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Chapter 5 : Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives

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Abstract:

This chapter describes the unique role of integrase (IN) in the human immunodeficiency virus type 1 (HIV-1) replication cycle and its interaction with different cellular proteins. It addresses the efficacy and toxicity data of the new drugs targeting IN, along with their biochemical, pharmacokinetic, and pharmacodynamic characteristics. It also discusses clinical perspectives and viral resistance against IN inhibitors as well as recently identified new antiviral targets in HIV IN. Since retroviral integration is a multistep process, the different cofactors can theoretically play a role during one of the following steps: (i) catalysis, (ii) nuclear import of the PIC, (iii) target site selection, and (iv) repair of the DNA gaps. The chapter gives an overview of the search for HIV-1 IN inhibitors, and discusses current IN inhibitors in clinical development. The major mechanism of clearance of MK-0518 (raltegravir) in humans is UDP-glucuronyltransferase (UGT) isoform, 1A1-mediated glucuronidation. In a multicenter, double-blind, randomized study (MK-0518 protocol 005), the safety and efficacy of MK-0518 versus placebo, both regimens also using optimized background therapy (OBT), were evaluated. This study was designed to include highly antiretroviral therapy (ART)-experienced patients with a documented genotypic/phenotypic resistance for more than one drug in each of the three classes (NNRTI, NRTI, and PI) with HIV RNA levels of >5,000 copies and CD4 counts of >50 cells/mm. Resistance to IN inhibitors has been relatively well defined for a new class of antiretroviral agents. IN has only been recently validated in clinical trials as a target for antiretroviral therapy.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5

Key Concept Ranking

Non-Nucleoside Reverse Transcriptase Inhibitors
0.507514
Reverse Transcriptase Inhibitors
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Human immunodeficiency virus 1
0.48606855
Highly Active Antiretroviral Therapy
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0.507514
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Figures

Image of Figure 1.
Figure 1.

(A) HIV IN. HIV-1 IN is a 288-amino-acid protein (32 kDa) that is encoded by the 3’ end of the HIV gene. IN contains three distinct functional domains. The N-terminal domain (amino acids 1 through 50) is believed to be involved in protein multimerization. The central or catalytic core domain (CCD) spanning amino acids 51 through 212 contains the catalytic triad consisting of aspartic acid (Asp-D) 64, Asp (D) 116, and glutamic acid (E) 152, a classical DDE. The less conserved C-terminal domain of IN (amino acids 213 through 288) has nonspecific but strong DNA binding activity, similar to that of the full-length IN. (B) Model of HIV IN binding the viral DNA. This model ( ) shows the binding of the viral DNA to HIV-1 IN in the cytoplasm. Most probably HIV-1 IN acts as a dimer with each monomer capable of binding one end of the viral DNA. (C) Model of HIV IN binding after the 3’ processing step. After reverse transcription, IN removes a pGT dinucleotide at each 3’ end of the viral LTRs adjacent to a highly conserved CA dinucleotide ( ). The binding of the viral DNA to IN after the 3’ processing is shown in this model.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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Image of Figure 2.
Figure 2.

The HIV-1 replication cycle and potential drugs targeting the integration process. The respective drugs and their mechanisms of action are noted under each step of the integration process: strand transfer inhibitors and 3’ processing inhibitors. The viral RNA is transcribed into double-stranded DNA during reverse transcription. Double-stranded DNA forms can be quantified by PCR. IN binds to specific sequences in the LTR region of viral DNA, which results in stable viral DNA IN complex formation. IN-DNA binding inhibitors such as pyranodipyrimidines and styrylquinolines can inhibit this step. The PIC is a cytoplasmic, virally derived, nucleoprotein structure that contains RT, IN, matrix, and nucleocapsid. In the following step the PIC is transported to the nucleus. IN removes a pGT dinucleotide at each end of the viral DNA LTRs producing new 3’-hydroxyl ends (CA-3’-OH). 3’ Processing inhibitors such as styrylquinolines do interfere with LTR/IN binding through a competitive inhibition mechanism. In the next step IN binds to the host chromosomal DNA and mediates a concerted nucleophilic attack by the 3’-hydroxyl residues of the viral DNA on phosphodiester bridges in the target DNA. The processed CA-3’-OH viral DNA ends are ligated to the 5’--phosphate ends of the target DNA, covalently attaching the viral DNA to the cellular DNA. Strand transfer inhibitors such as MK-0518 and GS-9137 interfere with this step. Through the unproductive pathways of DNA circularization, 1- and 2-LTR circles are made in the nucleus. The number of 2-LTR circles serves as a quantitative measurement for nuclear import in the absence of an inhibitor of strand transfer. The number of 2-LTR circles increases by interfering with the strand transfer reaction or by inhibition of the LEDGF/p75-IN interaction. During the following gap repair, the reaction intermediate will be repaired. This is accomplished by host cell DNA repair enzymes. Finally, a Q-PCR assay using primer annealing to repetitive host cell DNA (e.g., Alu sequence) and one primer annealing to the viral DNA allows quantification of integrated viral DNA ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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Image of Figure 3.
Figure 3.

Domain structure of LEDGF/p75. The p75 and p52 splice variants are indicated. LEDGF/p75 contains 530 amino acids and several functional domains. In the N-terminal part of LEDGF/p75 the PWWP domain of 92 residues functions as a protein-protein interaction domain ( ) and/or DNA-binding domain ( ). A functional nuclear localization signal (NLS), GRKRKAEKQ (amino acids 148 to 156), is present ( ). In accord with its ability to interact with HIV-1 IN, an evolutionary conserved IBD of approximately 80 amino acids (amino acids 347 to 429) was recently mapped to the C terminus ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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Image of Figure 4.
Figure 4.

Results of all phase II and III clinical trials performed with MK-0518. (A) Protocol 004, evaluation of the safety and efficacy of MK-0518 in naive patients. In the MK-0518 protocol 004, patients received tenofovir + 3TC as backbone, combined with 100 mg ( = 39), 200 mg ( = 40), 400 mg ( = 41), or 600 mg ( = 40) of MK-0518 twice daily (b.i.d.) or 600 mg of efavirenz ( = 38) once daily (q.d.) in the control arm in a double-blinded trial. (B) Results of protocol 005, evaluation of the safety and efficacy of MK-0518 in multiresistant patients. In the MK-0518 protocol 005, the safety and efficacy of MK-0518 (200, 400, or 600 mg orally twice daily) compared to placebo, both with OBT, were evaluated in a multicenter, double-blind, randomized study in multiresistant patients. The percentage of patients with HIV RNA levels of <50 copies/ml is shown over a period of at least 24 weeks. (C and D) Results of BENCHMRK-1 (C) and of BENCHMRK-2 (D) studies. The addition of raltegravir to standard of care in heavily treatment-experienced patients was evaluated. The percentage of patients with HIV RNA levels of <50 copies/ml is shown over a period of 24 weeks.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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Image of Figure 5.
Figure 5.

Evaluation of the antiviral activity and safety of GS-9137. The antiviral activity and safety of GS-9137 were evaluated in a prospective, randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1-infected treatment-naive and -experienced patients ( ). GS-9137 was administered with food for 10 days at a dose of 200, 400, or 800 mg twice daily, 800 mg once daily, or 50 mg boosted with 100 mg of RTV once daily (six subjects taking active drugs and two taking placebo per cohort).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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Image of Figure 6.
Figure 6.

Mutations at 29 positions on HIV-1 that may reduce susceptibility to IN inhibitors ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
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References

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Tables

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Table 1.

Disposition characteristics and pharmacokinetic parameters of raltegravir and elvitegravir

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Generic image for table
Table 2.

Data from drug-drug interaction studies performed to date

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Generic image for table
Table 3.

Comparison of mutant and wild-type HIV-1 susceptibility to IN inhibitors

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5

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