Molecular characterization of interferon-resistant HIV-1 using novel imaging techniques

Project: Research project

Project Details

Description

HIV-1 is a causative pathogen that can cause AIDS in humans. Although type I
interferon (IFN) is known to suppress viral replication both in the early and in the late
stage of HIV-1’s replication cycle, the molecular mechanism of inhibition remains to be
elucidated. Treatment of cells with IFN leads to upregulation of IFN-inducible genes
encoding anti HIV-1 host factors such as BST-2 (Tetherin), SAMHD1 and Mx2. We
have been interested in the mechanism of suppression imposed by IFN-β treatment in
the early stage (steps between entry of viral core into the cytosol and integration into
host genome) of HIV-1 infection. Recent studies suggest that the early stage of HIV-1
infection is blocked by Mx2 but also by unidentified mechanisms in IFN-β-treated cells.
Consistent with the findings, our preliminary experiments show that HIV-1 infection is
blocked by Mx2-indepenent mechanism in IFN-β-treated cells. In this research proposal,
we want to clarify the underlying mechanisms that control the IFN-β sensitivity. Our
biggest advantage is that we already obtained mutant viruses that are
partially/completely resistant to IFN-β treatment. These mutants contain mutations in
the capsid protein (CA). CA orchestrates multiple step of HIV-1’s replication cycle
including uncoating, reverse transcription, nuclear entry and integration of
pre-integration complex into host cell chromatin. We became interested in relationship
between uncoating kinetics and IFN-β sensitivity. Our hypothesis is that IFN-β-resistant
CA mutants alter the uncoating kinetics in order to change the timing or localization not
to be exposed to inhibitory factor. Therefore, the studies proposed here are intended to
fill a critical void in our understanding of molecular mechanism of IFN-mediated
inhibition of HIV-1. First, we will examine the uncoating kinetics of these CA mutants
using newly established, novel live-cell imaging system. Second, we will test the
sensitivity of CA to mutants in primary cells such as CD4+ lymphocytes and
macrophages. Last, we investigate the mechanism of evasion. The information
generated in these studies will substantially alter our view of IFN-β-mediated inhibition
of HIV-1 and also lead to a discovery of novel strategy against HIV epidemic.
StatusFinished
Effective start/end date4/20/173/31/18

Funding

  • U.S. Civilian Research & Development Foundation (DAA2-17-62986-1//59-0210-2-160)
  • Department of Agriculture (DAA2-17-62986-1//59-0210-2-160)

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