Evolution of SIVsm in humanized mice towards HIV‐2

Abstract

Through the accumulation of adaptive mutations, HIV‐2 originated from SIVsm. To identify these evolutionary changes, a humanized mouse model recapitulated the process that likely enabled this cross‐species transmission event. Various adaptive mutations arose, as well as increased virulence and CD4+ T‐cell decline as the virus was passaged in humanized mice.

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

“…Viruses isolated from the subsequent serial passages at different stages of infection were subjected to sequence analysis to identify and ascertain if any common changes could be found among these viruses given their shared ancestry. These studies also recapitulated some key aspects of cross-species transmission that we described previously in humanized mice that centered on SIVcpz and SIVsm to shed light on the origins of HIV-1 and HIV-2 from these respective progenitor viruses (3,4,48,50). Of the key observations from this present study, one was that both SIVmac239 and SIV B670 were readily able to infect hu-mice (Figures 1A,B).…”

“…Overall, relative to SIVmac239 and SIVhu, SIV B670 accumulated the largest number of nonsynonymous mutations with corresponding amino acid changes throughout the viral genome (Figure 3B, Table 2). The majority of these changes were found in the 3 ′ end of the viral genome similar to that found in previous studies on SIVsm and SIVcpz in hu-mouse studies (3,37,(48)(49)(50). Interestingly, one of the most striking features amongst the three passaged viruses was the mutation at residue 216 in Gag that appeared within all three different strains of viruses in a highly conserved part of the genome (26,53).…”

“…All mice used in these studies were cared for in the Colorado State University Painter Animal Center. Fetal liver-derived human CD34 + cells obtained from Advanced Bioscience Resources (ABR, Alameda CA), were isolated, column purified (Miltenyi Biotec, San Diego, CA), cultured and assessed for purity using flow cytometry (3,4,39,48,84,85). To create humanized hematopoietic stem cell (hu-HSC) mice, neonatal (1-4 day old) Balb/c Rag1 −/− γc −/− or Balb/c Rag2 −/− γc −/− mouse pups were sublethally irradiated (350 rads) prior to intrahepatic injection of 0.5-1 × 10 6 CD34 + cells (3,34,86).…”

“…Both the models permit HIV infection due to the presence of full immune cell repertoire and have been used widely to investigate areas such as HIV pathogenesis, transmission, and latency (33,35,(44)(45)(46)(47). We previously used the hu-mouse model as a human surrogate system to dissect various aspects of the initial crossspecies transmission of SIV chimpanzee virus (SIVcpz) to the human giving rise to HIV-1 and the SIVsm progenitor virus in giving rise to HIV-2 (3,4,39,(48)(49)(50). These studies provided important insights into the important genetic changes these progenitor viruses had to undergo to quickly adapt to the human host and also shed light on the gradual genetic changes that arose as the viruses were serially passaged multiple times using this system.…”

Evolution of SIVmac239 following serial passaging in humanized mice

“…[1][2][3][4] Previously, we showed successful infection and serial passaging of SIVmac239 as well as other SIVs in the humanized mouse model, which harbors a fully functional human immune system. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] Here, we characterized SIVmac239 following four serial passages in humanized mice and identified the genetic adaptations that arose following in vivo adaptation to the human immune cell environment. Viral pathogenesis was determined by monitoring plasma viral loads weekly using qRT-PCR and CD4 + T cell decline biweekly…”