Epidemiological and biological evidence for a compensatory effect of connection domain mutation N348I on M184V in HIV-1 reverse transcriptase.
BACKGROUND
The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V.


METHODS
Genotypic resistance data for patients receiving monotherapy or dual therapy with AZT, lamivudine (3TC), or AZT/3TC were analyzed. Rates of N348I emergence were compared between treatment groups. Mutant reverse transcriptases (RTs) containing M184V and/or N348I were generated to study enzymatic and virological properties.


RESULTS
We included 50 AZT-treated, 11 3TC-treated, and 10 AZT/3TC-treated patients. N348I was observed in 3 (6%), 0, and 4 (40%) of these patients, respectively. The rate of N348I emergence was increased by 5-fold in the AZT/3TC group (11.7 instances [95% confidence interval {CI}, 3.2-30.1 instances] per 100 person-years of receipt of AZT), compared with the rate noted for the AZT group (2.3 instances [95% CI, 0.4-6.8 instances] per 100 person-years of receipt of AZT; P = .04). Biochemical data show that N348I can partially compensate for the diminution in processive DNA synthesis and the reduction in AZT excision associated with M184V. Furthermore, virological analyses demonstrate that N348I confers low-level resistance to AZT and partly restores the reduced RT activity of the M184V variant.


CONCLUSIONS
In vivo selection of N348I is driven by AZT and is further facilitated when 3TC is coadministered. Compensatory interactions between N348I and M184V help to explain these findings.
von Wyl
Viktor
V
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich, Switzerland. huldrych.guenthard@usz.ch
Ehteshami
Maryam
M
Symons
Jori
J
Bürgisser
Philippe
P
Nijhuis
Monique
M
Demeter
Lisa M
LM
Yerly
Sabine
S
Böni
Jürg
J
Klimkait
Thomas
T
Schuurman
Rob
R
Ledergerber
Bruno
B
Götte
Matthias
M
Günthard
Huldrych F
HF
D002460:Cell Line; D004279:DNA, Viral; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus; D012641:Selection, Genetic; D018709:Statistics, Nonparametric; D015215:Zidovudine / Q000494:pharmacology*
D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus