Abstract
Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic analysis for drug resistance is limited to the first ∼300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance.
Highlights
The first cases of acquired immunodeficiency syndrome (AIDS) and HIV-1 infection were reported in the early 1980s [1,2,3]
A third mechanism for nucleoside reverse transcriptase inhibitors (NRTIs) drug resistance was proposed by Nikolenko et al, in which mutations that reduce RNase H cleavage can contribute to the NRTI-resistant phenotype by providing more time for reverse transcriptase (RT) to carry out nucleotide excision and resume productive DNA synthesis [32,33,34]
To further test the RNase H-dependent nonnucleoside reverse transcriptase inhibitors (NNRTIs) resistance model, Nikolenko et al introduced mutations in the NNRTI binding pocket, which would be expected to reduce the affinity of EFV and ETR to the RT [86]. When they analyzed the effects of D549N in the presence of the NNRTI binding pocket mutations, they found that the RNase H mutation further increased EFV and ETR resistance
Summary
The first cases of acquired immunodeficiency syndrome (AIDS) and HIV-1 infection were reported in the early 1980s [1,2,3]. Recent data has emerged to suggest that mutations that lie outside of the pol domain, within the C-terminal domain of RT (amino acids 312-560), can significantly increase resistance to nucleoside as well as non-nucleoside RT inhibitors These findings indicate that standard genotypic and phenotypic analyses of drug resistance should include the C-terminal domains of RT. There are eight NRTIs (abacavir [ABC], zidovudine [AZT], zalcitabine [ddC], didanosine [ddI], stavudine [d4T], emtricitabine [FTC], lamivudine [3TC], and tenofovir disoproxil fumarate [TDF]) and four NNRTIs (delaviridine [DLV], efavirenz [EFV], etravirine [ETR], and nevirapine [NVP]) approved for use in treatment of HIV-1 infection. As with NRTIs, 33 NNRTI accessory mutations in the pol domain have been identified from patient databases to be associated with NNRTI therapy including K101Q, I135T/M and L228H/R (reviewed in [17]). Closer examination of the accessory mutations is needed to assess their role in influencing the evolution of drug resistance in patients
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