PMID- 9431997
OWN - NLM
STAT- MEDLINE
DCOM- 19980205
LR  - 20190620
IS  - 0014-2956 (Print)
IS  - 0014-2956 (Linking)
VI  - 250
IP  - 1
DP  - 1997 Nov 15
TI  - The fidelity of misinsertion and mispair extension throughout DNA synthesis 
      exhibited by mutants of the reverse transcriptase of human immunodeficiency virus 
      type 2 resistant to nucleoside analogs.
PG  - 106-14
AB  - The AIDS-causing retroviruses, human immunodeficiency virus types 1 and type 2 
      (HIV-1 and HIV-2, respectively) undergo extensive genetic variations, which 
      effect their pathogenesis and resistance to drug therapy. It was postulated that 
      this genetic hypervariability results from high rates of viral replication in 
      conjugation with a relatively low fidelity of DNA synthesis [typical to the 
      reverse transcriptases (RT) of these retroviruses]. As part of studying 
      structure/function relationship in HIV RT, mutational analyses were conducted to 
      identify amino acid residues which are involved in affecting the fidelity of DNA 
      synthesis. The formation of 3'-mispaired DNA due to nucleotide misinsertions, and 
      the subsequent elongation of this mismatched DNA were shown to be major 
      determinants in affecting those substitutions during DNA synthesis (exhibited in 
      vitro by HIV RT). It was interesting to find a correlation between sensitivity to 
      nucleoside analogs (due to the ability to incorporate or reject an incoming 
      analog) and the fidelity of DNA synthesis (which depends on the capacity to 
      incorporate and extend a wrong nucleotide). Such a connection has already been 
      found for several drug-resistant mutants of HIV-1 RT, with an increased fidelity 
      of DNA synthesis relative to the wild-type RT. In the present study we have 
      examined the fidelity of DNA synthesis using the same parameters of misinsertion 
      and mispair extension for five novel drug-resistant mutants of HIV-2 RT; i.e. the 
      single mutants [Val74]RT, [Gly89]RT and [Tyr215]RT and the double mutants 
      [Val74,Tyr215]RT and [Gly89, Tyr215]RT. This comparative study suggests that 
      unlike the Val74 mutant of HIV-1 RT, which was shown earlier to display a 
      substantially enhanced fidelity, the comparable mutant of HIV-2 RT has fidelity 
      similar to that of the wild-type RT. Depending on the assay employed and the DNA 
      sequences extended, most other mutants of HIV-2 RT display moderate effects on 
      the enzyme, leading to mild increases in fidelity of DNA synthesis. This implies 
      a more complex and less distinctive correlation between drug-resistance, 
      misinsertion and mispair extension in HIV-2 RT in contrast to HIV-1 RT, providing 
      evidence for potential biochemical differences between these two related RT.
FAU - Taube, R
AU  - Taube R
AD  - Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv 
      University, Israel.
FAU - Avidan, O
AU  - Avidan O
FAU - Hizi, A
AU  - Hizi A
LA  - eng
PT  - Journal Article
PL  - England
TA  - Eur J Biochem
JT  - European journal of biochemistry
JID - 0107600
RN  - 0 (Anti-HIV Agents)
RN  - 0 (DNA Primers)
RN  - 0 (DNA, Viral)
RN  - 0 (Deoxyribonucleotides)
RN  - 0 (Nucleosides)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 2)
RN  - EC 2.7.7.49 (HIV Reverse Transcriptase)
RN  - EC 2.7.7.49 (RNA-Directed DNA Polymerase)
SB  - IM
MH  - Anti-HIV Agents/*pharmacology
MH  - Base Composition
MH  - DNA Mutational Analysis
MH  - DNA Primers/metabolism
MH  - DNA, Viral/*biosynthesis/genetics
MH  - Deoxyribonucleotides/metabolism
MH  - Drug Resistance, Microbial
MH  - HIV Reverse Transcriptase
MH  - HIV-2/drug effects/*enzymology/genetics/metabolism
MH  - Humans
MH  - Kinetics
MH  - *Mutation
MH  - Nucleosides/*pharmacology
MH  - RNA-Directed DNA Polymerase/*genetics/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Structure-Activity Relationship
MH  - Templates, Genetic
EDAT- 1998/02/07 00:00
MHDA- 1998/02/07 00:01
CRDT- 1998/02/07 00:00
PHST- 1998/02/07 00:00 [pubmed]
PHST- 1998/02/07 00:01 [medline]
PHST- 1998/02/07 00:00 [entrez]
AID - 10.1111/j.1432-1033.1997.00106.x [doi]
PST - ppublish
SO  - Eur J Biochem. 1997 Nov 15;250(1):106-14. doi: 10.1111/j.1432-1033.1997.00106.x.