Pre-clinical development of a recombinant, replication-competent adenovirus serotype 4 vector vaccine expressing HIV-1 envelope 1086 clade C.
Pre-clinical development of a recombinant, replication-competent adenovirus serotype 4 vector vaccine expressing HIV-1 envelope 1086 clade C.
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DOI：
10.1371/journal.pone.0082380
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mayall T
中科院分区：
文献类型：
--
作者：
Alexander J;Mendy J;Vang L;Avanzini JB;Garduno F;Manayani DJ;Ishioka G;Farness P;Ping LH;Swanstrom R;Parks R;Liao HX;Haynes BF;Montefiori DC;LaBranche C;Smith J;Gurwith M;Mayall T
众所周知，人们需要一种有效的艾滋病疫苗来预防 HIV-1 感染或限制体内病毒复制。这些研究的目的是开发一种基于表达 HIV-1 包膜 (Env) 1086 clade C 糖蛋白的腺病毒血清型 4 (Ad4) 病毒的具有复制能力的疫苗载体。对表达 Env gp160 (Ad4Env160)、Env gp140 (Ad4Env140) 和 Env gp120 (Ad4Env120) 的 Ad4 重组载体进行了评估。重组 Ad4 载体是通过完全删除 Ad4 的 E3 区来生成的，以适应 env 基因序列。感染 A549 细胞后，在体外评估候选疫苗的 Env 特异性蛋白表达以及通过广泛中和抗体 (bNAb) 的结合监测的翻译后转运到细胞表面的情况。在兔子中评估了 Ad4Env 疫苗诱导体液免疫的能力，以检测 Env gp140 和 V1V2 特异性结合抗体以及 HIV-1 假病毒中和作用。评估用 Ad4Env160 疫苗免疫的小鼠对重叠 Env 肽组的特异性 IFNγ T 细胞反应。通过蛋白质印迹分析和多种 bNAb 对细胞表面 Env gp160 的识别，证实了 Env 蛋白的稳定表达。 Ad4Env 疫苗在兔子中诱导体液免疫反应，该反应识别源自 1086 clade C、A244 clade AE 和 gp70 V1V2 CASE A2 clade B 融合蛋白的 Env 1086 gp140 和 V1V2 多肽序列。免疫血清有效地中和了1级C分支假病毒MW965.26，并在较小程度上中和了同源和异源2级假病毒。 Ad4Env160 载体免疫后，小鼠体内也诱导了 Env 特异性 T 细胞反应。 Ad4Env 疫苗载体表达高水平的 Env 糖蛋白，并诱导 Env 特异性体液和细胞免疫，从而支持这一新的 Ad4 HIV-1 Env 疫苗平台在 1 期临床试验中的进一步开发。
There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV-1 infection or limits in vivo viral replication. The objective of these studies is to develop a replication-competent, vaccine vector based on the adenovirus serotype 4 (Ad4) virus expressing HIV-1 envelope (Env) 1086 clade C glycoprotein. Ad4 recombinant vectors expressing Env gp160 (Ad4Env160), Env gp140 (Ad4Env140), and Env gp120 (Ad4Env120) were evaluated. The recombinant Ad4 vectors were generated with a full deletion of the E3 region of Ad4 to accommodate the env gene sequences. The vaccine candidates were assessed in vitro following infection of A549 cells for Env-specific protein expression and for posttranslational transport to the cell surface as monitored by the binding of broadly neutralizing antibodies (bNAbs). The capacity of the Ad4Env vaccines to induce humoral immunity was evaluated in rabbits for Env gp140 and V1V2-specific binding antibodies, and HIV-1 pseudovirus neutralization. Mice immunized with the Ad4Env160 vaccine were assessed for IFNγ T cell responses specific for overlapping Env peptide sets. Robust Env protein expression was confirmed by western blot analysis and recognition of cell surface Env gp160 by multiple bNAbs. Ad4Env vaccines induced humoral immune responses in rabbits that recognized Env 1086 gp140 and V1V2 polypeptide sequences derived from 1086 clade C, A244 clade AE, and gp70 V1V2 CASE A2 clade B fusion protein. The immune sera efficiently neutralized tier 1 clade C pseudovirus MW965.26 and neutralized the homologous and heterologous tier 2 pseudoviruses to a lesser extent. Env-specific T cell responses were also induced in mice following Ad4Env160 vector immunization. The Ad4Env vaccine vectors express high levels of Env glycoprotein and induce both Env-specific humoral and cellular immunity thus supporting further development of this new Ad4 HIV-1 Env vaccine platform in Phase 1 clinical trials.
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影响因子：
3.7
作者：
Guenaga J;Dosenovic P;Ofek G;Baker D;Schief WR;Kwong PD;Karlsson Hedestam GB;Wyatt RT
通讯作者：
Wyatt RT
影响因子：
46.9
作者：
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--
影响因子：
3.7
作者：
Corti D;Langedijk JP;Hinz A;Seaman MS;Vanzetta F;Fernandez-Rodriguez BM;Silacci C;Pinna D;Jarrossay D;Balla-Jhagjhoorsingh S;Willems B;Zekveld MJ;Dreja H;O'Sullivan E;Pade C;Orkin C;Jeffs SA;Montefiori DC;Davis D;Weissenhorn W;McKnight A;Heeney JL;Sallusto F;Sattentau QJ;Weiss RA;Lanzavecchia A
通讯作者：
Lanzavecchia A
影响因子：
5.6
作者：
Checkley MA;Luttge BG;Freed EO
通讯作者：
Freed EO
影响因子：
3.7
作者：
Gorny, Miroslaw K.;Pan, Ruimin;Zolla-Pazner, Susan
通讯作者：
Zolla-Pazner, Susan