Mucosal priming with a recombinant influenza A virus-vectored vaccine elicits T-cell and antibody responses to HIV-1 in mice

• Published in: Journal of virology 2021-05, Vol.95 (12)
• Main Authors: Wang, Jinlin, Shu, Tao, Deng, Weiqi, Zheng, Yali, Liao, Min, Ye, Xianmiao, Han, Lujie, He, Ping, Zheng, Xuehua, Li, Ting, Feng, Ying, Hu, Fengyu, Li, Pingchao, Sun, Caijun, Chen, Ling, Li, Feng, Feng, Liqiang
• Format: Article
• Language: English
• Subjects: Vaccines and Antiviral Agents
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.00059-21

Recombinant influenza A viral (IAV) vectors are potential to stimulate systemic and mucosal immunity, but the packaging capacity is limited and only one or a few epitopes can be carried. Here, we report the generation of a replication-competent IAV vector that carries a full-length HIV-1 gene linked to the 5'-terminal coding region of the segment via a protease cleavage sequence (IAV-p24). IAV-p24 was successfully rescued and stably propagated, and P24 protein was efficiently expressed in infected mammalian cells. In BALB/c mice, IAV-p24 showed attenuated pathogenicity than the parental A/PR/8/34 (H1N1) virus did. An intranasal inoculation with IAV-p24 elicited moderate HIV-specific cell-mediated immune (CMI) responses in the airway and vaginal tracts and in the spleen, and an intranasal boost with a replication-incompetent adenovirus type 2 vector expressing HIV-1 gene (Ad2-gag) greatly improved these responses. Importantly, compared to an Ad2-gag prime plus IAV-p24 boost regimen, the IAV-p24 prime plus Ad2-gag boost regimen had a greater efficacy in eliciting HIV-specific CMI responses. P24-specific CD8 T cells and antibodies were robustly provoked both systemically and in mucosal sites and showed long-term durability, revealing that IAV-p24 may be used as a mucosa-targeted priming vaccine. Our results illustrate that IAV-p24 is able to prime systemic and mucosal immunity against HIV-1 and warrants further evaluation in nonhuman primates. An effective HIV-1 vaccine remains elusive despite nearly 40 years of research. CD8 T cells and protective antibodies may both be desirable for preventing HIV-1 infection in susceptible mucosal sites. Recombinant influenza A virus (IAV) vector has the potential to stimulate these immune responses, but the packaging capacity is extremely limited. Here, we describe a replication-competent IAV vector expressing HIV-1 gene (IAV-p24). Unlike most other IAV vectors that carried one or several antigenic epitopes, IAV-p24 stably expressed the full-length P24 protein which contains multiple epitopes and is highly conserved among all known HIV-1 sequences. Compared to the parental A/PR/8/34 (H1N1) virus, IAV-p24 showed an attenuated pathogenicity in BALB/c mice. When combined with an adenovirus vector expressing HIV-1 gene, IAV-p24 was able to prime P24-specific systemic and mucosal immune responses. IAV-p24 as an alternative priming vaccine against HIV-1 warrants further evaluation in nonhuman primates.