Experimental adaptive evolution of SIVcpz to pandemic HIV-1 using a humanized mouse model

HIV-1, the causative agent of AIDS, is originated from SIVcpz, the chimpanzee 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 (MB897, EK505, and MT145), four pandemic HIV-1 (NL4-3, NLCSFV3, JRCSF and AD8) and 2 non-pandemic HIV-1 (YBF30 and DJO0131) strains. Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a comparable peak viral load to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strains EK505 or MT145 as well as non-pandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is pre-adapted to humans when compared to the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation inenv, 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 bothin vitrocell 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.ImportanceFrom the mid-20th century, humans are exposed to the menace of viral infectious diseases such as SARS coronavirus, Ebola virus and Zika virus. These outbreaks of emerging/re-emerging viruses can be triggered by cross-species viral transmission from wild animals to humans or zoonoses. HIV-1, the causative agent of AIDS, was emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzee, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. By using a hematopoietic stem cell-transplanted humanized mouse model, here we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, has pre-adapted to infect humans comparing to 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.