Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.
Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.
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DOI：
10.1371/journal.pone.0033715
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Murphey-Corb M
中科院分区：
文献类型：
--
作者：
Fuller DH;Rajakumar P;Che JW;Narendran A;Nyaundi J;Michael H;Yager EJ;Stagnar C;Wahlberg B;Taber R;Haynes JR;Cook FC;Ertl P;Tite J;Amedee AM;Murphey-Corb M
免疫疗法，诱导持久的免疫控制慢性艾滋病毒感染可能会消除需要终身依赖药物。我们研究了一种用新型遗传佐剂配制的DNA疫苗，该佐剂刺激血液和肠道中的免疫应答，以提高SIV慢性感染恒河猴的治疗能力。利用SIV-猕猴艾滋病模型，我们表明表皮共递送表达SIV Gag、RT、Nef和Env的质粒，以及粘膜佐剂，热不稳定的E。与未接种疫苗的对照组相比，在抗逆转录病毒治疗（ART）期间接种大肠杆菌肠毒素（LT）诱导肠道和血液中平均病毒负荷显著降低2-4-log倍，并在停药后提供持久的病毒反弹和疾病进展保护。这种效应与血液和肠道中IFN-γ T细胞应答显著增加以及血液中具有TNF-α和细胞溶解效应子双重功能的SIV特异性CD 8 + T细胞相关。重要的是，在肠道而不是血液中观察到的T细胞应答的更广泛特异性与粘膜组织中病毒产生的减少和血浆中病毒负荷的降低显著相关。我们的结论是，免疫接种疫苗，诱导粘膜肠道组织的免疫反应，可以减少药物治疗过程中残留的病毒水库，并改善人类艾滋病毒感染的长期治疗。
Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2–4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans.
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DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
3.1
作者：
Daynes, RA;Enioutina, EY;Araneo, BA
通讯作者：
Araneo, BA
影响因子：
5.4
作者：
Chen, DX;Periwal, SB;Payne, LG
通讯作者：
Payne, LG
影响因子：
5.4
作者：
Fuller, DH;Rajakumar, PA;Murphey-Corb, M
通讯作者：
Murphey-Corb, M
影响因子：
0.7
作者：
Fuller, DH;MurpheyCorb, M;Haynes, JR
通讯作者：
Haynes, JR