HIV-1 reverse transcriptase and antiviral drug resistance. Part 1

Abstract

HIV-1 reverse transcriptase (RT) contributes to the development of resistance to all anti-AIDS drugs by introducing mutations into the viral genome. At the molecular level, mutations in RT result in resistance to RT inhibitors. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have illuminated different conformational and functional states of the enzyme. Understanding the molecular mechanisms of resistance to NRTIs and NNRTIs, and their complex relationships, may help in designing new drugs that are periodically required to overcome existing as well as emerging trends of drug resistance.

Figure 1

HIV-1 RT structure and sites for common drug resistance mutations. (a) A ribbon representation of the structure of HIV-1 RT-DNA-dNTP complex. (b) Sites of commonly observed NRTI resistance mutations (magenta) and NNRTI resistance mutations (cyan) in the fingers and palm subdomains of HIV-1 RT.

Figure 2

Five structurally characterized conformational states of HIV-1 RT; only the polymerase domain (fingers (blue), palm (red), and thumb (green)) of RT is shown. (a) Thumb is positioned near the fingers in closed conformation that occupies the nucleic acid binding cleft in apo HIV-1 RT structures [29]. (b) Upon binding of a nucleic acid substrate, the thumb is lifted up and acts as a clamp to hold the nucleic acid [14]; the primer 3′-end is positioned at the polymerase active site (D110, D185, and D186) that is highlighted by a dotted ellipse. (c) Binding of a dNTP to RT-DNA complex results in closing of the fingers to bind a dNTP in a catalytically competent state [30]. (d) Binding of an NNRTI to RT causes several conformational changes; thumb subdomain is lifted to a hyper-extended position and the nucleic acid-binding cleft is open even in absence of a nucleic acid [13]. (e) Binding of an NNRTI to RT-DNA complex resulted in reduction of DNA interactions with the polymerase domain of RT, and repositioning of the primer 3′-end away from the polymerase active site [31••]; the structural study revealed no ordered dNTP binding to RT-DNA-NNRTI complex.

Figure 3

The chemical structures of anti-AIDS drugs that target HIV-1 RT: (a) The clinically approved NRTIs are: (i) AZT (zidovudine, ZDV, azidothymidine, Retrovir®) has a 3′-azido group substituted for the 3′-OH of dTTP; (ii) ddC (dideoxycytidine, zalcitabine, Hivid®) (iii) ddI (didanosine, Videx®), and (iv) d4T (stavudine, Zerit®) lack 3′-OH groups; (v) ABC (abacavir, Ziagen®) has a cyclopentene ring, (vi) 3TC (lamivudine, Epivir®) has an altered β-L-pseudo-ribose ring, (vii) FTC (emtricitabine, Emtriva®), and (viii) TFV (tenofovir) is a nucleotide analog that has an acyclic methoxypropyl moiety substituted for the deoxyribose ring of dATP; tenofovir is formulated as tenofovir disoproxil fumarate (TDF, PMPA, Viread®). (b) Chemical structures of the five NNRTI drugs approved for treating HIV-1 infections. (i) Nevirapine (NEV, Viramune®), (ii) delavirdine (DLV,Rescriptor®), (iii) etravirine (ETR, Intelence®), and (iv) rilpivirine (RPV, Edurant®).

Figure 4

Wiggling and jiggling of an NNRTI to retain potency against drug-resistance mutations. (a) Chemical structure of rilpivirine; the five torsionally flexible bonds define the conformational freedom of the NNRTI. (b) Thermal ellipsoid representation of rilpivirine drawn using the anisotropic B-factors of individual atoms from 1.5 Å resolution structure of RT-rilpivirine complex (PDB ID 4G1Q) [25•]. The interacting side chains and water molecules (red) are displayed. (c & d) Comparison of the binding modes of rilpivirine to wild-type RT (gray) vs. L100I + K103N mutant RT (cyan) revealed how the drug jiggle and wiggles, respectively, to evade the effects of drug-resistance mutations [23•]; the mutations modifies the side chains from yellow to orange.