Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4+ T cells from virus-induced depletion in SCID mice transplanted with human cells
Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4+ T cells from virus-induced depletion in SCID mice transplanted with human cells
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DOI：
10.1006/viro.1999.9869
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发表时间：
1999-10-10
期刊：
影响因子：
3.7
通讯作者：
Belardelli, F
中科院分区：
文献类型：
--
作者：
Lapenta, C;Santini, SM;Belardelli, F
虽然有几项研究可在体外抑制活性的I型干扰素（IFN）对HIV-1的复制，这些细胞因子在艾滋病的发病机制中的作用仍然是猜测的问题。已经设想了有益的和不利的作用，并认为这是在HIV-1感染患者中开发IFN或adi-IFN疗法的可能理由。在本研究中，我们已经评估了人I型IFN对HIV-1感染和病毒诱导的人CD 4 T细胞耗竭在两种模型中建立的SCID小鼠的疗效。在移植了人U937细胞的SCID小鼠（U937-SCID小鼠模型）中，用I型共有IFN（CIFN）连续治疗导致HIV-1感染的完全抑制。这种抑制作用上级于AZT处理后获得的抑制作用。在移植有对照或用Tat诱导的IFN-α基因转导的遗传修饰的人U937细胞（LTR-IFN-A2 U937）的SCID小鼠中的实验结果表明，由于病毒感染而局部产生的低水平的IFN-α在抑制急性HIV感染和病毒复制方面极其有效。令人感兴趣的是，LTR-IFN-A2 U937细胞赋予共注射的旁观者U937细胞强的抗HIV-1保护。值得注意的是，用人PBL重建的SCID小鼠（hu-PBL-SCID小鼠模型）的实验表明，CIFN治疗比AZT治疗更有效地抑制HIV-1复制。值得注意的是，用CIFN治疗导致了对病毒诱导的人CD 4 T细胞耗竭的明确保护，这也与在50%的病毒注射的异种移植物中产生针对HIV-1抗原的抗体应答有关。这些结果表明，I型IFN不仅通过诱导靶细胞的抗病毒状态，而且通过刺激体内抗HIV-1的人体免疫应答，有效地保护了hu-PBL-SCID小鼠中的人CD 4（+）细胞免受病毒诱导的损伤。(C)北京：科学出版社.
Although several studies are available on the in vitro inhibitory activities of type I interferon (IFN) on HIV-1 replication, the role of these cytokines in the pathogenesis of AIDS is still matter of conjecture. Both beneficial and adverse effects have been envisaged and considered as a possible rationale for the development of either IFN or adi-IFN therapies in HIV-1-infected patients. In the present study, we have evaluated the efficacy of human type I IFN on HIV-1 infection and virus-induced depletion of human CD4 T cells in two models established in SCID mice. In SCID mice transplanted with human U937 cells (U937-SCID mouse model), continuous treatment with type I consensus IFN (CIFN) resulted in a total suppression of HIV-1 infection. This inhibitory effect was superior to that obtained after AZT treatments. Results from an ensemble of experiments in SCID mice transplanted with either control or genetically modified human U937 cells transduced with a Tat-inducible IFN-alpha gene (LTR-IFN-A2 U937) indicated that low levels of IFN-alpha, produced locally as a result of virus infection, were extremely effective in inhibiting acute HIV infection and virus replication. Of interest, LTR-IFN-A2 U937 cells conferred a strong anti-HIV-1 protection to coinjected bystander U937 cells. Notably, experiments with SCID mice reconstituted with human PBL (hu-PBL-SCID mouse model) showed that treatment with CIFN inhibited HIV-1 replication more effectively than AZT treatment. Remarkably, treatment with CIFN resulted in a clear-cut protection from the virus-induced depletion of human CD4 T cells, which was also associated with the generation of an antibody response toward HIV-1 antigens in 50% of the virus-injected xenografts. These results suggest that type I IFN efficiently preserves human CD4(+) cells from virus-induced damage in hu-PBL-SCID mice, not only by inducing an antiviral state in target cells but also by stimulating anti-HIV-1 human immune responses in vivo. (C) 1999 Academic Press.