Why Some Primates, But Not Humans, Can Live With Immunodeficiency Viruses 为什么某些灵长类动物可以和人类不能免疫的病毒共存

By researcher from Emory University translated by Shadow

Key differences in immune system signaling and the production of specific immune regulatory molecules may explain why some primates are able to live with an immunodeficiency virus infection without progressing to AIDS-like illness, unlike other primate species, including rhesus macaques and humans, that succumb to disease.

advertisement

Following the identification of HIV (Human Immunodeficiency Virus) as the cause of AIDS 25 years ago, an extensive search was undertaken to identify the source of the virus. These studies led to the discovery that chimpanzees and sooty mangabeys are infected in the wild with simian immunodeficiency viruses (SIV), whose transmission to humans and macaques leads to AIDS.

Surprisingly, the natural hosts for the AIDS viruses, such as the mangabeys and numerous other African primate species who have been found to harbor SIVs in the wild, remain healthy despite infection. Understanding how the natural hosts evolved to resist the development of immunodeficiency disease has long represented a key unsolved mystery in our understanding of AIDS. Furthermore, definition of the mechanisms by which they resist disease could help explain the mechanisms underlying AIDS progression in humans.

A team of scientists from Yerkes National Primate Research Center and the Emory Vaccine Center has discovered that the immune systems of sooty mangabeys are activated to a significantly lower extent during SIV infection than are the immune systems of rhesus macaques, and that this difference may explain why SIV and HIV infection leads to AIDS in some primate species but not others.

"During both HIV infection in humans and SIV infection in macaques, the host immune system becomes highly activated, experiences increased destruction and decreased production of key immune effector cells and progressively fails as a result. In contrast, natural hosts for SIV infection, like sooty mangabeys, do not exhibit aberrant immune activation and do not develop AIDS despite high levels of ongoing SIV replication. Our studies sought to understand the basis for the very different responses to AIDS virus infections in different species," says Mark Feinberg, MD, PhD, the paper's senior author. Feinberg is a former investigator at the Emory Vaccine Center and the Yerkes Research Center and a professor of medicine at the Emory University School of Medicine. He currently serves as vice president of medical affairs and policy for vaccines and infectious diseases at Merck & Co., Inc.

The reasons are found in significant differences in immune signaling in a specific type of dendritic cells in AIDS-susceptible or resistant host species. Dendritic cells are part of the immune system that play a key role in alerting the body to the presence of invading viruses or bacteria, and in initiating immune responses that enable clearance of these infections. They detect the invaders using molecules called Toll-like receptors.

Feinberg's team found that in sooty mangabeys, dendritic cells produce much less interferon alpha--an alarm signal to the rest of the immune system--in response to SIV. As a result, the dendritic cells are not activated during the initial or chronic stages of SIV infection, and mangabeys fail to mount a significant immune response to the virus. In contrast to mangabeys, dendritic cells from humans and macaques that are susceptible to developing AIDS are readily activated by HIV and SIV.

The difference in whether or not dendritic cells become activated upon AIDS virus exposure in specific primate hosts appears to result from species-specific differences in patterns of Toll-like-receptor signaling. Because host immune responses are unable to clear AIDS virus infections, ongoing virus replication leads to unrelenting activation of the immune system in humans and macaques.

Unfortunately, rather than promoting clearance of the infection, chronic dendritic cell stimulation may result in chronic immune activation and significant unintended damage to the immune system in AIDS-susceptible species. Such chronic immune activation is now recognized to be a major driving force for the development of AIDS.

The observation that mangabey dendritic cells are less susceptible to activation by SIV may explain why mangabeys do not exhibit abnormal immune activation and do not develop AIDS. Thus, in mangabeys, the generation of a less vigorous immune response to SIV may represent an effective evolutionary response to a virus that is so resistant to clearance by antiviral immune responses.

The authors suggest new treatment strategies that would steer the immune system away from over-activation, thereby protecting against the unintended damage caused by host immune responses. Such treatment approaches that focus on the host response to the AIDS virus may provide a valuable means of complementing the use of antiretroviral drugs that focus directly on inhibition of virus replication.

Understanding the particular details of Toll-like receptor signaling pathways in the mangabeys may help guide the development of specific therapeutic approaches that could beneficially limit chronic immune activation in HIV-infected humans.

"Better understanding of the biological basis by which sooty mangabeys and the numerous primate species that represent natural hosts for AIDS virus infections have evolved to resist disease promises to teach us a great deal about the emergence of the AIDS pandemic, and about the mechanisms underlying AIDS progression in humans. In addition, such insights will hopefully help inform new approaches to treat HIV infection most effectively." Feinberg says.

"Also, better understanding how natural hosts for SIV remain healthy may provide clues as to the future evolutionary trajectory of human populations in response to the profound selective pressures now being felt in regions of the world where the tragic consequences of HIV infection are most severe."

First authors of the paper are Judith N. Mandl from the Graduate Program in Population Biology, Ecology and Evolution at Emory University and Ashley P. Barry who formerly was with the Emory Vaccine Center and Yerkes National Primate Research Center.

为什么某些灵长类动物可以和人类不能免疫的病毒共存

作者： 埃默里大学研究员 翻译： 影SHADOW

免疫系统信号传导和特异性免疫调节分子产生的关键差异解释了为什么某些灵长类动物能够与人类不能免疫的病毒一起生活而不会发展为类似AIDS的疾病。而包括恒河猴和人类在内的灵长动物却能致病。

25年前科学家将HIV（人类免疫缺陷病毒）鉴定为AIDS的病因，并进行了广泛的探索以查明该病毒的来源。这些研究发现黑猩猩和煤烟黑夜蛾在野外被病毒SIV感染后，如果该病毒向人和猕猴传播会导致艾滋病。

令人惊讶的是艾滋病病毒的天然宿主，如在野外带有SIV的美洲虎和许多其他非洲灵长类物种尽管受到感染，却仍然健康。长期以来，了解自然宿主如何抵抗免疫缺陷疾病的发展一直是我们对艾滋病认识的一个未解之谜。破解这个谜对它们抵抗疾病的机制的定义可以帮助解释人类艾滋病发展的潜在机制。

来自耶克斯国家灵长类动物研究中心和埃默里疫苗中心的科学家团队发现，与恒河猴的免疫系统相比，在SIV感染期间，煤烟黑夜蛾的免疫系统被激活的程度要低得多，这种差异解释了为什么SIV和HIV感染在某些灵长类动物中导致AIDS，但在其他物种中则不会。

“在人类感染HIV和猕猴感染SIV的过程中，宿主免疫系统被高度激活，破坏力增强，关键免疫效应细胞的产生减少，结果逐渐衰竭。相反，天然SIV感染宿主，如煤烟黑夜蛾，尽管SIV持续大量复制，但它们并没有表现出异常的免疫激活作用，也没有发展成AIDS。我们的研究试图了解对不同物种对AIDS病毒感染做出不同反应的基础。”该论文的作者Feinberg是埃默里 疫苗中心和耶克斯研究中心的前研究员，也是埃默里大学医学院的医学教授。他目前担任默克公司的疫苗和传染病医疗事务和政策副总裁。

在AIDS易感或抗性宿主物种中，特定类型的树突状细胞的免疫信号不同，其原因被是树突状细胞作为免疫系统的一部分，在提醒机体注意入侵病毒或细菌的存在以及启动能够清除这些感染的免疫反应中起关键作用。

费恩伯格的研究小组发现，在煤烟黑夜蛾身上，树突状细胞对SIV的反应产生的干扰少得多，这是对其余免疫系统的警报信号。结果，树突状细胞在SIV感染的初始阶段或慢性阶段没有被激活，而猕猴无法对病毒产生明显的免疫反应。与恒河猴相反，人类和猕猴的树突状细胞容易感染艾滋病，很容易被HIV和SIV激活。由于宿主的免疫反应无法清除AIDS病毒感染，因此持续的病毒复制会导致人类和猕猴无休止地激活免疫系统。

不幸的是，长期树突状细胞刺激并不会促进清除感染，反而会导致慢性免疫激活，并在艾滋病易感物种中对免疫系统造成重大意外损坏。现在公认这种慢性免疫激活是艾滋病发展的主要驱动力。

恒河猴树突状细胞不易被SIV激活的观察结果可以解释为什么恒河猴不表现出异常的免疫激活并且不发展为AIDS。

作者提出了新的治疗策略，可以让免疫系统避免过度激活，从而防止宿主免疫反应引起意外伤害。侧重于宿主对AIDS病毒反应的此类治疗方法可以着眼于抑制病毒复制的抗逆转病毒药物的使用。

。

“更深入地理解煤烟黑夜蛾和别的艾滋病病毒感染自然宿主的许多灵长类物种的生物基础已经发展为抵抗疾病，使我们对艾滋病流行的产生以及艾滋病潜在的机制了解更深入。此外，这些见识将有助于为更有效地为治疗HIV感染提供新方法。”芬伯格说：“更好地了解SIV的天然宿主如何保持健康可能会为人类未来的进化轨迹提供线索，以应对当今世界上艾滋病毒感染悲剧泛滥的地区所面临的巨大压力。 ”

该论文的第一作者是埃默里大学人口生物学，生态学与进化研究生课程的朱迪思·曼德尔教授，以及曾任埃默里疫苗中心和耶克斯国家灵长类动物研究中心的阿什利·巴里教授。