INHIBITORS OF KINASES REQUIRED FOR HIV-1 INFECTIVITY

Project: Research project

Project Details

Description

Infection of a target cell by human immunodeficiency virus type 1 (HIV-1)
involves interaction with the CD4 receptor, reverse transcription of viral
nucleic acids and transport of viral cDNA to the host cell nucleus where
integration occurs. Reverse transcription of viral nucleic acids and
transport of viral nucleic acids from the site of virus entry to the
nucleus occurs within the context of a high molecular weight nucleoprotein
complex. One component of the nucleoprotein reverse transcription complex,
namely the gag matrix (MA) protein, plays a central role in the transport
of this complex from the site of virus entry to the host cell nucleus. In
addition to its nuclear import function during virus infection, gag MA is
myristylated; a modification which is necessary from membrane targeting of
gag precursors during virus assembly. We have recently demonstrated that
phosphorylation of gag MA both on tyrosine and on serine regulates its
opposing nuclear import and membrane targeting functions. Inhibitors of
tyrosine or serine kinase activity markedly attenuate HIV-1 infectivity by
preventing membrane dissociation of this complex at the site of virus
entry. Thus, cellular kinases are required for optimal HIV-1 infectivity.

The object of this NCDDG-HIV proposal is to evaluate whether kinases which
mediate phosphorylation of gag MA constitute a cellular target for
intervention of HIV-1 infectivity. Studies to be undertaken by the
research components of the NCDDG include:

1. Provide biochemical and virological support for efforts to clone
kinases which act on gag MA and for efforts to identify specific inhibitors
of these kinases.

2. Through targeted screening, identify agents which inhibit the activity
of kinases involved in HIV-1 gag MA phosphorylation and which, as a
consequence, block HIV-1 infectivity.

3. Utilize biochemical and genetic approaches to identify and clone
kinases involved in phosphorylation of gag MA.

It is anticipated that these studies will lead to the derivation of novel
agents for athe treatment of HIV-1 infection.
StatusFinished
Effective start/end date5/1/964/30/01

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases

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