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HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle

Denise Jurczyszak1,2, Wen Zhang3, Sandra N Terry2

  • 1The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United State of America.

Plos Pathogens
|February 14, 2020
PubMed

Insights

The YTHDF3 protein restricts HIV replication by limiting reverse transcription. HIV protease cleaves YTHDF3 within viral particles, enhancing infectivity, a process blocked by protease inhibitors.

Area of Science:

  • Virology
  • Molecular Biology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) is the most prevalent RNA modification in HIV.
  • The role of the m6A reader protein YTHDF3 in HIV replication remains unclear.

Purpose of the Study:

  • To investigate the interplay between YTHDF3 and HIV replication.
  • To determine YTHDF3's function in HIV infection and its fate within viral particles.

Main Methods:

  • CRISPR-Cas9 knockout of YTHDF3 in human CD4+ T-cells.
  • Overexpression of YTHDF3 in HIV-producing cells.
  • Analysis of YTHDF3 incorporation into HIV particles.
  • Mass-spectrometry to identify viral protein processing.
  • Assessment of viral infectivity in the presence of YTHDF3 and protease inhibitors.

Main Results:

  • YTHDF3 knockout in CD4+ T-cells increased HIV infection, indicating YTHDF3 acts as a restriction factor.
  • YTHDF3 overexpression in producer cells reduced the infectivity of newly formed viruses.
  • YTHDF3 is incorporated into HIV particles via a nucleocapsid-dependent mechanism.
  • HIV protease cleaves incorporated YTHDF3, enhancing virion infectivity.
  • Proteolytic processing of YTHDF3 was confirmed by mass spectrometry and inhibited by protease inhibitors.

Conclusions:

  • YTHDF3 restricts HIV replication by limiting reverse transcription in target cells.
  • HIV protease targets and cleaves virion-encapsidated YTHDF3, in addition to viral polyproteins, to ensure optimal viral infectivity.
  • This cleavage mechanism presents a potential therapeutic target for HIV treatment.

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