Abstract
Simian immunodeficiency virus native to sooty mangabeys (SIVsm) is believed to have given rise to HIV-2 through cross-species transmission and evolution in the human. SIVmac239 and SIVB670, pathogenic to macaques, and SIVhu, isolated from an accidental human infection, also have origins in SIVsm. With their common ancestral lineage as that of HIV-2 from the progenitor SIVsm, but with different passage history in different hosts, they provide a unique opportunity to evaluate cross-species transmission to a new host and their adaptation/evolution both in terms of potential genetic and phenotypic changes. Using humanized mice with a transplanted human system, we evaluated in vivo replication kinetics, CD4+ T cell dynamics and genetic adaptive changes during serial passage with a goal to understand their evolution under human selective immune pressure. All the three viruses readily infected hu-mice causing chronic viremia. While SIVmac and SIVB670 caused CD4+ T cell depletion during sequential passaging, SIVhu with a deletion in nef gene was found to be less pathogenic. Deep sequencing of the genomes of these viruses isolated at different times revealed numerous adaptive mutations of significance that increased in frequency during sequential passages. The ability of these viruses to infect and replicate in humanized mice provides a new small animal model to study SIVs in vivo in addition to more expensive macaques. Since SIVmac and related viruses have been indispensable in many areas of HIV pathogenesis, therapeutics and cure research, availability of this small animal hu-mouse model that is susceptible to both SIV and HIV viruses is likely to open novel avenues of investigation for comparative studies using the same host.
Highlights
The causative agents of AIDS, both HIV-1 and HIV-2, remain entrenched in the human population and continue their onslaught in the ongoing global health crisis
SIVB670 is a derivative of Simian immunodeficiency virus native to sooty mangabeys (SIVsm) that was originally isolated from rhesus macaques that had been inoculated with cutaneous lepromatous leprosy lesion tissue homogenates from SIVsm infected sooty mangabeys
Within 1 week of inoculation, SIVmac239 RNA was detected in the plasma using qRT-PCR in all five infected hu-hematopoietic stem cells (HSC) mice demonstrating that SIVmac239 can infect human cells in vivo (Figure 1A)
Summary
The causative agents of AIDS, both HIV-1 and HIV-2, remain entrenched in the human population and continue their onslaught in the ongoing global health crisis. The ability of SIVmac239 to cause the rapid onset of AIDS-like symptoms in rhesus macaques has led to SIVmac239 and its derivatives becoming important surrogate lentiviruses commonly used for understanding HIV pathogenesis [7, 8]. Since the majority of endogenous SIVs do not cause AIDS-like symptoms in their native hosts [6, 11], SIVmac239 serves as a useful tool for understanding the genetic adaptive changes contributing to the increased virological fitness and mobility between host species. Infected macaque lymphoid tissues were co-cultured with a human T cell line to isolate the virus SIVB670 [6, 14] This virus has been commonly used in HIV research due to its aggressive pathology and immunosuppression [15, 16]
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