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MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in

Robert Lodge1, Zaikun Xu2, Mckenna Eklund2

  • 1Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal (IRCM) , Montreal, Quebec, Canada.

Mbio
|September 29, 2023
PubMed
Abstract

Insights

Human Immunodeficiency Virus (HIV) counters host antiviral proteins using Vpu. Vpu induces microRNAs-25 and -93, downregulating MARCH1 to enhance viral particle production.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Human Immunodeficiency Virus (HIV) replication is restricted by host cell antiviral proteins.
  • MARCH1 (Membrane-Associated Ring-CH-Type Finger 1) is a host protein that restricts HIV infection by limiting viral envelope glycoprotein incorporation.
  • HIV must overcome MARCH1 restriction to efficiently produce infectious viral particles.

Purpose of the Study:

  • To identify host factors that HIV-1 utilizes to counteract MARCH1-mediated restriction.
  • To elucidate the mechanism by which HIV-1 accessory protein Vpu downregulates MARCH1.
  • To understand the role of specific microRNAs in HIV-1 pathogenesis.

Main Methods:

  • Identification of regulatory RNAs induced by HIV-1 Vpu.
  • Quantification of MARCH1 mRNA levels in response to Vpu and identified microRNAs.
  • Investigation of the role of the β-catenin pathway in Vpu-mediated microRNA induction in macrophages.

Main Results:

  • Two cellular microRNAs, microRNA-25 and microRNA-93, were identified as being induced by the HIV-1 accessory protein Vpu.
  • These induced microRNAs directly downregulate MARCH1 mRNA, thereby reducing MARCH1 protein levels.
  • Vpu hijacks the cellular β-catenin pathway to induce microRNA-25 and microRNA-93 expression in macrophages.

Conclusions:

  • HIV-1 has evolved a mechanism involving Vpu-induced microRNAs to suppress the host antiviral factor MARCH1.
  • This Vpu-mediated downregulation of MARCH1 facilitates the efficient production of infectious viral particles.
  • The findings highlight the critical role of MARCH1 in the host antiviral response against HIV-1.
Keywords:
HIV-1 countermeasuresMARCH proteinsVpubeta-cateninhuman immunodeficiency virusmacrophagesmicroRNArestriction factortype-I interferon responseviral glycoproteins

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