Virologic and Enzymatic Studies Revealing the Mechanism of K65R- and Q151M-Associated HIV-1 Drug Resistance Towards Emtricitabine and Lamivudine

Emtricitabine (FTC) and lamivudine (3TC) are deoxycytidine analogues with potent and selective inhibition of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication. The K65R mutation in the HIV reverse transcriptase (RT) confers reduced susceptibility to 3TC, ddC, ddI, abacavir,...

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Published in:Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2006-01, Vol.25 (1), p.89-107
Main Authors: Feng, Joy Y., Myrick, Florence T., Margot, Nicolas A., Mulamba, Gilbert B., Rimsky, Laurence, Borroto-Esoda, Katyna, Selmi, Boulbaba, Canard, Bruno
Format: Article
Language:English
Subjects:
3TC
Amino Acid Substitution
Anti-HIV Agents - pharmacology
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Drug Resistance, Viral - drug effects
Emtricitabine
Enzyme Inhibitors - pharmacology
FTC
Glutamine - genetics
Glutamine - metabolism
Hepatitis B virus
HIV Reverse Transcriptase - antagonists & inhibitors
HIV Reverse Transcriptase - genetics
HIV Reverse Transcriptase - metabolism
HIV-1 - drug effects
HIV-1 - enzymology
HIV-1 - genetics
HIV-1 RT
Human immunodeficiency virus 1
K65R
Kinetics
Lamivudine
Lamivudine - pharmacology
Lysine - genetics
Lysine - metabolism
Mutation - genetics
Pre-steady state
Q151M
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Summary:Emtricitabine (FTC) and lamivudine (3TC) are deoxycytidine analogues with potent and selective inhibition of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication. The K65R mutation in the HIV reverse transcriptase (RT) confers reduced susceptibility to 3TC, ddC, ddI, abacavir, and tenofovir in vitro. The Q151M mutation confers reduced susceptibility to many of the approved anti-HIV nucleoside analogues with the exception of 3TC and tenofovir. The double mutation K65R/Q151M has been shown to be more resistant to many NRTIs than either of the single mutations alone. In this study, we measured the antiviral activity of FTC and 3TC against HIV-1 containing K65R, Q151M, and K65R/Q151M mutations. We also studied the steady-state kinetic properties for the inhibition of dCTP incorporation by FTC 5′-triphosphate (TP) and 3TC-TP. In addition, we measured the incorporation of dCTP, FTC-TP, and 3TC-TP into a random sequence DNA/DNA primer/template by the HIV-1 RTs using pre-steady-state kinetic analysis. Finally, we studied the incorporation of these deoxycytidine analogues into a HIV-1 genomic DNA/DNA primer/template by K65R HIV-1 RT to address certain concerns associated with DNA sequence specificity. Overall, this study demonstrated that K65R and K65R/Q151M related drug resistance to FTC and 3TC was mainly due to a significant decrease in the rate of incorporation. There was little to no effect on the binding affinities of the mutant HIV-1 RTs for the deoxycytidine analogues. The Q151M mutation remained sensitive to both FTC and 3TC in both cell culture and enzymatic assays. At a molecular level, FTC-TP was incorporated at least as efficiently as 3TC-TP for all of the HIV-1 RT and primer/templates tested.
ISSN:1525-7770
1532-2335
DOI:10.1080/15257770500379157