Slower Uncoating Is Associated with Impaired Replicative Capability of Simian-Tropic HIV-1

Ken Kono, Eri Takeda, Hiromi Tsutsui, Ayumu Kuroishi, Amy E. Hulme, Thomas J. Hope, Emi E. Nakayama, Tatsuo Shioda*

*Corresponding author for this work

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5 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1) productively infects only humans and chimpanzees, but not Old World monkeys, such as rhesus and cynomolgus (CM) monkeys. To establish a monkey model of HIV-1/AIDS, several HIV-1 derivatives have been constructed. We previously generated a simian-tropic HIV-1 that replicates efficiently in CM cells. This virus encodes a capsid protein (CA) with SIVmac239-derived loops between α-helices 4 and 5 (L4/5) and between α-helices 6 and 7 (L6/7), along with the entire vif from SIVmac239 (NL-4/5S6/7SvifS). These SIVmac239-derived sequences were expected to protect the virus from HIV-1 restriction factors in monkey cells. However, the replicative capability of NL-4/5S6/7SvifS in human cells was severely impaired. By long-term cultivation of human CEM-SS cells infected with NL-4/5S6/7SvifS, we succeeded in partially rescuing the impaired replicative capability of the virus in human cells. This adapted virus encoded a G-to-E substitution at the 116th position of the CA (NL-4/5SG116E6/7SvifS). In the work described here, we explored the mechanism by which the replicative capability of NL-4/5S6/7SvifS was impaired in human cells. Quantitative analysis (by real-time PCR) of viral DNA synthesis from infected cells revealed that NL-4/5S6/7SvifS had a major defect in nuclear entry. Mutations in CA are known to affect viral core stability and result in deleterious effects in HIV-1 infection; therefore, we measured the kinetics of uncoating of these viruses. The uncoating of NL-4/5S6/7SvifS was significantly slower than that of wild type HIV-1 (WT), whereas the uncoating of NL-4/5SG116E6/7SvifS was similar to that of WT. Our results suggested that the lower replicative capability of NL-4/5S6/7SvifS in human cells was, at least in part, due to the slower uncoating of this virus.

Original languageEnglish (US)
Article numbere72531
JournalPloS one
Volume8
Issue number8
DOIs
StatePublished - Aug 13 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kono, K., Takeda, E., Tsutsui, H., Kuroishi, A., Hulme, A. E., Hope, T. J., Nakayama, E. E., & Shioda, T. (2013). Slower Uncoating Is Associated with Impaired Replicative Capability of Simian-Tropic HIV-1. PloS one, 8(8), [e72531]. https://doi.org/10.1371/journal.pone.0072531