Limits...
Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.

Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA - Nat. Struct. Mol. Biol. (2009)

Bottom Line: The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion.Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism.Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street JFB 826, Boston, Massachusetts 02115, USA. jianhua_sui@dfci.harvard.edu

ABSTRACT
Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

Show MeSH

Related in: MedlinePlus

Prophylactic and therapeutic efficacy of anti-H5 nAbs in mice(a and b) Prophylactic efficacy. % survival of mice treated with anti-H5 nAbs or control mAb 1h before lethal challenge by i.n. inoculation with (a) H5-VN04 or (b) H5-HK97 viruses. (c-f). Therapeutic efficacy. Mice were inoculated with H5-VN04 and injected with nAbs at 24, 48, 72h post-inoculation (hpi) (c, e and f) or with H5-HK97 at 24 hpi (d).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2692245&req=5

Figure 2: Prophylactic and therapeutic efficacy of anti-H5 nAbs in mice(a and b) Prophylactic efficacy. % survival of mice treated with anti-H5 nAbs or control mAb 1h before lethal challenge by i.n. inoculation with (a) H5-VN04 or (b) H5-HK97 viruses. (c-f). Therapeutic efficacy. Mice were inoculated with H5-VN04 and injected with nAbs at 24, 48, 72h post-inoculation (hpi) (c, e and f) or with H5-HK97 at 24 hpi (d).

Mentions: The protective efficacy of the three IgG1s against H5N1 virus infection was evaluated in a BALB/c mouse model (Fig. 2). Mice were treated with IgG1s before (prophylactically) or after (therapeutically) lethal viral challenge. Prophylaxis using 10 mg kg-1 of IgG1s effectively protected (80-100%) mice when challenged with a high lethal dose of H5-VN04 (Clade 1) or A/HongKong/483/97 (H5-HK97) (Clade 0) (Fig. 2a-b). Therapeutic treatment with 15 mg kg-1 (an achievable dose in humans) of IgG1 at 24h post-inoculation also protected 80-100% of the mice challenged with either H5-VN04 or H5-HK97 virus (Fig. 2c-d). Mice treated at later times (48 or 72h post-inoculation) with H5-VN04 showed similar or higher levels of protection (Fig. 2e-f). Furthermore, surviving mice remained healthy and showed minimal body weight loss over the 2-week observation period (data not shown).


Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.

Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA - Nat. Struct. Mol. Biol. (2009)

Prophylactic and therapeutic efficacy of anti-H5 nAbs in mice(a and b) Prophylactic efficacy. % survival of mice treated with anti-H5 nAbs or control mAb 1h before lethal challenge by i.n. inoculation with (a) H5-VN04 or (b) H5-HK97 viruses. (c-f). Therapeutic efficacy. Mice were inoculated with H5-VN04 and injected with nAbs at 24, 48, 72h post-inoculation (hpi) (c, e and f) or with H5-HK97 at 24 hpi (d).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2692245&req=5

Figure 2: Prophylactic and therapeutic efficacy of anti-H5 nAbs in mice(a and b) Prophylactic efficacy. % survival of mice treated with anti-H5 nAbs or control mAb 1h before lethal challenge by i.n. inoculation with (a) H5-VN04 or (b) H5-HK97 viruses. (c-f). Therapeutic efficacy. Mice were inoculated with H5-VN04 and injected with nAbs at 24, 48, 72h post-inoculation (hpi) (c, e and f) or with H5-HK97 at 24 hpi (d).
Mentions: The protective efficacy of the three IgG1s against H5N1 virus infection was evaluated in a BALB/c mouse model (Fig. 2). Mice were treated with IgG1s before (prophylactically) or after (therapeutically) lethal viral challenge. Prophylaxis using 10 mg kg-1 of IgG1s effectively protected (80-100%) mice when challenged with a high lethal dose of H5-VN04 (Clade 1) or A/HongKong/483/97 (H5-HK97) (Clade 0) (Fig. 2a-b). Therapeutic treatment with 15 mg kg-1 (an achievable dose in humans) of IgG1 at 24h post-inoculation also protected 80-100% of the mice challenged with either H5-VN04 or H5-HK97 virus (Fig. 2c-d). Mice treated at later times (48 or 72h post-inoculation) with H5-VN04 showed similar or higher levels of protection (Fig. 2e-f). Furthermore, surviving mice remained healthy and showed minimal body weight loss over the 2-week observation period (data not shown).

Bottom Line: The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion.Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism.Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street JFB 826, Boston, Massachusetts 02115, USA. jianhua_sui@dfci.harvard.edu

ABSTRACT
Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

Show MeSH
Related in: MedlinePlus