Molecular interactions between the subunits of the HIV-1 reverse transcriptase

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/235030

Funding Status
Closed

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Funded Activity Summary

Human immunodeficiency virus type 1 (HIV-1) infection is a serious public health problem affecting millions of individuals world-wide. HIV-1 infection can be controlled or prevented by antiretroviral drugs. However, these drugs eventually become ineffective because the virus can mutate to become resistant to them. Therefore, it is important to identify new targets in the virus life-cycle for chemotherapeutic intervention. A successful target for anti-HIV-1 drugs has been the reverse transcriptase (RT) enzyme, which converts the viral RNA genome into a proviral DNA precursor, and is absolutely essential for virus replication. The RT is a dimer consisting of two polypeptides of 66 and 51kDa, and formation of this heterodimer is required for its enzymatic functions. We believe that destabilisation or enhancement of the RT subunits represents a potential target for chemotherapeutic intervention. We have developed a novel system in yeast which we can use to study this interaction and determine any mutations that either enhance or decrease the interaction between the two RT subunits. These mutations will then be assessed for their effects on RT activity and HIV-1 replication. Using this system we have made the novel discovery that certain types of anti-HIV drugs called nonnucleoside reverse transcriptase inhibitors (NNRTIs) can increase the interaction between the two RT subunits. This suggests that increased subunit interaction may, in part, explain the inhibitory activity of RT dimerisation enhancing NNRTIs. Elucidation of the mechanism and structural basis of this phenomenon is of interest to provide insight into the actions of NNRTIs and into the dimerisation process, neither of which is well understood.

Funded Activity Details

Start Date: 01-01-2003

End Date: 01-01-2005

Funding Scheme: NHMRC Project Grants

Funding Amount: $347,625.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Applied immunology (incl. antibody engineering xenotransplantation and t-cell therapies)

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

HIV-1 retrovirus | acquired immunodeficiency syndrome | antiviral | antiviral drug | infectious diseases | protein:protein interaction | reverse transcriptase | virus replication

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