|
|
| [PMID]: | 28275193 |
| [Au] Autor: | Chuang GY; Geng H; Pancera M; Xu K; Cheng C; Acharya P; Chambers M; Druz A; Tsybovsky Y; Wanninger TG; Yang Y; Doria-Rose NA; Georgiev IS; Gorman J; Joyce MG; O'Dell S; Zhou T; McDermott AB; Mascola JR; Kwong PD |
| [Ad] Endereço: | Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. |
| [Ti] Título: | Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity. |
| [So] Source: | J Virol;91(10), 2017 May 15. | | [Is] ISSN: | 1098-5514 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The HIV-1 envelope (Env) trimer is a target for vaccine design as well as a conformational machine that facilitates virus entry by transitioning between prefusion-closed, CD4-bound, and coreceptor-bound conformations by transitioning into a postfusion state. Vaccine designers have sought to restrict the conformation of the HIV-1 Env trimer to its prefusion-closed state as this state is recognized by most broadly neutralizing, but not nonneutralizing, antibodies. We previously identified a disulfide bond, I201C-A433C (DS), which stabilizes Env in the vaccine-desired prefusion-closed state. When placed into the context of BG505 SOSIP.664, a soluble Env trimer mimic developed by Sanders, Moore, and colleagues, the engineered DS-SOSIP trimer showed reduced conformational triggering by CD4. Here, we further stabilize DS-SOSIP through a combination of structure-based design and 96-well-based expression and antigenic assessment. From 103 designs, we identified one, named DS-SOSIP.4mut, with four additional mutations at the interface of potentially mobile domains of the prefusion-closed structure. We also determined the crystal structures of DS-SOSIP.4mut at 4.1-Å resolution and of an additional DS-SOSIP.6mut variant at 4.3-Å resolution, and these confirmed the formation of engineered disulfide bonds. Notably, DS-SOSIP.4mut elicited a higher ratio of tier 2 autologous titers versus tier 1 V3-sensitive titers than BG505 SOSIP.664. DS-SOSIP.4mut also showed reduced recognition of CD4 and increased thermostability. The improved antigenicity, thermostability, and immunogenicity of DS-SOSIP.4mut suggest utility as an immunogen or a serologic probe; moreover, the specific four alterations identified here, M154, M300, M302, and L320 (4mut), can also be transferred to other HIV-1 Env trimers of interest to improve their properties. One approach to elicit broadly neutralizing antibodies against HIV-1 is to stabilize the structurally flexible HIV-1 envelope (Env) trimer in a conformation that displays predominantly broadly neutralizing epitopes and few to no nonneutralizing epitopes. The prefusion-closed conformation of HIV-1 Env has been identified as one such preferred conformation, and a current leading vaccine candidate is the BG505 DS-SOSIP variant, comprising two disulfides and an Ile-to-Pro mutation of Env from strain BG505. Here, we introduced additional mutations to further stabilize BG505 DS-SOSIP in the vaccine-preferred prefusion-closed conformation. In guinea pigs, our best mutant, DS-SOSIP.4mut, elicited a significantly higher ratio of autologous versus V3-directed neutralizing antibody responses than the SOSIP-stabilized form. We also observed an improvement in thermostability and a reduction in CD4 affinity. With improved antigenicity, stability, and immunogenicity, DS-SOSIP.4mut-stabilized trimers may have utility as HIV-1 immunogens or in other antigen-specific contexts, such as with B-cell probes. |
| [Mh] Termos MeSH primário: |
Antígenos CD4/imunologia
Antígenos CD4/metabolismo
Antígenos HIV/imunologia
HIV-1/imunologia
Produtos do Gene env do Vírus da Imunodeficiência Humana/química
Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
|
| [Mh] Termos MeSH secundário: |
Vacinas contra a AIDS/química
Vacinas contra a AIDS/imunologia
Animais
Anticorpos Neutralizantes/sangue
Anticorpos Neutralizantes/imunologia
Cobaias
Anticorpos Anti-HIV/sangue
Anticorpos Anti-HIV/imunologia
Antígenos HIV/química
Antígenos HIV/metabolismo
HIV-1/genética
Seres Humanos
Multimerização Proteica
Estabilidade Proteica
Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (AIDS Vaccines); 0 (Antibodies, Neutralizing); 0 (CD4 Antigens); 0 (HIV Antibodies); 0 (HIV Antigens); 0 (env Gene Products, Human Immunodeficiency Virus) |
| [Em] Mês de entrada: | 1707 |
| [Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170310 |
| [St] Status: | MEDLINE |
| |
|
|
