Affiliation:
1. Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan
2. Laboratory of Systems Virology, Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
3. CREST, Japan Science and Technology Agency, Saitama, Japan
4. Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
5. Graduate School of Biostudies, Kyoto University, Kyoto, Japan
6. Graduate School of Medicine, Kyoto University, Kyoto, Japan
7. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
Abstract
ABSTRACT
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
env
, 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
in vitro
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.
IMPORTANCE
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.
Funder
Imai Memorial Trust Foundation
Chube Ito Foundation
Fordays Self-Reliance Support in Japan
Mishima Kaiun Memorial Foundation
TOBE MAKI Scholarship Foundation
Takeda Science Foundation
Ministry of Health, Labour and Welfare
Uehara Memorial Foundation
Mochida Memorial Foundation for Medical and Pharmaceutical Research
Japan Agency for Medical Research and Development
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
Sumitomo Foundation
Suzuken Memorial Foundation
Salt Science Research Foundation
Ministry of Education, Culture, Sports, Science and Technology
MEXT | Japan Society for the Promotion of Science
MEXT | Japan Science and Technology Agency
Kanae Foundation for the Promotion of Medical Science
Smoking Research Foundation
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology