Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.
Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.
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DOI：
10.1371/journal.pmed.0050016
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发表时间：
2008-01-15
期刊：
影响因子：
15.8
通讯作者：
Garcia JV
中科院分区：
文献类型：
--
作者：
Denton PW;Estes JD;Sun Z;Othieno FA;Wei BL;Wege AK;Powell DA;Payne D;Haase AT;Garcia JV
在全球范围内，阴道传播目前占新感染 HIV-1 感染的一半以上。尽管迫切需要开发和实施能够预防艾滋病毒传播的新方法，但由于缺乏足够的小动物模型进行临床前功效和安全性测试，这一进程受到阻碍。鉴于这种传播途径的重要性，我们研究了人源化小鼠对阴道内 HIV-1 感染的易感性。我们发现人源化骨髓-肝脏-胸腺（BLT）小鼠的雌性生殖道是用人类 CD4+ T 和其他相关人类细胞重建的，使这些人源化小鼠容易受到 HIV-1 阴道内感染。 HIV-1 感染的影响包括肠道相关淋巴组织 (GALT) 中 CD4+ T 细胞的消耗，这与 HIV-1 感染者中观察到的情况非常相似。我们还表明，使用抗逆转录病毒药物进行暴露前预防是预防 HIV-1 阴道传播的高效方法。虽然阴道接种 HIV-1 的 BLT 小鼠中有 88% (7/8) 受到感染，但接受恩曲他滨 (FTC)/富马酸替诺福韦二吡呋酯 (TDF) 暴露前预防的动物 (0/5) 均未显示出感染证据（卡方 = 7.5，df = 1，p = 0.006）。 人源化 BLT 小鼠易受阴道内感染的事实使该系统成为杀菌剂和暴露前预防方案临床前评估的绝佳候选者。在 BLT 小鼠模型中，暴露前预防可以预防 HIV-1 阴道内传播，这尤其凸显了人源化小鼠在研究 HIV-1 阴道内传播方面的实用性。 J. Victor Garcia 及其同事表明，具有由人类骨髓、肝脏和胸腺移植物重建的免疫系统的小鼠提供了预防阴道内 HIV 感染的模型。自1981年出现第一例获得性免疫缺陷综合症（艾滋病）以来，艾滋病疫情迅速蔓延。现在大约有 3300 万人感染了人类免疫缺陷病毒 (HIV)，这是艾滋病的病因。现在，一半以上的新感染病例发生在女性身上，主要是通过与受感染的男性伴侣进行无保护的阴道性交。从生物学角度来说，女性在阴道性交时比男性更容易感染艾滋病毒，而且往往无法说服伴侣使用安全套。因此，迫切需要预防艾滋病毒阴道内传播（通过阴道感染）的替代策略，特别是妇女可以在未经伴侣同意的情况下使用的策略。疫苗是理想的选择，但有效的艾滋病毒疫苗可能需要很多年才能问世，因此研究人员正在研究其他预防策略，例如使用杀微生物剂（在阴道内使用时可以预防艾滋病毒的化合物）以及使用抗逆转录病毒药物进行暴露前治疗（预防）。在女性尝试任何预防阴道内艾滋病毒传播的新策略之前，必须在动物身上进行测试。目前，这只能在猕猴身上完成，这是一种昂贵的选择。在这项研究中，研究人员调查了是否可以使用“人源化 BLT”小鼠来代替。当艾滋病毒在阴道性交过程中进入人体时，它会粘附在阴道内壁的树突状细胞（一种免疫系统细胞）上。这些细胞将病毒携带到人体的淋巴组织（免疫细胞的集合），在那里感染并杀死 CD4+ T 细胞（另一种类型的免疫细胞）。树突状细胞和 CD4+ T 细胞表面有 HIV 识别的分子。小鼠通常不易感染艾滋病毒，因为它们的免疫系统细胞缺乏这些分子。人源化 BLT 小鼠拥有接近人类的免疫系统——BLT 代表骨髓、肝脏、胸腺。它们是通过将人类胎儿肝脏和胸腺（T细胞学习识别外来入侵者的器官）碎片植入免疫缺陷小鼠（天生没有免疫系统的动物）的肾囊下，然后将人类造血干细胞（主要免疫系统细胞的来源）移植到小鼠体内而产生的。当研究人员检查人源化 BLT 小鼠的雌性生殖道中的人类免疫系统细胞时，他们发现 CD4+ T 细胞、树突状细胞和巨噬细胞，所有这些都与 HIV 感染有关。此外，BLT 小鼠的一半血细胞是人类血细胞。研究人员报告说，大多数 BLT 小鼠都容易受到阴道内 HIV 感染，例如血液中人类 CD4+ T 细胞的快速流失。然而，用抗逆转录病毒药物（恩曲他滨和富马酸替诺福韦二吡呋酯的混合物）预处理的 BLT 小鼠对阴道内 HIV 感染具有抵抗力。与人类 HIV 感染一样，阴道内 HIV 感染后，BLT 小鼠的其他几个器官中的 CD4+ T 细胞也被耗尽。同样，这种消耗可以通过抗逆转录病毒暴露前预防来预防。最后，感染 HIV 后，BLT 小鼠的肠道相关淋巴组织（人类 HIV 疾病期间 HIV 复制和 CD4+ T 细胞耗竭的重要部位）中的人类 CD4+ T 细胞也消失了。这些发现表明，人源化 BLT 小鼠很容易受到 HIV 阴道内感染，并且这些小鼠中 HIV 感染的许多方面与人类感染非常相似。此外，通过表明使用抗逆转录病毒药物进行暴露前预防可以预防 HIV 感染，这些结果表明人源化 BLT 小鼠可用于测试旨在预防阴道内感染的新策略。与所有动物模型一样，任何适用于人源化 BLT 小鼠的方法仍需在人体中进行测试。尽管如此，这些发现提供了临床前证据，表明使用抗逆转录病毒药物进行暴露前预防可能是预防艾滋病毒阴道内传播的有效方法，因此为该方法的临床试验提供了宝贵的支持。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0050016。可从美国国家过敏和传染病研究所获取有关 HIV 感染和艾滋病以及女性 HIV 感染的信息。 HIVInSite 提供有关 HIV/艾滋病各个方面的综合信息，包括有关女性和 HIV 以及安全性行为的文章，其中包括有关暴露前预防和杀微生物剂的信息。 可从国际艾滋病慈善机构 Avert 获取有关 HIV 预防、女性、HIV 和艾滋病以及杀微生物剂的信息。 美国疾病控制与预防中心提供以下信息： HIV/艾滋病，包括有关妇女艾滋病毒/艾滋病的信息以及 CDC 对艾滋病毒暴露前预防试验的信息（英文版和一些西班牙文信息） PrEP Watch 是有关艾滋病毒暴露前预防的综合信息源
Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection. We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1–infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006). The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model. J. Victor Garcia and colleagues show that mice with immune systems reconstituted from human bone marrow, liver, and thymus transplants provide a model for prevention of intravaginal HIV infection. Since the first cases of acquired immunodeficiency syndrome (AIDS) in 1981, the AIDS epidemic has spread rapidly. About 33 million people are now infected with the human immunodeficiency virus (HIV), the cause of AIDS. More than half of newly acquired infections now occur in women, mostly through unprotected vaginal sex with an infected male partner. Women are biologically more susceptible than men to HIV infection during vaginal intercourse and often cannot persuade their partner to use a condom. Consequently, alternative strategies that prevent intravaginal transmission of HIV (infection through the vagina) are urgently needed, particularly strategies that women can use without their partner's agreement. A vaccine would be ideal but it could be many years before an effective HIV vaccine is available so researchers are investigating other preventative strategies such as the use of microbicides—compounds that protect against HIV when applied inside the vagina—and pre-exposure treatment (prophylaxis) with antiretroviral drugs. Before any new strategy to prevent intravaginal HIV transmission is tried by women, it has to be tested in animals. Currently, this can only be done in macaques, an expensive option. In this study, the researchers have investigated whether “humanized BLT” mice could be used instead. When HIV enters the human body during vaginal intercourse, it sticks to dendritic cells (a type of immune system cell) in the vaginal lining. These cells carry the virus to the body's lymphoid tissues (collections of immune cells), where it infects and kills CD4+ T cells (another type of immune cell). Dendritic cells and CD4+ T cells have molecules on their surface that HIV recognizes. Mice are not normally susceptible to infection with HIV because their immune system cells lack these molecules. Humanized BLT mice have a nearly human immune system—BLT stands for bone marrow, liver, thymus. They are produced by implanting pieces of human fetal liver and thymus (the organ where T cells learn to recognize foreign invaders) under the kidney capsule of immunodeficient mice (animals born without an immune system) and then transplanting human hematopoietic stem cells (the source of the major immune system cells) into the mice. When the researchers examined the female reproductive tract of humanized BLT mice for human immune system cells, they found CD4+ T cells, dendritic cells and macrophages, all of which are involved in HIV infection. Furthermore, half of the blood cells of the BLT mice were human. Most of the BLT mice, the researchers report, were susceptible to intravaginal HIV infection as shown, for example, by a rapid loss of human CD4+ T cells from their blood. However, BLT mice pretreated with antiretroviral drugs (a mixture of emtricitabine and tenofovir disoproxil fumarate) were resistant to intravaginal HIV infection. As in human HIV infections, CD4+ T cells were also depleted in several other organs of the BLT mice after intravaginal HIV infection. Again, this depletion was prevented by antiretroviral pre-exposure prophylaxis. Finally, human CD4+ T cells also disappeared from the gut-associated lymphoid tissue (an important site for HIV replication and CD4+ T cell depletion during human HIV disease) of the BLT mice after infection with HIV. These findings show that humanized BLT mice are susceptible to intravaginal infection with HIV and that many aspects of HIV infection in these mice closely mimic infection in people. In addition, by showing that pre-exposure prophylaxis with antiretroviral drugs prevents HIV infection, these results suggest that humanized BLT mice could be used to test new strategies designed to prevent intravaginal infection. As with all animal models, any approach that works in humanized BLT mice will still have to be tested in people. Nevertheless, these findings provide preclinical evidence that pre-exposure prophylaxis with antiretroviral drugs may be an effective way to prevent intravaginal transmission of HIV and, therefore, provide valuable support for clinical trials of this approach. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050016. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women HIVInSite has comprehensive information on all aspects of HIV/AIDS, including articles on women and HIV and on safer sex, which includes information on pre-exposure prophylaxis and microbicides Information is available from Avert, an international AIDS charity, on HIV prevention, on women, HIV, and AIDS, and on microbicides The US Centers for Disease Control and Prevention provides information on HIV/AIDS, including information on HIV/AIDS among women and on CDC trials of pre-exposure prophylaxis for HIV prevention (in English and some information in Spanish) PrEP Watch is a comprehensive information source on pre-exposure prophylaxis for HIV prevention
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影响因子：
32.4
作者：
Hladik, Florian;Sakchalathorn, Polachai;Ballweber, Lamar;Lentz, Gretchen;Fialkow, Michael;Eschenbach, David;McElrath, M. Juliana
通讯作者：
McElrath, M. Juliana
影响因子：
3.8
作者：
Di Fabio, S;Giannini, G;Vella, S
通讯作者：
Vella, S
影响因子：
56.9
作者：
MCCUNE, JM;NAMIKAWA, R;WEISSMAN, IL
通讯作者：
WEISSMAN, IL
影响因子：
4.9
作者：
FRICK, LW;LAMBE, CU;NELSON, DJ
通讯作者：
NELSON, DJ
DOI：
10.1084/jem.20041196
发表时间：
2004-09-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mehandru S;Poles MA;Tenner-Racz K;Horowitz A;Hurley A;Hogan C;Boden D;Racz P;Markowitz M
通讯作者：
Markowitz M