Abstract
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are widely used to treat HIV-1-infected individuals; indeed most first-line antiretroviral therapies typically include one NNRTI in combination with two nucleoside analogs. In 2008, the next-generation NNRTI etravirine was approved for the treatment of HIV-infected antiretroviral therapy-experienced individuals, including those with prior NNRTI exposure. NNRTIs are also increasingly being included in strategies to prevent HIV-1 infection. For example: (1) nevirapine is used to prevent mother-to-child transmission; (2) the ASPIRE (MTN 020) study will test whether a vaginal ring containing dapivirine can prevent HIV-1 infection in women; (3) a microbicide gel formulation containing the urea-PETT derivative MIV-150 is in a phase I study to evaluate safety, pharmacokinetics, pharmacodynamics and acceptability; and (4) a long acting rilpivirine formulation is under-development for pre-exposure prophylaxis. Given their widespread use, particularly in resource-limited settings, as well as their low genetic barriers to resistance, there are concerns about overlapping resistance between the different NNRTIs. Consequently, a better understanding of the resistance and cross-resistance profiles among the NNRTI class is important for predicting response to treatment, and surveillance of transmitted drug-resistance.
Highlights
HIV-1-infected individuals; most first-line antiretroviral therapies typically include one nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) in combination with two nucleoside analogs
Due to its essential role in HIV-1 replication, RT is a major target for antiviral drug development and two classes of inhibitors, (1) the nucleoside and nucleotide RT inhibitors (NRTIs) and (2) the nonnucleoside RT inhibitors (NNRTIs), have been approved by the FDA for the treatment of HIV-1 infection
Polymerase catalytic site, especially the highly conserved tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif and proposed that this class of drugs inhibits DNA polymerization by locking the polymerase active site in an inactive conformation [5]; (2) Hsiou et al observed that NNRTI binding deformed the structural elements that comprise the ―primer grip‖, a region in RT that is involved in the precise positioning of the primer DNA strand in the polymerase active site [6]
Summary
Reverse transcription of the single-stranded (+) RNA genome into double-stranded DNA is an essential step in the HIV-1 replication life-cycle [1]. RT initiates (−) strand DNA synthesis at the 3'end of a cellular lysyl-tRNALys molecule that is hybridized to the primer binding site (PBS) of the viral RNA genome. This nascent DNA strand is elongated by the RNA-dependent DNA polymerase activity (RDDP) of RT until the 5' end of the HIV-1 RNA is reached. RT uses its RNase H activity to hydrolyze the RNA strand of the RNA/DNA duplex which allows the DNA to hybridize with a repeat sequence at the 3' end of the HIV-1 RNA Following this strand transfer, the viral DNA strand is elongated by the RDDP activity of RT until the entire RNA template has been copied. The HIV-1 RT DDDP activity including strand-displacement activity completes the synthesis of the double stranded proviral DNA precursor
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