NUCLEAR IMPORT OF HIV-1 PRE-INTEGRATION COMPLEXES

Project: Research project

Description

Integration of the retroviral genome with host-cell DNA is an essential
step in retrovirus replication. The integration reaction is catalyzed by a
virus-encoded integrase (IN) which, after reverse transcription of genomic
viral RNA, remains associated with the viral cDNA in a high molecular
weight nucleoprotein pre-integration complex. Thus, targeting of the viral
pre-integration complex to host-cell DNA is dependent upon transport of
this complex to the nucleus of the host cell. Our studies provide evidence that nuclear import of the pre-integration
complex of HIV-1 is a rapid and active process which is independent of the
cell cycle. This active transport process is mediated by the nucleophilic
properties of the gag matrix protein (MA p17) which contains a nuclear
localization sequence (NLS) at its N terminus, and which is associated with
the pre-integration complex of HIV-1. In support of this tenet we provide
evidence that peptide analogues containing the NLS of HIV-1 MA p17 prevent
establishment of proviral HIV-1 DNA. In addition, HIV-1 variants bearing
MA p17 NLS mutations are replication defective. Specifically, we propose to: A.Characterize viral and host cell components of the pre-integration
complex of HIV-1 and their role in nuclear import of HIV-1 pre-integration
complexes.
I. Analyze nucleophilic properties of viral pre-integration complex
components.
II. Examine role of cellular proteins in nuclear import of HIV-1 pre-
integration complexes.
III. Analyze replicative and nuclear targeting properties of HIV-1 variants
bearing MA p17 NLS mutations. B. Evaluate inhibitory properties of NLS peptide analogues on HIV-1 pre-
integration complex transport and virus replication.
I. Analyze inhibitory properties of MA p17 NLS peptide analogues on HIV-1
and host cell NLS function in a microinjection assay.
II. Evaluate antiviral and cytocidal properties of NLS peptide analogues. It is expected that these studies will provide fundamental insight into
critical early events in the life cycle of HIV-1 and provide novel targets
for therapy aimed at preventing nuclear localization of HIV-1 pre-
integration complexes and establishment of the integrated provirus.
StatusFinished
Effective start/end date9/1/927/31/12

Funding

  • National Institutes of Health: $312,000.00
  • National Institutes of Health: $185,698.00
  • National Institutes of Health: $312,000.00
  • National Institutes of Health: $312,000.00
  • National Institutes of Health
  • National Institutes of Health: $358,678.00
  • National Institutes of Health: $312,000.00
  • National Institutes of Health: $358,678.00
  • National Institutes of Health: $355,092.00
  • National Institutes of Health: $234,482.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $306,291.00
  • National Institutes of Health: $253,614.00
  • National Institutes of Health: $330,988.00
  • National Institutes of Health: $365,625.00
  • National Institutes of Health: $312,000.00
  • National Institutes of Health

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Cell Nucleus Active Transport
HIV-1
Primate Lentiviruses
Nuclear Envelope
Viruses
HIV Infections
Virus Assembly
Macrophages
HIV
Nuclear Export Signals
Virion
Proviruses
gag Gene Products
Virus Diseases
Complementary DNA
Cell Nucleus
Protein-Serine-Threonine Kinases
Retroviridae
Nuclear Proteins
Reverse Transcription

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)