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Review
. 2013 Apr;3(2):119-28.
doi: 10.1016/j.coviro.2013.03.014. Epub 2013 Apr 19.

HIV-1 Reverse Transcriptase and Antiviral Drug Resistance. Part 2

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Free PMC article
Review

HIV-1 Reverse Transcriptase and Antiviral Drug Resistance. Part 2

Kalyan Das et al. Curr Opin Virol. .
Free PMC article

Abstract

Structures of RT and its complexes combined with biochemical and clinical data help in illuminating the molecular mechanisms of different drug-resistance mutations. The NRTI drugs that are used in combinations have different primary mutation sites. RT mutations that confer resistance to one drug can be hypersensitive to another RT drug. Structure of an RT-DNA-nevirapine complex revealed how NNRTI binding forbids RT from forming a polymerase competent complex. Collective knowledge about various mechanisms of drug resistance by RT has broader implications for understanding and targeting drug resistance in general. In Part 1, we discussed the role of RT in developing HIV-1 drug resistance, structural and functional states of RT, and the nucleoside/nucleotide analog (NRTI) and non-nucleoside (NNRTI) drugs used in treating HIV-1 infections. In this part, we discuss structural understanding of various mechanisms by which RT confers antiviral drug resistance.

Figures

Figure 1
Figure 1
NRTI-TP (or dNTP) binding and mechanisms of NRTI resistance. (a) Positioning of an AZTTP molecule in an open dNTP-binding cleft of RT (represented by the electrostatic potential surface) in an RT-DNA complex [••68]. (b) RT-DNA-dTTP polymerase complex prior to catalysis was modeled using structural information from RT-DNA-dTTP complex [1], RT-ATP (a non-productive complex) [69], and RT-DNA-AZTTP complexes [••68]; the surrounding residues (cyan) can mutate to confer resistance to NRTIs. (c) A schematic representation of dNTP binding with the help of base-pairing, base-stacking, interaction with RT, and metal chelation; the catalytic reaction of DNA polymerization proceeds with an octahedral coordination environment for two Mg2+ ions. (d) An active-site superposition of K65R RT-DNA-dATP [•8] and EEM RT-DNA-AZTppppA complexes [••23] shows the relative locations of three distinct sites that confer resistance to three classes of NRTIs (3TC/FTC, TDF, and AZT). The 3TC-resistance mutation introduces a β-branch, TDF-resistance mutation K65R forms the K65R-R72 guanidinium plane, and primary EEMs T215Y and K70R help binding of an ATP molecule as the excision substrate; mutations at one site, in general, are incompatible with mutations at the other two sites which provides a partial structural/biochemical basis for synergy between NRTIs. (e) Molecular surface representing the support to template-dNTP base pair provided by R72 and L74 side-chains. (f) An L74V mutation would disrupt the platform, and the mutation is incompatible with the K65R induced K65R+R72 part of the platform. (g) A schematic representation of catalytic reaction of polymerization vs. excision by HIV-1 RT [••23]. (h) Binding of AZTppppA, the ATP-mediated excision product of AZTMP, to HIV-1 RT (shown as green molecular surface) in complex with DNA [••23].
Figure 2
Figure 2
Structural basis for the inhibition of DNA polymerization by an NNRTI. (a) Structure of RT-DNA-AZTTP ternary complex obtained by soaking AZTTP into crystals of RT-DNA complex. (b) Soaking of nevirapine into the crystal created the NNRTI pocket, repositioning the “primer grip” (on the β12–β13–β14 sheet) that moved the primer terminus away from the polymerase active site. (c) Electrostatic potential surface of RT bound to DNA and nevirapine. The crystallization experiments and structures showed an open dNTP-binding cleft into which dNTPs/NRTI-TPs can enter; however, structural aberration by NNRTI binding did not allow a dNTP to chelate metals and form base-pairing and base-stacking interactions. (d) These structural constraints preclude the formation of an RT-DNA-dNTP polymerase competent (P) complex, rather forms a non-productive (P′) complex in the presence of an NNRTI – a structural basis for NNRTI inhibition [••68].

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