Recapitulating Cross-Species Transmission of SIVcpz to Humans Using Humanized-BLT Mice

Authors

Zhe Yuan, University of Nebraska-LincolnFollow
Guobin Kang, University of Nebraska–LincolnFollow
Fangrui Ma, University of Nebraska-LincolnFollow
Wuxun Lu, University of Nebraska-Lincoln,Follow
Wenjin Fan, University of Nebraska-LincolnFollow
Christine M. Fennessey, Frederick National Laboratory for Cancer Research
Brandon F. Keele, Frederick National Laboratory for Cancer Research
Qingsheng Li, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2016

Citation

Journal of Virology Accepted Manuscript Posted Online 15 June 2016
J. Virol. doi:10.1128/JVI.00860-16

Comments

Copyright © 2016, American Society for Microbiology. Used by permission.

Abstract

The origins of HIV-1 have been widely accepted to be the consequence of simian immunodeficiency viruses from wild chimpanzees (SIVcpz) crossing over to humans. However, there has not been any in vivo study of SIVcpz infection of humans. Also, it remains largely unknown why only specific SIVcpz strains have achieved cross-species transmission and what transmission risk might exist for those SIVcpz strains that have not been found to infect humans. Closing this knowledge gap is essential for better understanding cross-species transmission and predicting the likelihood of additional cross-species transmissions of SIV into humans. Here we show hu-BLT mice are susceptible to all studied strains of SIVcpz, including the inferred ancestral viruses of pandemic and non-pandemic HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505), also strains that have not been found in humans (SIVcpzMT145 and SIVcpzBF1167). Importantly, the ability of SIVcpz to cross the interspecies barrier to infect humanized mice correlates with their phylogenetic distance to pandemic HIV-1. We also identified mutations of SIVcpzMB897 (Env G411R & G413R) and SIVcpzBF1167 (Env H280Q & Q380R) at 14 weeks post inoculation. Together, our results have recapitulated the events of SIVcpz cross-species transmission to humans and identified mutations that occurred during the first 16 weeks of infection, providing in vivo experimental evidence that the origins of HIV-1 are the consequence of SIVcpz crossing over to humans. This study also revealed that SIVcpz viruses whose inferred descendants have not been found in humans still have the potential to cause HIV-1 like zoonosis.