Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core

Cell Rep. 2020 Mar 17;30(11):3766-3777.e6. doi: 10.1016/j.celrep.2020.02.100.

Abstract

Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and CD4+ T cells. Our results show that inhibition of HIV-1 infection caused by disrupting CypA-capsid interactions is dependent on human tripartite motif 5α (TRIM5αhu), showing that TRIM5αhu restricts HIV-1 in CD4+ T cells. Accordingly, depletion of TRIM5αhu in CD4+ T cells rescues HIV-1 that fail to interact with CypA, such as HIV-1-P90A. We found that TRIM5αhu binds to the HIV-1 core. Disruption of CypA-capsid interactions fail to affect HIV-1-A92E/G94D infection, correlating with the loss of TRIM5αhu binding to HIV-1-A92E/G94D cores. Disruption of CypA-capsid interactions in primary cells has a greater inhibitory effect on HIV-1 when compared to Jurkat cells. Consistent with TRIM5α restriction, disruption of CypA-capsid interactions in CD4+ T cells inhibits reverse transcription. Overall, our results reveal that CypA binding to the core protects HIV-1 from TRIM5αhu restriction.

Keywords: CD4(+) T cells; CypA; HIV-1; TRIM5α(hu); capsid; core; cyclosporine A; restriction; reverse transcription; uncoating.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Capsid / metabolism
  • Cell Line
  • Cyclophilin A / metabolism*
  • Cyclosporine / pharmacology
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Lymphocytes / virology*
  • Mutation / genetics
  • Protein Binding / drug effects
  • Reverse Transcription / drug effects
  • Reverse Transcription / genetics
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Tripartite Motif Proteins
  • Cyclosporine
  • TRIM5 protein, human
  • Ubiquitin-Protein Ligases
  • Cyclophilin A