered 4 h after challenge (P < 0.001), even 30% of mice survived when given 24 hours after DENV4 challenge (P < 0.05) (Fig 4B). These results strongly indicated the therapeutic potential of 1G6 in antibody based therapy against DENV4 infection.

Bottom Line: Furthermore, site-directed mutagenesis assay identified two critical residues (T388 and H390).The epitope is variable among different DENV serotypes but is highly conserved among four DENV4 genotypes.Affinity measurement showed that naturally occurring variations in ED3 outside the epitope region did not alter the binding of mAb 1G6.

View Article: PubMed Central - PubMed

Affiliation: Department of Traditional Chinese Medicine, Navy General Hospital, Beijing, China; International Joint Cancer Institute, Second Military Medical University, Shanghai, China.

ABSTRACT
The dengue virus (DENV) envelope protein domain III (ED3) has been suggested to contain receptor recognition sites and the critical neutralizing epitopes. Up to date, relatively little work has been done on fine mapping of neutralizing epitopes on ED3 for DENV4. In this study, a novel mouse type-specific neutralizing antibody 1G6 against DENV4 was obtained with both prophylactic and therapeutic effects. The epitope was mapped to residues 387-390 of DENV4 envelope protein. Furthermore, site-directed mutagenesis assay identified two critical residues (T388 and H390). The epitope is variable among different DENV serotypes but is highly conserved among four DENV4 genotypes. Affinity measurement showed that naturally occurring variations in ED3 outside the epitope region did not alter the binding of mAb 1G6. These findings expand our understanding of the interactions between neutralizing antibodies and the DENV4 and may be valuable for rational design of DENV vaccines and antiviral drugs.

No MeSH data available.


Related in: MedlinePlus