HIV RT NRTI Resistance Mechanisms Sample Clauses

HIV RT NRTI Resistance Mechanisms. Current HAART treatments involve two NRTIs and either a PI or NNRTI in order to improve the efficacy of the drugs being used as well as to delay drug resistance.42 However, with the common use of NRTIs, drug resistance eventually developments decreasing the efficacy of these therapeutics for long-term use. Two factors that lead to the emergence of drug resistance are the high replication rate and high mutation rate of HIV. In an untreated patient there are ~1010 new virions produced each day with 107 replication cycles also occurring each day.46 In addition, mutations are introduced into the HIV genome by the error-prone HIV RT at a rate of 3 x 10-5 per base per replication cycle.47 Coupled with the number of replication cycles that occur each day, a mutation may occur at every nucleotide in the HIV genome each day. These drug resistant variants are thus selected for by incomplete viral suppression resulting from non-compliance to a drug regimen, drug pharmacokinetics, or lack of drug potency. A number of NRTI resistant mutations have arisen in clinical practice. These mutations confer resistance to NRTIs through either a mechanism of discrimination or excision. Nucleotide discrimination is caused by mutations in the HIV RT active site that lead to recognition of structural differences between inhibitors and natural substrates. Mutations that lead to discrimination usually affect either the affinity of the nucleotide for the RT polymerase active site (Kd) or the catalytic rate constant (kpol).7 Mutations that have arisen in the clinic that result in discrimination due to an increase in Kd are the M184V and V75T mutations.7 These mutations did not have any significant impact on kpol. On the other hand the mutations K65R, Q151M, L74V, and K70E result in discrimination due to a decrease in kpol.7 It has been reported that K65R also has a small impact on Kd.7,49 The excision mechanism of resistance is a result of thymidine associated mutations (TAMs) that are selected for by AZT and d4T.5,42,48-49 TAMs usually emerge in two patterns: M41L/L210W/T215Y and D67N/K70R/T215F/K219Q.5 While TAMs are only selected for by thymidine analogues, the excision of any of the NRTIs can take place, though excision of AZT and d4T is most efficient. The outcome of excision is reverse polymerization in which an incorporated NRTI monophosphate (NRTI-MP) is removed from DNA (Figure 29).5 This results in a primer shortened by one nucleotide and exposes a 3’-OH group allowing DNA syn...
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