VARIANTS OF HIV WITH INCREASED POLYMERASE FIDELITY

Project: Research project

Project Details

Description

The investigator has discovered recently that a nucleoside analog-
resistance mutation In RT exhibits increased fidelity of dNTP
insertion. The prototype of such an enzyme is resistant to 3TC,
and it has the genotype M184V. The investigator postulates that
mutations resulting in increased fidelity could be beneficial in
combination therapy by decreasing the frequency of RT resistance to
other antiviral agents. The following 3 Specific Aims are
proposed: 1) To identify other RT mutations that cause an increase
in polymerase fidelity. A panel of selected mutants will be
assessed in biochemical assays to measure errors by misinsertion,
misextension and slippage. Error rates in RNA-dependent and DNA-
dependent polymerization steps will be compared: 2) to compare the
mutation rates in vitro and in a single-cycle HIV replication
assay: and 3) to examine the influence of increased fidelity in
clinical settings. In this Specific Aim, the investigator proposes
to study the clinical significance of increased fidelity of 3TC-
resistant HIV variants, which he postulates will reduce the
frequency of mutations in patients receiving 3TC and other drugs.
Samples will be obtained from a clinical trial, in which patients
will be treated first with 3TC and given ritonavir as a second arm
only after the appearance of 3TC-resistant RT is confirmed. The
investigator plans to study the frequency at which ritonavir-
resistance will emerge in such patients and attempt to correlate
this with the in vivo mutation rate dictated by mutant RT.
StatusFinished
Effective start/end date1/15/971/14/98

Funding

  • National Institute of Allergy and Infectious Diseases

ASJC

  • Genetics
  • Molecular Biology

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