Sato Kei, Misawa Naoko, Takeuchi Junko S, Kobayashi Tomoko, Izumi Taisuke, Aso Hirofumi, Nagaoka Shumpei, Yamamoto Keisuke, Kimura Izumi, Konno Yoriyuki, Nakano Yusuke, Koyanagi Yoshio
Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan
Laboratory of Systems Virology, Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
J Virol. 2018 Jan 30;92(4). doi: 10.1128/JVI.01905-17. Print 2018 Feb 15.
Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, originated from simian immunodeficiency virus from chimpanzees (SIVcpz), the precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz strains (MB897, EK505, and MT145), four pandemic HIV-1 strains (NL4-3, NLCSFV3, JRCSF, and AD8), and two nonpandemic HIV-1 strains (YBF30 and DJO0131). Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a peak viral load comparable to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strain EK505 or MT145 as well as nonpandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is preadapted to humans, unlike the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation in , a G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in both cell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1. From the mid-20th century, humans have been exposed to the menace of infectious viral diseases, such as severe acute respiratory syndrome coronavirus, Ebola virus, and Zika virus. These outbreaks of emerging/reemerging viruses can be triggered by cross-species viral transmission from wild animals to humans, or zoonoses. HIV-1, the causative agent of AIDS, emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzees, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. Here, by using a hematopoietic stem cell-transplanted humanized-mouse model, we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, preadapted to infect humans over other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.
1型人类免疫缺陷病毒（HIV-1）是艾滋病的病原体，大约在100年前起源于黑猩猩的猿猴免疫缺陷病毒（SIVcpz），即人类病毒的前身。这表明HIV-1是通过SIVcpz从黑猩猩跨物种传播给人类而出现的。然而，SIVcpz如何在人类中演变成大流行的HIV-1仍不清楚。为了解决这个问题，我们接种了三种SIVcpz毒株（MB897、EK505和MT145）、四种大流行的HIV-1毒株（NL4-3、NLCSFV3、JRCSF和AD8）以及两种非大流行的HIV-1毒株（YBF30和DJO0131）。感染了SIVcpz毒株MB897（一种在系统发育上与大流行的HIV-1相似的病毒）的人源化小鼠表现出与感染大流行HIV-1的小鼠相当的病毒载量峰值，而感染SIVcpz毒株EK505或MT145以及非大流行HIV-1毒株的小鼠的峰值病毒载量则显著较低。这些结果表明，与其他SIVcpz毒株不同，SIVcpz毒株MB897对人类具有预适应性。此外，对感染MB897的人源化小鼠进行的病毒RNA测序在gp120中发现了一个非同义突变，即G413R替代。MB897的gp120 G413R突变体的感染性显著高于亲本MB897。此外，我们证明MB897的gp120 G413R突变体增强了在细胞培养物和人源化小鼠中病毒复制的能力。综上所述，这是首次使用动物模型进行的实验研究，以证明SIVcpz向大流行HIV-1的功能获得性进化。从20世纪中叶开始，人类一直面临着诸如严重急性呼吸综合征冠状病毒、埃博拉病毒和寨卡病毒等传染性病毒疾病的威胁。这些新出现/再次出现的病毒爆发可能由野生动物向人类的跨物种病毒传播，即人畜共患病引发。HIV-1是艾滋病的病原体，大约在100年前通过HIV-1在黑猩猩中的前身SIVcpz的跨物种传播而出现。然而，SIVcpz在人类中进化为HIV-1的过程仍不清楚。在这里，通过使用造血干细胞移植的人源化小鼠模型，我们通过实验再现了SIVcpz进化为HIV-1的过程。我们提供的证据表明，一种SIVcpz毒株MB897比其他SIVcpz毒株更能预适应感染人类。我们进一步证明了SIVcpz在感染的人源化小鼠中的功能获得性进化。我们的研究表明，大流行的HIV-1至少通过两个步骤出现：预适应和随后的功能获得性突变。
