Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.
Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.
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DOI：
10.1038/nature13554
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发表时间：
2014-07-31
期刊：
影响因子：
64.8
通讯作者：
Douek, Daniel C.
中科院分区：
文献类型：
--
作者：
Sandler, Netanya G.;Bosinger, Steven E.;Estes, Jacob D.;Zhu, Richard T. R.;Tharp, Gregory K.;Boritz, Eli;Levin, Doron;Wijeyesinghe, Sathi;Makamdop, Krystelle Nganou;del Prete, Gregory Q.;Hill, Brenna J.;Timmer, J. Katherina;Reiss, Emma;Yarden, Ganit;Darko, Samuel;Contijoch, Eduardo;Todd, John Paul;Silvestri, Guido;Nason, Martha;Norgren, Robert B., Jr.;Keele, Brandon F.;Rao, Srinivas;Langer, Jerome A.;Lifson, Jeffrey D.;Schreiber, Gideon;Douek, Daniel C.
HIV感染中的炎症预示着非艾滋病的发病率和死亡率、更高的设定点血浆病毒载量和病毒获得；因此，治疗药物正在开发中，以减少其原因和后果。然而，炎症可能同时带来有害和有益的影响。这种二分法特别适用于I型干扰素（IFN-I），它虽然有助于先天控制感染，但也在急性感染期间为病毒提供靶细胞，损害CD4 t细胞的恢复，并与疾病进展有关。在这里，我们在猕猴猴免疫缺陷病毒（SIV）传播和急性感染期间，通过两种互补的体内干预来操纵IFN-I信号传导。我们发现，阻断IFN-I受体导致抗病毒基因表达减少，SIV库大小增加，CD4 t细胞耗竭加速，尽管t细胞活化降低，但随着艾滋病的进展。相比之下，IFN-α2a最初上调抗病毒基因的表达，并预防全身感染。然而，持续的IFN-α2a治疗诱导IFN- i脱敏和抗病毒基因表达降低，使SIV库大小增加，CD4 t细胞损失加速。因此，急性SIV感染中ifn诱导的先天反应的时机深刻地影响了整个疾病进程，并且超过了免疫激活增加的有害后果。然而，操纵IFN信号的临床后果很难在体内预测，在人体研究中的治疗干预应谨慎对待。
Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.
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DOI：
10.1097/qai.0b013e3182898392
发表时间：
2013-07-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
McElrath MJ;Smythe K;Randolph-Habecker J;Melton KR;Goodpaster TA;Hughes SM;Mack M;Sato A;Diaz G;Steinbach G;Novak RM;Curlin ME;Lord JD;Maenza J;Duerr A;Frahm N;Hladik F;NIAID HIV Vaccine Trials Network
通讯作者：
NIAID HIV Vaccine Trials Network
影响因子：
6.7
作者：
Fraietta JA;Mueller YM;Yang G;Boesteanu AC;Gracias DT;Do DH;Hope JL;Kathuria N;McGettigan SE;Lewis MG;Giavedoni LD;Jacobson JM;Katsikis PD
通讯作者：
Katsikis PD
影响因子：
20.3
作者：
Brenchley, Jason M.;Vinton, Carol;Estes, Jacob D.
通讯作者：
Estes, Jacob D.
DOI：
10.1073/pnas.1304288110
发表时间：
2013-04-23
影响因子：
11.1
作者：
Parrish, Nicholas F.;Gao, Feng;Hahn, Beatrice H.
通讯作者：
Hahn, Beatrice H.
影响因子：
7.6
作者：
Schellekens, H;Niphuis, H;Heeney, JL
通讯作者：
Heeney, JL