Potent Induction of Envelope-Specific Antibody Responses by Virus-Like Particle Immunogens Based on HIV-1 Envelopes from Patients with Early Broadly Neutralizing Responses.
Potent Induction of Envelope-Specific Antibody Responses by Virus-Like Particle Immunogens Based on HIV-1 Envelopes from Patients with Early Broadly Neutralizing Responses.
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DOI：
10.1128/jvi.01343-21
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发表时间：
2022-01-12
影响因子：
5.4
通讯作者：
Yuste E
中科院分区：
文献类型：
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作者：
Beltran-Pavez C;Bontjer I;Gonzalez N;Pernas M;Merino-Mansilla A;Olvera A;Miro JM;Brander C;Alcami J;Sanders RW;Sanchez-Merino V;Yuste E
对 HIV-1 感染者的纵向研究表明，需要 2 至 3 年的感染时间才能产生广泛的中和抗体。然而，我们之前已经鉴定出在早期 HIV-1 感染中具有广泛中和活性 (bNA) 的个体，这表明疫苗可能能够在短期抗原暴露后诱导 bNA。在这里，我们描述了来自感染前 100 天内产生 bNA 的个体的 5 个 HIV-1 包膜序列（早期中和剂），并选择其中两个来设计基于 HIV-1-Gag 病毒样颗粒（VLP）的免疫原。这些 VLP 是同质的，并包含相应的包膜（1010 个 VLP 中含有 7 至 9μg gp120）。两个包膜 (Env) 均与特征明确的广泛中和抗体 (bNAb) 结合，包括三聚体特异性抗体（PGT145、VRC01 和 35022）。为了进行免疫原性测试，我们用 Env-VLP 或相应的稳定可溶性包膜三聚体对兔子进行免疫。使用简短的免疫方案（105 天）来重现这两个人感染 HIV-1 后观察到的早期 nAb 诱导。尽管用 Env-VLP 的 gp120 少 30 倍来免疫兔子，但所有 VLP 和三聚体包膜免疫原均诱导了相对较强的抗 gp120 反应。此外，用VLP配制的Envs免疫的动物诱导抗体交叉识别相应的可溶性稳定三聚体，反之亦然，尽管没有观察到中和活性。尽管如此，我们的数据可能提供一个新的免疫原平台，基于早期广泛中和反应患者的 HIV-1 包膜，有可能使用类似于经典预防性疫苗中使用的疫苗接种方案产生保护性免疫反应。重要性 人们普遍认为，有效的 HIV-1 疫苗应该能够诱导广谱中和抗体。由于大多数这些抗体需要在体内长时间的体细胞成熟，因此一些研究小组正在开发基于 HIV 包膜蛋白的免疫原，这需要复杂而漫长的免疫方案，而这在普通人群中很难实施。在这里，我们展示了用来自两个个体的新包膜（VLP 配制）进行免疫的兔子，这些包膜在感染后很早就表现出广泛的中和活性，并在短期免疫方案后诱导了特异性 HIV-1 抗体。这一证据为通过经典疫苗接种方案产生保护性免疫反应提供了基础，其中疫苗原型基于来自已产生早期广泛中和反应的个体的 HIV 包膜序列。
Longitudinal studies in HIV-1-infected individuals have indicated that 2 to 3 years of infection are required to develop broadly neutralizing antibodies. However, we have previously identified individuals with broadly neutralizing activity (bNA) in early HIV-1 infection, indicating that a vaccine may be capable of bNA induction after short periods of antigen exposure. Here, we describe 5 HIV-1 envelope sequences from individuals who have developed bNA within the first 100 days of infection (early neutralizers) and selected two of them to design immunogens based on HIV-1-Gag virus-like particles (VLPs). These VLPs were homogeneous and incorporated the corresponding envelopes (7 to 9 μg of gp120 in 1010 VLPs). Both envelopes (Envs) bound to well-characterized broadly neutralizing antibodies (bNAbs), including trimer-specific antibodies (PGT145, VRC01, and 35022). For immunogenicity testing, we immunized rabbits with the Env-VLPs or with the corresponding stabilized soluble envelope trimers. A short immunization protocol (105 days) was used to recapitulate the early nAb induction observed after HIV-1 infection in these two individuals. All VLP and trimeric envelope immunogens induced a comparably strong anti-gp120 response despite having immunized rabbits with 30 times less gp120 in the case of the Env-VLPs. In addition, animals immunized with VLP-formulated Envs induced antibodies that cross-recognized the corresponding soluble stabilized trimer and vice versa, even though no neutralizing activity was observed. Nevertheless, our data may provide a new platform of immunogens, based on HIV-1 envelopes from patients with early broadly neutralizing responses, with the potential to generate protective immune responses using vaccination protocols similar to those used in classical preventive vaccines. IMPORTANCE It is generally accepted that an effective HIV-1 vaccine should be able to induce broad-spectrum neutralizing antibodies. Since most of these antibodies require long periods of somatic maturation in vivo, several groups are developing immunogens, based on the HIV envelope protein, that require complex and lengthy immunization protocols that would be difficult to implement in the general population. Here, we show that rabbits immunized with new envelopes (VLP formulated) from two individuals who demonstrated broadly neutralizing activity very early after infection induced specific HIV-1 antibodies after a short immunization protocol. This evidence provides the basis for generating protective immune responses with classic vaccination protocols with vaccine prototypes based on HIV envelope sequences from individuals who have developed early broadly neutralizing responses.