Recapitulating Cross-Species Transmission of Simian Immunodeficiency Virus SIVcpz to Humans by Using Humanized BLT Mice

Abstract

The origins of human immunodeficiency virus type 1 (HIV-1) have been widely accepted to be the consequences 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 crossspecies 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 that humanized bone marrow, thymus, and liver (hu-BLT) mice are susceptible to all studied strains of SIVcpz, including the inferred ancestral viruses of pandemic and nonpandemic HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) as well as 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 and G413R) and SIVcpzBF1167 (Env H280Q and Q380R) at 14 weeks postinoculation. 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 an HIV-1-like zoonosis. IMPORTANCEIt is believed that the origins of HIV-1 are the consequence of SIV from wild chimpanzees crossing over to humans. However, the origins of HIV-1 have been linked back to only specific SIVcpz strains. There have been no experiments that directly test the in vivo cross-species transmissibility of SIVcpz strains to humans. This is the first in vivo study of SIVcpz cross-species transmission. With the humanized-BLT mouse model, we have provided in vivo experimental evidence of multiple SIVcpz strains crossing over to humans and identified several important mutations of divergent SIVcpz strains after long-term replication in human cells. We also found that the cross-species transmission barrier of SIVcpz to humans correlates with their phylogenetic distance to pandemic HIV-1 group M. Importantly, this work provides evidence that SIVcpz viruses, whose inferred descendants have not been found in humans, still have the potential to cause a future HIV-1-like zoonotic outbreak. H uman immunodeficiency virus type 1 (HIV-1) infections have claimed millions of human lives since the pandemic began in 1981, and HIV-1 still infects about 2.3 million people every year (1, 2). Based on comparative phylogenetic analyses of HIV-1 and simian immunodeficiency viruses from chimpanzee (SIVcpz), it has ...

A glycan shield on chimpanzee CD4 protects against infection by primate lentiviruses (HIV/SIV)

“…3 D and E). This is consistent with previous reports that SIVcpz can utilize human CD4 (45)(46)(47)(48), collectively supporting the idea that human CD4 was not a barrier in either of the zoonotic transmissions leading to HIV-1 group M and group N.…”

Modeling the evolution of SIV sooty mangabey progenitor virus towards HIV-2 using humanized mice

“…Interestingly, only two non-synonymous mutations in env , both in SIVcpzMB897 and SIVcpzBF1167, at 14 weeks post-inoculation were found (Yuan et al, 2016). This is likely due to the short 14-week period of evaluation during a single passage and that the whole genome was not analyzed by next-generation sequencing.…”

Experimental Adaptive Evolution of Simian Immunodeficiency Virus SIVcpz to Pandemic Human Immunodeficiency Virus Type 1 by Using a Humanized Mouse Model

“…Particularly, the Vpu of HIV-1M, but not those of SIVcpz or the other types of HIV-1, antagonizes human tetherin (28)(29)(30), suggesting that the Vpu-mediated antitetherin ability is crucial for increasing viral fitness and the efficiency of human-to-human viral spread (31). However, although SIVcpzPtt is partially capable of replicating in human tissue cultures (32) and a humanized-mouse model (33), the process by which SIVcpzPtt evolved to become HIV-1 in humans remains unclear. Moreover, although a recent study by Yuan et al used a bone marrow/liver/thymus (BLT)-humanized-mouse model for SIVcpz infection and detected a nonsynonymous mutation in env in SIVcpz-infected humanized mice (33), the virological significance of this mutation has not been addressed.…”

“…However, although SIVcpzPtt is partially capable of replicating in human tissue cultures (32) and a humanized-mouse model (33), the process by which SIVcpzPtt evolved to become HIV-1 in humans remains unclear. Moreover, although a recent study by Yuan et al used a bone marrow/liver/thymus (BLT)-humanized-mouse model for SIVcpz infection and detected a nonsynonymous mutation in env in SIVcpz-infected humanized mice (33), the virological significance of this mutation has not been addressed.…”