Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.
Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.
复制标题
作者：
在原发HIV/SIV感染期间大规模、系统性病毒复制的快速发生和这些病毒的免疫逃避能力对依赖于初始病毒复制来刺激效应T细胞扩增和分化的疫苗提出了根本性问题。我们假设，疫苗设计，以维持分化的“效应记忆”T细胞（TEM）的反应，在病毒进入网站可能会提高疗效，损害病毒复制在其最早的阶段，因此开发了SIV蛋白编码载体的基础上恒河猴巨细胞病毒（RhCMV），原型诱导剂的终身TEM反应。表达SIV Gag、Rev/Nef/达特和Env的RhCMV载体持续感染恒河猴（RM），而不管预先存在的RhCMV免疫力如何，并且在不存在中和抗体的情况下引发并维持稳健的SIV特异性、CD 4+和CD 8 + TEM应答（特征在于协调的TNF、IFN-γ和MIP-1β表达、细胞毒性脱粒和在淋巴外位点的积累）。与对照RM相比，这些接种疫苗的RM在重复、有限剂量、直肠内攻击后显示出对获得进行性SIVmac 239感染的抗性增加，包括4只控制直肠粘膜感染而没有进行性全身传播的动物。这些数据提出了艾滋病疫苗开发的新范式：能够产生和维持艾滋病毒特异性TEM的疫苗可能会降低性接触后感染艾滋病毒的发生率。
The rapid onset of massive, systemic viral replication during primary HIV/SIV infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated “effector memory” T cell (TEM) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM responses. RhCMV vectors expressing SIV Gag, Rev/Nef/Tat, and Env persistently infected rhesus macaques (RM), regardless of pre-existing RhCMV immunity, and primed and maintained robust SIV-specific, CD4+ and CD8+ TEM responses (characterized by coordinate TNF, IFN-γ and MIP-1β expression, cytotoxic degranulation, and accumulation at extra-lymphoid sites) in the absence of neutralizing antibodies. Compared to control RM, these vaccinated RM showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated, limiting dose, intra-rectal challenge, including four animals that controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development: that vaccines capable of generating and maintaining HIV-specific TEM might decrease the incidence of HIV acquisition after sexual exposure.
登录
查看更多内容
影响因子：
15.9
作者：
Picker, Louis J.;Reed-Inderbitzin, Edward F.;Villinger, Francois
通讯作者：
Villinger, Francois
DOI：
10.1084/jem.20060134
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gauduin MC;Yu Y;Barabasz A;Carville A;Piatak M;Lifson JD;Desrosiers RC;Johnson RP
通讯作者：
Johnson RP
影响因子：
15.3
作者：
Casazza, Joseph P.;Betts, Michael R.;Price, David A.;Precopio, Melissa L.;Ruff, Laura E.;Brenchley, Jason M.;Hill, Brenna J.;Roederer, Mario;Douek, Daniel C.;Koup, Richard A.
通讯作者：
Koup, Richard A.
DOI：
10.1073/pnas.0802203105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Keele, Brandon F.;Giorgi, Elena E.;Shaw, George M.
通讯作者：
Shaw, George M.
影响因子：
4.4
作者：
Pipeling, Matthew R.;West, Erin E.;McDyer, John F.
通讯作者：
McDyer, John F.