Sangare Kotou, Tuero Iskra, Rahman Mohammad Arif, Hoang Tanya, Miller-Novak Leia K, Vargas-Inchaustegui Diego A, Venzon David J, LaBranche Celia, Montefiori David C, Robert-Guroff Marjorie, Thomas Michael A
Department of Biology, Howard University, Washington, DC, USA.
Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
J Virol. 2021 Mar 10;95(7). doi: 10.1128/JVI.02253-20. Epub 2021 Jan 13.
Adenovirus (Ad) is being explored for use in the prevention and treatment of a variety of infectious diseases and cancers. Ad with a deletion in early region 3 () provokes a stronger immune response than Ad with deletions in early regions 1 and E3 (). The ΔE1/ΔE3 Ads are more popular because they can carry a larger transgene and because of the deleted E1 (E1A and E1B), are perceived safer for clinical use. Ad with a deletion in E1B55K (ΔE1B55K) has been in phase III clinical trials for use in cancer therapy in the US and has been approved for use in head and neck tumor therapy in China, demonstrating that Ad containing E1A are safe for clinical use. We have shown previously that ΔE1B55K Ad, even while promoting lower levels of an inserted transgene, promoted similar levels of transgene-specific immune responses as a Ad. Products of the Ad early region 4 () limit the ability of cells to mount an innate immune response. Using this knowledge, we deleted the Ad E4 open reading frames 1-4 (E4orf1-4) from the ΔE1B55K Ad. Here, we show that innate cytokine network genes are elevated in the Ad-infected cells beyond that of Ad-infected cells. Further, in immunized mice the IgG2a subclass was favored as was the IgG1 subclass in immunized nonhuman primates. Thus, Ad E4 impacts immune responses in cells, in immunized mice, and immunized nonhuman primates. These Ad may offer advantages that are beneficial for clinical use. Adenovirus (Ad) is being explored for use in the prevention and treatment of a variety of infectious diseases and cancers. Here we provide evidence in cells, mice, and nonhuman primates supporting the notion that Ad early gene-products limit specific immune responses. Ad constructed with deletions in early genes and expressing HIV envelope protein was shown to induce greater HIV-specific cellular immune responses and higher titer antibodies compared to the parental Ad with the early genes. In addition to eliciting enhanced immunity, the deleted Ad possesses more space for insertion of additional or larger transgenes needed for targeting other infectious agents or cancers.
腺病毒（Ad）正被探索用于预防和治疗多种传染病及癌症。早期区域3（E3）缺失的腺病毒比早期区域1和E3（E1和E3）缺失的腺病毒引发更强的免疫反应。ΔE1/ΔE3腺病毒更受欢迎，因为它们能携带更大的转基因，且由于E1（E1A和E1B）缺失，被认为临床使用更安全。E1B55K缺失的腺病毒（ΔE1B55K）已在美国进入癌症治疗的III期临床试验，并在中国被批准用于头颈肿瘤治疗，这表明含E1A的腺病毒临床使用是安全的。我们之前已表明，ΔE1B55K腺病毒即使促进插入转基因的水平较低，但与野生型腺病毒相比，促进相似水平的转基因特异性免疫反应。腺病毒早期区域4（E4）的产物限制细胞产生先天免疫反应的能力。利用这一知识，我们从ΔE1B55K腺病毒中删除了腺病毒E4开放阅读框1 - 4（E4orf1 - 4）。在此，我们表明先天细胞因子网络基因在野生型腺病毒感染的细胞中比在ΔE1B55K腺病毒感染的细胞中升高得更多。此外，在免疫小鼠中IgG2a亚类占优势，在免疫非人类灵长类动物中IgG1亚类占优势。因此，腺病毒E4影响细胞、免疫小鼠和免疫非人类灵长类动物中的免疫反应。这些腺病毒可能具有对临床使用有益的优势。腺病毒（Ad）正被探索用于预防和治疗多种传染病及癌症。在此我们在细胞、小鼠和非人类灵长类动物中提供证据，支持腺病毒早期基因产物限制特异性免疫反应这一观点。与具有早期基因的亲本腺病毒相比，构建有早期基因缺失并表达HIV包膜蛋白的腺病毒显示出诱导更强的HIV特异性细胞免疫反应和更高滴度的抗体。除了引发增强的免疫力外，缺失的腺病毒拥有更多空间用于插入针对其他传染病原体或癌症所需的额外或更大的转基因。
