Abstract
A major issue for present HIV-1 research is to establish model systems that reflect or mimic viral replication and pathogenesis actually observed in infected humans. To this end, various strategies using macaques as infection targets have long been pursued. In particular, experimental infections of rhesus macaques by HIV-1 derivatives have been believed to be best suited, if practicable, for studies on interaction of HIV-1 and humans under various circumstances. Recently, through in vitro genetic manipulations and viral cell-adaptations, we have successfully generated a series of HIV-1 derivatives with CXCR4-tropism or CCR5-tropism that grow in macaque cells to various degrees. Of these viruses, those with best replicative potentials can grow comparably with a pathogenic SIVmac in macaque cells by counteracting major restriction factors TRIM5, APOBEC3, and tetherin proteins. In this study, rhesus macaques were challenged with CXCR4-tropic (MN4/LSDQgtu) or CCR5-tropic (gtu + A4CI1) virus. The two viruses were found to productively infect rhesus macaques, being rhesus macaque-tropic HIV-1 (HIV-1rmt). However, plasma viral RNA was reduced to be an undetectable level in infected macaques at 5–6 weeks post-infection and thereafter. While replicated similarly well in rhesus peripheral blood mononuclear cells, MN4/LSDQgtu grew much better than gtu + A4CI1 in the animals. To the best of our knowledge, this is the first report demonstrating that HIV-1 derivatives (variants) grow in rhesus macaques. These viruses certainly constitute firm bases for generating HIV-1rmt clones pathogenic for rhesus monkeys, albeit they grow more poorly than pathogenic SIVmac and SHIV clones reported to date.
Highlights
HIV-1 has emerged from ancestral viruses by extensive recombination and/or adaptation events (Sharp and Hahn, 2011)
Due to the exceptionally narrow host range of HIV-1, primarily based on its sophisticatedly regulated replication, animal models for experimental infections have been difficult to develop from the dawn period to the present stage of HIV-1 research
After confirming the replication ability in M1.3S cells, we comparatively examined the three HIV-1rmt clones (MN4/LSDQgtu, MN5/LSDQgtu, and gtu + A4CI1 in Figure 1) for their growth properties in rhesus peripheral blood mononuclear cells (PBMCs) as previously described (Nomaguchi et al, 2013b, 2014)
Summary
HIV-1 has emerged from ancestral viruses by extensive recombination and/or adaptation events (Sharp and Hahn, 2011). Rhesus macaques of Indian origin are best characterized, most utilized and most successfully used NHPs for SIV- or SHIV-based model studies on HIV-1/AIDS (Nomaguchi et al, 2011; Hatziioannou and Evans, 2012).
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