SIV progenitor evolution toward HIV: A humanized mouse surrogate model for SIVsm adaptation toward HIV‐2

Abstract

How SIV progenitors evolved into deadly HIV-1 and HIV-2 following initial cross-species transmission still remains a mystery. Here we used humanized mice as a human surrogate system to evaluate SIVsm evolution into HIV-2. Increased viral virulence to human CD4+ T cells and adaptive genetic changes were observed during serial passages.

Mimicking SIV chimpanzee viral evolution toward HIV‐1 during cross‐species transmission

“…For the initial infection, 200 μl (TCID 50 2.0x10 5 ) virus was injected intraperitoneally into five (>75% CD45 + , >60% CD4 + ) hu‐HSC mice. SIVcpzLB715‐infected mice with the highest viral titer after 6 months were euthanized, and infected tissues were cultured to harvest the first passage stock virus as described previously 13,14 . For the next generation, a new cohort of five hu‐HSC mice was injected with 200 μl of first passage virus.…”

“…CD4 + T‐cell decline was determined by staining whole blood with fluorophore‐conjugated anti‐human CD45‐FitC (eBioscience), CD3‐PE (eBioscience), and CD4‐PE/Cy5 (BD Pharmigen, San Jose, CA) antibodies. BD Accuri C6 FACS Analyzer was used to determine cell counts as described previously 13,14 . The CD4 + T‐cell decline between the infected and uninfected mice was assessed using a two‐tailed Student’s t ‐test ( P < .001).…”

“…Here, we experimentally simulated the human exposures of SIVcpzLB715 and serial propagation in multiple human immune environments to determine the mutations that led to the generation of the pathogenic HIV‐1 Group M virus. We used humanized hematopoietic stem cell (hu‐HSC) mice harboring a complete repertoire of human immune cells susceptible to SIV and HIV infection to model these genetic adaptions 8‐15 . SIVcpzLB715 was used to infect a cohort of hu‐HSC mice and passaged into a second generation of mice (Figure 1A ) .…”

Evolution of SIVsm in humanized mice towards HIV‐2

“…SIVsmE041 (GenBank accession HM059825.1), isolated from sooty mangabey PBMC, was used to infect hu‐HSC mice as previously described 9,10 . Approximately 24 weeks after inoculation, mice with the highest plasma viral loads were euthanized to propagate the virus as previously described 6,9,10 . This process was repeated for 8 sequential passages.…”

“…SIV sooty mangabey (SIVsm) is believed to have accumulated a number of genetic changes during cross‐species transmission events between humans and sooty mangabeys that eventually resulted in HIV‐2 1‐3 . Humanized hematopoietic stem cell (hu‐HSC) mice are an effective model to study this question, as they provide an in vivo human immune environment that mimics the selective pressures of natural human infections 4‐11 . Here, we used serial passaging to simulate the repeated cross‐species exposures of SIVsm and reproduce the mutations that likely facilitated the transition of SIVsm into HIV‐2 12‐14 .…”