SIVcpz closely related to the ancestral HIV-1 is less or non-pathogenic to humans in a hu-BLT mouse model

Zhe Yuan,Guobin Kang,Lance Daharsh,Wenjin Fan,Qingsheng Li

doi:10.1038/s41426-018-0062-9

Zhe Yuan, Guobin Kang + Show 3 more

Open Access

https://doi.org/10.1038/s41426-018-0062-9

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Abstract

The HIV-1 pandemic is a consequence of the cross-species transmission of simian immunodeficiency virus in wild chimpanzees (SIVcpz) to humans. Our previous study demonstrated SIVcpz strains that are closely related to the ancestral viruses of HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) and two SIVcpz lineages that are not associated with any known HIV-1 infections in humans (SIVcpzMT145 and SIVcpzBF1167), all can readily infect and robustly replicate in the humanized-BLT mouse model of humans. However, the comparative pathogenicity of different SIVcpz strains remains unknown. Herein, we compared the pathogenicity of the above four SIVcpz strains with HIV-1 using humanized-BLT mice. Unexpectedly, we found that all four SIVcpz strains were significantly less pathogenic or non-pathogenic compared to HIV-1, manifesting lower degrees of CD4+ T-cell depletion and immune activation. Transcriptome analyses of CD4+ T cells from hu-BLT mice infected with SIVcpz versus HIV-1 revealed enhanced expression of genes related to cell survival and reduced inflammation/immune activation in SIVcpz-infected mice. Together, our study results demonstrate for the first time that SIVcpz is significantly less or non-pathogenic to human immune cells compared to HIV-1. Our findings lay the groundwork for a possible new understanding of the evolutionary origins of HIV-1, where the initial SIVcpz cross-species transmission virus may be initially less pathogenic to humans.

Highlights

The HIV-1 pandemic is a consequence of cross-species transmission of simian immunodeficiency virus from wild chimpanzees (SIVcpz) to humans[1,2,3]
That the simian immunodeficiency virus in wild chimpanzees (SIVcpz) strains that are closely related to the ancestral viruses of groups M and N, as well as the lineages of SIVcpz that are not associated with any known HIV-1 infections in humans, are all significantly less pathogenic or non-pathogenic in hu-BLT mice compared with HIV-1, manifesting significantly lower degrees of CD4+ T-cell depletion and cell activation compared with uninfected controls and HIV-1infected animals
We compared the plasma viral load kinetics of four SIVcpz strains, including SIVcpz strains that are closely related to the ancestral viruses of HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) and two lineages of SIVcpz that are not associated with any known HIV-1 infections in humans (SIVcpzMT145 and SIVcpzBF1167), and current pandemic HIV-1 using hu-BLT mice

Summary

Introduction

The HIV-1 pandemic is a consequence of cross-species transmission of simian immunodeficiency virus from wild chimpanzees (SIVcpz) to humans[1,2,3]. The most likely time period of crossspecies transmission of SIVcpz as the ancestral HIV-1 group M virus to humans is between 1853 and 1908. Consistent with these estimates, the earliest spread of HIV-1 within humans was reported around 1920 in Kinshasa[8]. There are no recorded AIDS-related deaths before the first documented HIV-1 infection in the Congo in 1959, whose actual cause of death remains unknown[9] These data suggest that SIVcpz early crossspecies infections of humans appear to be clinically “silent” for at least five decades. These questions are fundamentally important for understanding the evolutionary origins of the devastating pandemic of HIV-1 infections and for predicting the likelihood of the occurrence of another HIV-1-like infection in humans, as more than 30 African non-human primate (NHP) species are still infected with more than 40 different strains of SIVs3

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