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Inter- and Intra-Species Transmission and Pathogenesis of Simian Immunodeficiency Viruses
It is accepted that the origins of human immunodeficiency virus type-1 (HIV-1) are the consequences of simian immunodeficiency viruses in chimpanzees (SIVcpz) cross-species transmission to humans. However, there have been no in vivo experiments that investigate the cross-species transmissibility of SIVcpz to humans, the initial virus-host interaction, and its pathogenesis due to ethical reasons. In Chapter Two, we conducted the first in vivo experiments and found that multiple SIVcpz strains can readily infect humanized-BLT mice. We identified several important mutations of SIVcpz after long-term adaptation in hu-BLT mice. The cross-species transmission barrier of SIVcpz to humans correlates with their phylogenetic distance to the pandemic HIV-1 group M. Importantly, this work also found that SIVcpz that have not been found in humans can readily infect human cells, suggesting they have the potential to cause a HIV-1 like zoonosis in the future.^ In Chapter Three, we investigated the initial interaction between SIVcpz and humans and compared the pathogenic differences of SIVcpz with HIV-1 using hu-BLT mice. We found SIVcpz strains are less pathogenic than HIV-1 despite similarly high levels of viremia. Our findings challenge the conventional view that SIVcpz first crossed over into humans is as pathogenic as the current pandemic HIV-1 and provided new insights into the evolutional history of HIV-1 pandemic.^ In Chapter Four, we investigated the early events of human mucosal transmissions of HIV-1 using a SIV-rhesus macaque model. We found that there was no tissue compartmentalization of founder viruses during very early rectal transmission of SIV in the majority of rhesus macaques and that the founder viruses are preferentially derived from rare variants in the inoculum. We also found that founder viruses are animal-specific despite identical viral inoculums. After viruses cross the mucosal barriers, the host further reduces viral diversity by converting transmitted viruses into defective viruses through frameshift rather than APOBEC derived mutations. To my knowledge, this is the first study of founder viruses at multiple tissue sites during very early transmission. ^
Yuan, Zhe, "Inter- and Intra-Species Transmission and Pathogenesis of Simian Immunodeficiency Viruses" (2017). ETD collection for University of Nebraska - Lincoln. AAI10270999.