A humanized mouse model to study HIV evolution from SIV

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Throughout history many pathogens have successfully crossed from animals into humans; however, few are as deadly as HIV. While HIV-1 originated from chimpanzees and gorillas, it is believed that HIV-2 arose from a virus native to Sooty Mangabeys (SIVsm) that humans were exposed to repeatedly over time. How the original virus evolved by picking up critical mutations needed for human adaptation and virulence has been unclear due to the lack of a suitable experimental system. By exploiting a unique humanized mouse model with a transplanted human immune system, we were able to recreate the conditions that may have facilitated these cross-species transmission and viral evolution events. Infection of hu-mice with the original SIVsm virus readily gave rise to chronic viremia, and upon successive serial passages, a more rapid loss of CD4 helper T cells. These results recapitulated key aspects of AIDS pathogenesis. Next-generation sequencing (NGS) was used to delineate the evolutionary viral genetic changes. A number of mutations spanning the entire genome were identified during five generations of sequential viral passaging/adaptation. Some of the mutations occurred in genomic regions important for viral adaption to human immune cells, thus shedding light on how these types of cross-species transmission events occur.

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13-10-2017 10-48-11The idea for this work was initially hatched in Sydney, Australia, at a HIV conference during a dinner conversation with Preston Marx of Tulane University. Collaborative work followed subsequently. The ‘Aha!’ moment came when we were able to successfully infect-hu-mice with the SIVsm viral isolate and detected chronic viremia thus permitting serial passaging. Our work is interdisciplinary with collaborators Preston Marx, Shelby O’Connor and Mark Stenglein contributing expertise in different areas.

As with any research project, certain obstacles needed to be overcome. In comparison with HIV-1, there is lack of sufficient information about HIV-2’s interactions with a wide range of host cellular restriction factors that the virus must overcome for cross-species transmission. HIV-1 and HIV-2 are sufficiently different that only limited parallels can be drawn. Furthermore, there was limited available whole genome sequence data for the SIVsmE041 strain we used. Through comparison with other related HIV-2 subtypes, it became possible to assess the importance of certain fixed mutations.

We are now using the same strategy to throw light on SIV chimpanzee viral human adaptive evolution into HIV-1 and hoping to identify the critical intermediate genetic changes.

Overall, this work opens the door to a plethora of potential new avenues to be explored in the search for the evolutionary changes giving rise not only to deadly HIV strains, but also other new human pathogens, and underlines the importance of hu-mice in this endeavor.

Introducing the author

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Pictured (left to right) are Leila Remling-Mulder (Research associate), Ramesh Akkina (Professor and PI), Kimberly Schmitt (Senior postdoctoral associate) and James Curlin (Graduate student) in the Department of Microbiology, Immunology and Pathology at Colorado State University.

About the research

Modeling the evolution of SIV sooty mangabey progenitor virus towards HIV-2 using humanized mice
Kimberly SchmittDipu Mohan KumarJames CurlinLeila Remling MulderMark StengleinShelby O’ConnorPreston MarxRamesh Akkina
Virology, Volume 510, October 2017, Pages 175-184