Short communication Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance
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1 Short communication Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance Max Lataillade 1 *, Jennifer Chiarella 1 and Michael J Kozal 1,2 1 Yale University School of Medicine, New Haven, CT, USA 2 VA Connecticut Healthcare System, New Haven, CT, USA Antiviral Therapy 12: *Corresponding author: Tel: ; Fax ; Max.Lataillade@yale.edu Background: Two inhibitors of the HIV-1 integrase enzyme (INIs) are in late stage clinical development. To date, approximately 42 mutations within the HIV-1 integrase (IN) gene have been associated with INI drug resistance. Naturally occurring IN gene polymorphisms may have important implications for INI development. In this study, we evaluated clinical HIV-1 strains from INI-naive patients to determine the prevalence of IN gene polymorphisms, and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance and at sites crucial for LEDGF/p75 binding and HIV-1 integration. Methods: The IN gene from 67 INI-naive, HIV-1 clade B-infected patients were sequenced using standard population-based DNA sequencing methods. In addition, 176 unique full-length HIV-1 clade B IN gene sequences from INI-naive patients obtained from the HIV Los Alamos database were analysed. Results: Analysis of 243 IN genes from HIV-1 clade B, INI-naive clinical strains revealed that 64% of the aa positions were polymorphic. Of the 42 aa substitutions currently associated with INI resistance, 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y/A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K. IN aa positions crucial to LEDGF/P75 binding and HIV-1 integration were well conserved. Conclusion: Major INI mutations within the catalytic domain and extended active sites associated with high level resistance to the compounds in late stage development, especially strand transfer inhibitors (STIs), were infrequent in our study, which may help explain the excellent virological responses demonstrated in clinical trials. Introduction Inhibitors of the HIV-1 integrase enzyme (INIs) block the integration of viral double-stranded DNA into the host cell s chromosomal DNA [1]. The integrase (IN) enzyme is essential and unique to HIV-1 without any similar human analogue, a characteristic that has so far led to low side effects and toxicity in INI clinical trials [2]. HIV-1 IN is a 288 amino acid (aa) long polypeptide chain that folds into three distinct functional domains: the N-terminal domain (NTD), the central or catalytic core domain (CCD) and the C-terminal domain (CTD). The NTD (aa 1 50) is believed to be involved in protein multimerization and contains a histidine histidine cystine cystine (HHCC) motif that coordinates zinc binding [1,3]. The CCD (aa ) contains the catalytic trio of acidic amino acids, aspartic acid (Asp-D) 64, Asp (D) 116 and glutamic acid (E) 152, the DDE motif [1,3]. The DDE motif forms an active site that coordinates a divalent metal ion, either magnesium or manganese, which is required for catalytic activity [3 5]. The CCD of IN binds to human lens epithelium-derived growth factor (LEDGF/p75), which is an essential HIV integration cofactor linking IN to chromatin [6 7]. The CTD of IN (aa ) has non-specific but strong DNA binding activity, similar to that of the full-length IN, and is thought to play a role in binding to viral and host DNA [1,3]. HIV-1 retroviral integration can be described as a multistep process: (1) assembly of a stable complex between IN and specific viral DNA sequences at the end of the HIV-1 long terminal repeats, (2) 3 processing, (3) preintegration complex translocation, (4) strand transfer, and (5) DNA gap repair and ligation [2,4]. All 2007 International Medical Press
2 M Lataillade et al. Table 1. Class and status of integrase inhibitors Integrase inhibitor Integrase inhibitor class Status Reference L-708,906 Diketo-Acid STI Preclinical [1,2,17,18,32,33,35] L-731,988 Diketo-Acid STI Preclinical [1,2,17,18,32,33,35] S-1360 Diketo-acid STI Previous Phase II: [14,33] withdrawn L870,810 Naphthyridine carboxamide Previous Phase II: [1,219,20,34,35] STI withdrawn MK-0518 (Raltegravir) Pyrimidone STI Phase III [2,8,9,21,34,35] MK-2048 Second Generation STI Preclinical [35] GS-9137 (Elvitegravir) Dihydroquinoline carboxylic Phase II [2,10,20,34,35] Acid STI Enrolling in Phase III L-CA L-Chicoric Acid STI Early compound [26] 5-CITEP DKA derivative STI Early compound [27] V-165 PyranoDipyriminidine Preclinical [1,2,15,16,32] integrase DNA Binding inhibitor FZ41 Styrylquinolines Preclinical [1,2,22,23] 3 Processing Inhibitor integration steps can potentially be inhibited and each step can be considered a possible drug target. Multiple INIs are currently in different phases of development and can be divided into five classes: (1) integrase DNA binding inhibitors, (2) 3 processing inhibitors, (3) nuclear translocation/ import inhibitors, (4) strand transfer inhibitors (STIs) and (5) gap repair inhibitors [1 2]. To date, the STIs have been the most successful class of INIs and presently are the only class of INIs in advanced human clinical trials (see Table 1) [8 10]. As with other antiretroviral classes, drug resistance has been shown to occur with the INIs. Each class of INIs has a distinct mechanism of action and carry their respective resistance profile and mutations. A summary of IN mutations associated with specific compounds, the decrease susceptibility of the IN mutants and INI cross resistance patterns can be found in Table 2 [11] Knowing the prevalence rate of mutations in viral strains from INI treatment-naive and -experienced patients can help investigators identify if clinically relevant viral mutations or natural polymorphisms are occurring under drug selection pressure. In addition, other IN aa positions have been identified as critical for LEDGF/p75/DNA binding and integration, yet little is known about the natural polymorphism of these IN sites [12 13]. In this study we determined the natural polymorphism of the HIV-1 clade B IN gene. Further, we identified the natural occurrence of IN aa substitutions at positions associated with INI resistance, IN-DNA binding sites and at IN-LEDGF/P75 binding sites that are crucial for integration. Methods The HIV-1 clade B IN genes from 67 INI naive US patients were sequenced. HIV-1-infected plasma samples underwent HIV RNA extraction using QIAamp RNA mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer s instructions. An IN gene amplification and sequencing protocol was kindly provided to us by Michael Miller and Daria Hazuda of Merck Research Labs. HIV RNA underwent RT-PCR using a Superscript one-step kit (Invitrogen, Carlsbad, CA, USA); the integrase gene was amplified by nested RT-PCR with the following primers for the first round: 1) INFORI (5 -GGAATCATTCAAGCACAACCAGA- 3 ; nucleotide (NT) positions relative to HXB2 4,050 4,081) and INREV-I (5 -TCTCCTGTATGCA- GACCCCAATAT-3 ; NT: 5,244 5,267). PCR cycle parameters are: one cycle of 48 C for 30 min and 94 C for 5 min; 35 cycles of 94 C for 30 sec, 60 C for 1 min and 72 C for 2 min; and one cycle of: 72 C for 7 min. For the second round two additional primers were used: HIV+4141 (5 -TCTACCTGGCATGGGTA CCA- 3 ; NT: 4,141 4,160) and INREVII (5 -CCTAGTGGG ATGTGTACTTCTGA-3 ; NT: 5,197 5,219). PCR cycle parameters are: one cycle of 94 C for 5 min; 35 cycles of 94 C for 30 sec, 60 C for 1 min and 72 C for 2 min; and one cycle of 72 C for 7 min. Population based sequencing (ABI Technology TM, Foster City, CA, USA) was performed on the samples. All sequences (forward and reverse strands) were aligned and manually read using BioEdit software (Ibis Therapeutics, Carlsbad, CA, USA; GenBank accession EF EF472787) International Medical Press
3 Integrase inhibitors and natural polymorphisms Table 2. Integrase mutations associated with integrase inhibitor (INI) resistance and cross resistance (CR) patterns between different classes of INIs Mutations, single Decrease susceptibility of INIs versus multiple HIV-1 mutants to INIs Evidence of CR between INIs L-708,906* T66I, S153Y, M154I M154I: 2 5-fold CR to S-1360: fold L74M, S230R, N155S S153Y: 2 3-fold T66I/L74M/S230R: 26-fold T66I/M154I: 20-fold CR to GS-9137: fold T66I/L74M/S230R: 10 fold S153Y+T66I: 259-fold; N155S: 116-fold CR to MK-0518 (N155S):~12-fold CR to L870,810: (N155S): ~76-fold L-731,988 T66I, S153Y, M154I M154I: 2 5-fold; S153Y: no effect CR to L 708,906; CR to S-1360 T66I / M154I: 20-fold CR to L870,810: 22-fold; T66I / S153Y: 22-fold S-1360 T66I, L74M, Q146K T66I: 4-fold CR to L-708,906; Moderate to high S153A, K160D, V165I T66I/Q146K/V201I: 8-fold V201I, Q148K, A128T, T66I/Q146K/V201I/L74M/A128T/S153A/ E138K, N155S K160D/V165I >62-fold L870,810 F121Y, T125K, V72I, F121Y/T125K (6 months): 16-fold CR to GS-9137: 1,000-fold V151I, T97A, K156N V72I/F121Y/T125K (9 months): 20-fold F121Y/T125K/V151I/V72I: 1,000-fold V72I/F121Y/T125K/V151I :100-fold CR from GS-9137: fold E92Q + S147G: 101-fold CR to MK-0518: (F121Y): 3-fold MK-0518 (Raltegravir) E138K/A, G140S/A, Q148K/G140A/E138A: 388-fold # CR from GS-9137: fold Q148H/K/R, N155H, E92Q/N155H: 64-fold # E92Q: 3.5-fold E92Q, V151I, T97A, G140S/Q148H: 399-fold # CR from L : 3-fold G163R, L74I/M/A, G140S/Q148R: 239-fold # F121Y: 3-fold Y143R/C, I203M, S230R Q148R: 26-fold; Q148K: 40-fold # CR to GS-9137: ~200-2,000-fold N155H +(E92Q,V151I,T97A, Q148K/G140A/E138A: 395-fold G163R,L74M): IP G140S/Q148H: 2,194-fold Y143R/C +(L74I/A,E92Q,T97A, G140S/Q148R: 268-fold I203M, S230R): IP Q148K: 169-fold E92Q/N155H: 207-fold MK-2048 # T112I; resistance Resistance testing in progress CR testing in progress testing in progress GS-9137 (Elvitegravir)** H51Y, E92Q, S147G, E92Q / S147G: 356-fold CR to L-870,810 ( fold) E157Q, T66I, R263K H51Y/ E92Q/ S147G: 699-fold E92Q + S147G: 101 fold H51Y/E92Q/S147G/E157Q: 1,000-fold CR to MK-0518 (E92Q): fold T66I/R263K: 98-fold CR from L870,810 (1,000-fold) T66I (15.1 fold), R263K (5.1-fold) F121Y/T125K/V72I/V151I: 1,000-fold E157 (6.3 fold), E92Q (36-fold) CR from MK-0518: ~200-2,000-fold H51Y/E92Q/S147G/E157Q: 182-fold Q148K/G140A/E138A: 395-fold Q148H/G140S: 2,194-fold L-CA G140S G140S: 100-fold CR to DKAs 5-CITEP T66I/M154I Most likely similar effect as DKAs CR to DKAs V-165 ## V165I, T206S, S230N V165I: 15-fold No CR to DKAs; No CR from DKAs FZ41*** C280Y, V165I/V249I C280Y: 2 5 fold; V165I/V249I: 9-fold No CR to DKAs; No CR from DKAs In red: natural polymorphisms associated with INI resistance. CR, cross resistance; IP, testing in progress; STI, strand transfer inhibitor. *See [1,2,17,18,32,33,35]; See [1,2,17,18,32,33,35]; See [14,33]; See [1,219,20,34,35]; See [2,8,9,21,34,35]; # See [35]; **See [2,10,20,34,35]; see [20]; see [34]; See [26]; See [27]; ## See [1,2,15,16,32]; ***See [1,2,22,23]. In addition, 176 worldwide HIV-1 clade B (includes B recombinants) treatment-naive unique sequences were obtained from the Los Alamos HIV Database ( accessed 4 April 2006). The combined set of sequences (67 USA Clade B and 176 worldwide clade B samples; n=243) were compared and analysed in BioEdit. A new IN nucleotide and aa consensus was determined using the 243 samples and compared with the 2004 HIV-1 clade B subtype consensus. Antiviral Therapy 12:4 565
4 M Lataillade et al. Results A total of 243 HIV-1 clade B IN gene sequences from unique patient strains were analysed to determine the natural polymorphism of the clade B IN gene. These IN gene sequences came from patients from the USA (n=116), followed by samples from Australia, Argentina, China, South East Asia, Western Europe, Eastern Europe and Latin America. Analysis of the 243 IN clade B samples compared with the 2004 Los Alamos HIV-1 clade B consensus revealed that 64% (184/288) of the aa positions of IN were naturally polymorphic (Figure 1). IN aa residues within the DDE triad and the HHCC motif were relatively well conserved (Figure 1) [11]. Of the 42 aa substitutions currently associated with INI resistance (Table 2), 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, Figure 1. Natural polymorphism associated with the IN enzyme and mutations associated with INI resistance HHCC motif DEE motif aa position associated with INI resistance NP Natural polymorphism associated with INI resistance The consensus for the integrase IN gene for the 243 samples is represented on the top line. Natural polymorphisms are listed directly under the consensus amino acid (aa). Analysis of the 243 IN clade B samples compared to the 2004 Los Alamos HIV-1 clade B consensus revealed that 64% (184/288) of the aa positions of IN were naturally polymorphic. Codon 289 is a stop codon for IN and is not shown. Natural polymorphism associated with the N-terminal domain (NTD) of IN is represented by aa HHCC motif in purple is relatively well conserved with only two natural polymorphisms associated with the motif. Natural polymorphisms associated with IN inhibitor (INI) resistance were not found in the N-terminal domain of IN. Natural polymorphism associated with the catalytic core domain (CCD) of IN is represented by aa DDE motif in bold yellow is relatively well conserved. Of the 37 mutations associated with INI resistance in this domain (green), 19 occurred as natural polymorphisms (I72V, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y, S153A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M and T206S). The unique samples containing N155H and Q148H came from Australia (ref. AF042104; B. AU.96.MBCC 98) and Spain (ref. AF450096; BG.ES.00.X605) in the Los Alamos Database. Major aa substitutions located within the catalytic domain and the extended active sites, known to contribute to high level INI resistance (positions H51Y, T66I, L74M/A, E92Q, F121Y, T125K, E138A, G140S/A, Y143R/C, Q146K, S147G, Q148K/R, N155S and K160D) were not found to occur as natural polymorphisms. K156N associated with increased susceptibility to L870,810 and Raltegravir was present as natural polymorphism in ~9% (21/243) of the samples. I72V and V201I occurred concurrently in 20% (50/243) of sequences in our study. I72 was the consensus aa in this large sample set (51%) instead of previously described V72. Natural polymorphism associated with the C-terminal domain (CTD) of Integrase is represented by aa Of the five mutations associated with INI resistance in this domain (S230N, S230R, V249I, R263K, and C280Y in green), two mutations (S230N and R263K) occurred as natural polymorphism (in red). Approximately 42 mutations so far have been described to be associated with resistance to various INIs in preclinical and clinical phases of development. Twenty-one of these mutations were found as natural polymorphisms in our study (red). Other IN positions identified as critical for DNA binding (Q148), HIV-1 integration and replication (Q62, H67, N120, N144, Q148 and N155) were relatively well conserved within the IN CCD. Several point mutations within IN (C130G, W131A, I161A, V165A, R166A, Q168A/L/P, E170G, L172A, K173A, Q214L and Q216L) reported to be defective for interaction with LEDGF/p75, impairing chromosome tethering and HIV-1 replication were not found as natural polymorphisms in our study. In fact, the majority of these IN positions were highly conserved, lending support to the finding of the importance of these sites for LEDGF/p75 binding International Medical Press
5 Integrase inhibitors and natural polymorphisms V151I, S153Y, S153A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K (Table 2; Figure 1). Table 3 describes the IN natural polymorphisms associated with resistance to the different INIs. I72 was the consensus aa in this large sample set (51%) instead of previously described V72 [11]. IN polymorphisms at I72V (n=113), V201I (n=107), T206S (n=30), S230N (n=24) and K156N (n=21) occurred at high frequency. I72V and V201I occurred concurrently in 20% (50/243) of sequences in our study. V165I was found to occur in only 1 of 114 USA samples. The majority of samples containing a V165I were from Latin America (58%; 7/12). The unique samples containing N155H and Q148H came from Australia (ref. AF042104; B. AU.96.MBCC 98) and Spain (ref. AF450096; BG.ES.00.X605) in the Los Alamos Database. However, a number of major aa substitutions located within the catalytic domain and the extended active sites, known to contribute to high level INI resistance (positions H51Y, T66I, L74M/A, E92Q, F121Y, T125K, E138A, G140S/A, Y143R/C, Q146K, S147G, Q148K/R, N155S, K160D, S230R, V249I and C280Y), were not found to occur as natural polymorphisms (Table 2) [8,9,14 27,32 35]. Discussion INI resistance arises from the selection of viral variants with genetic mutations that change the target enzyme, such as, creating conformational changes in the IN catalytic site or affecting metal ion coordination which may result in reduced affinity for a drug [28]. Early in the development of protease inhibitors (PIs), investigators reported the HIV-1 clade B protease to be extremely polymorphic with 47.5% of the 99 aa positions being variable [29]. Some naturally occurring protease polymorphisms were found to contribute to PI resistance [30,31] Similar to PI resistance, the number of IN mutations present can carry an additive effect on INI resistance [8, 32 35]. In our study many of the mutations associated with resistance to INIs were found to occur naturally in clinical viral strains (Table 2) [8,34 35]. The identification of naturally occurring IN polymorphisms associated with INI resistance suggests that resistance to some INIs may occur faster in patients that harbour these polymorphic variants, since they may augment other mutation effects [8,9,20,32 35]. Recently, researchers reported resistance pathways to STIs, MK-0518 (Raltegravir) and GS-9137 (Elvitegravir; Table 2) [8,9,34]. Raltegravir failure was Table 3. Natural polymorphisms associated with integrase inhibitor resistance Class Compound Natural polymorphism Reference Strand transfer inhibitors L-708,906 S153Y/1, M154I/11 [1,2,5,8 10,14,17 21, 25 27,32 35] L-731,988 S153Y/1, M154I/11 S-1360 S153A/1, V165I/12 V201I/107, A128T/1 E138K/1 L870,810 I72V/113, V151I/12 T97A/1, K156N/21 MK-0518 N155H/1, Q148H/1 (L-900,612) L74I/1 T97A/1, E138K/1 K156N/21 G163R/5, I203M/5 GS-9137 E157Q/5, R263K/1 (JTK-303) MA/DA DKAs S153Y/1 5-CITEP M154I/11 MK-2048 T112I/14 In DNA binding inhibitors PDP: V165 V165I/12, T206S/30, [1,2,15,16,32] S230N/24 3 Processing inhibitors SQ L: FZ41 V165I/12 [1,2,22,23] NTI/NII SQ L: FZ41 V165I/12 [23] Bifunctional DKAs Profile under investigation [1,2,24] Natural polymorphisms described as: mutation/n (number of times seen within 243 samples). NTI/NII, nuclear translocation/import inhibitors. Antiviral Therapy 12:4 567
6 M Lataillade et al. generally associated with one of two genetic pathways corresponding with one of two major mutations N155H or Q148K/H/R: N155H+(E92Q, V151I, T97A, G163R or L74M) or Q148K/R/H+(G140S/A or E138K/A); another pathway Y143R/C+(L74A/I, E92Q, T97A, I203M or S230R) may also occur [8,9]. L74I, T97A, E138K, G163R, I203M, N155H and Q148H were all identified as natural polymorphisms in our study. Furthermore, Merck Research Laboratories described MK-2048 as a potent IN second generation STI [35]. MK-2048 has the potential to inhibit HIV-1-resistant variants generated with first generation compounds (high genetic barrier) and showed good pharmacokinetic profiles in preclinical species [35]. Primary mutation T112I observed with this compound was identified as a natural polymorphism in our study (Table 2, Table 3) [35]. In vitro studies have identified two primary resistance patterns for GS-9137 involving T66I or E92Q with secondary IN mutations H51Y, F121Y, S147G, S153Y, E157Q or R263K [20,34]. E157Q and R263K were identified as natural polymorphisms in our study. In an important study by Hackett et al., the HIV-1 IN gene diversity in group M, N and O viruses was evaluated [36]. The natural polymorphism rate for the subset of 81 clade B samples was ~39% [36]. This rate for clade B reported by Hackett et al. is lower than that found in our sample (64%); however, this disparity may be due to the sample size differences of the two studies. Recently, Zioni et al. reported an IN polymorphism rate (56%) similar to our study [37]. Furthermore, both Hackett et al. and Zioni et al. also reported that several IN aa substitutions associated with INI resistance occurred as natural polymorphisms: V72I, L74M, T97A, V151I, E157Q, G163R, V165I, V201I, I203M, T206S and S230N, and I141V, S153Y/A, M154I, N155H and K156N, respectively [36,37]. L74M reported by Hackett et al. associated with resistance to early compounds L-708,906 and S-1360 was not found as a natural polymorphism in our 243 clade B samples; however, the other mutations were confirmed as natural polymorphisms (Table 2, Figure 1) [36]. Other IN positions have been identified as critical for DNA binding (Q148), and HIV-1 integration and replication (Q62, H67, N120, N144, Q148 and N155) [38]. Our data demonstrate that these important positions are relatively well conserved within the IN CCD (Figure 1) [38]. Furthermore, LEDGF/p75 has been described as an essential HIV integration cofactor linking IN to chromatin [6,7,39]. The LEDGF/p75 IN binding domain is reported to interact with the IN CCD between aa and [6,7,12,13,40]. Several point mutations within IN, A128T, C130G, W131A, I161A, V165A, R166A, Q168A/L/P, E170G, L172A, K173A, Q214L and Q216L are defective for interaction with LEDGF/p75, impairing chromosome tethering and HIV-1 replication [6,7,12,13,40]. Besides A128T, none of these mutations were found as natural polymorphisms in our study. In fact, the majority of these IN positions were highly conserved, lending support to the finding of the importance of these sites for LEDGF/p75 binding. Our study is limited in that the sample size was composed of only 243 sequences from unique INInaive patients. Furthermore, as INI development has focused on clade B strains, we limited our analysis to only HIV-1 clade B samples which prevents us from extrapolating our results to broader more diverse populations. In addition, some of the mutations were identified only in a single sequence from a public database. These single mutation occurrences may be the result of sequencing errors and this could inflate the natural polymorphism rate of IN. However, the IN diversity is similar to that of the protease gene and suggests that the underlying diversity of this portion of HIV-1 pol is similar to other components. Populationbased sequencing was used in our study, and thus only the dominant variant sequence is likely represented. Future studies using ultrasensitive quantitative sequencing techniques would determine if additional minor viral-resistant variants are present. Despite these limitations, we were able to determine a consensus sequence for the clade B IN gene based on 243 samples, demonstrate the natural polymorphism of IN and identify the natural occurrence of many IN aa substitutions associated with decreased susceptibility to INIs. The identification of naturally occurring IN aa substitutions associated with resistance suggests that these changes may not adversely affect viral fitness. INIs that are affected by these substitutions could be at a disadvantage leading to rapid resistance development. The data also demonstrates the conserved nature of the IN-LEDGF/P75 binding sites and of aa positions crucial to integration. The launch of INIs represents a new era in HIV treatment as it provides clinicians with a potent new drug class to target HIV. Resistance to INIs likely will emerge in the clinic; ongoing studies will be needed to determine the effects of these naturally occurring IN polymorphisms on clinical responses in patients. Acknowledgements This data was presented in part at the XV International Workshop on HIV Drug Resistance, Sitges, Spain, abstract 23, June ML was supported by the NIH training grant: T32 AI MJK was supported by the VA Career Development Award International Medical Press
7 Integrase inhibitors and natural polymorphisms We would like to thank Daria Hazuda, PhD. and Michael Miller, PhD. of Merck Research Labs for sharing integrase gene amplification and sequencing protocols. Financial Disclosure MJK has received research grants form the VA, NIH and is the principal investigator on Merck integrase inhibitor trials at Yale University. ML is an investigator on Merck integrase inhibitor trials at Yale University. Role of funding source The sponsors had no role in study design, data collection, data analysis, data interpretation, writing, review or approval of manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. References 1. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 2005; 4: Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006; 7: Van Maele B, Debyser Z. HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral Proteins. AIDS Rev 2005; 7: Grobler JA, Stillmock K, Hu B, et al. Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc Natl Acad Sci U S A 2002; 99: Hazuda DJ. Inhibitors of human immunodeficiency virus type I. Retrovirology 2006; 3 Suppl 1:S7. 6. Debyser Z, Hombrouck A, Witvrouw M, De Rijck J, Hendrix J. Virus evolution reveals LEDGF/p75 as the sole mediator of chromosomal tethering. 14th Conference on Retroviral and Opportunistic Infections 2007, Los Angeles CA, USA. Feb 25 28; Abs Hombrouck A, De Rijck J, Busschots K, Christ F Debyser Z. Structure-function analysis of the interface between HIV-1 integrase and the cellular co-factor LEDGF/p75. 14th Conference on Retroviral and Opportunistic Infections 2007, Los Angeles CA, USA. Feb 25 28; Abs Cooper D, Gatell J, Rockstroh J, Katlama C, Isaacs R, Nguyen B. Results of BENCHMRK-1, a Phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abs. 105aLB. 9. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a Phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abs. 105bLB. 10. Zolopa AR, Mullen M, Berger D, Ruane P, Hawkins T. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abs. 143LB. 11. M Lataillade, J Chiarella, MJ Kozal. Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance. Antivir Ther 2006; 11:S Llano M, Vanegas M, Hutchins N, Thompson D, Delgado S, Poeschla EM. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J Mol Biol 2006; 360: Cherepanov P, Ambrosio AL, Rahman S, Ellenberger T, Engelman A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci U S A. 2005; 102: Billich A. S-1360 Shinogi-GlaxoSmithKline. Curr Opin Investig Drugs 2003; 4: Witvrouw M, Hantson A, Hombrouck A, et al. Multiple mutations in HIV-1 integrase confer resistance to the PyranoDipyrimidine V th HIV DRP Symposium on Antiretroviral Drug Resistance, November 2004 Chantilly, VA, USA. Abstract # Pannecouque C, Pluymers W, Van Maele B, et al. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr Biol 2002; 12: Hazuda DJ, Felock P, Witmer M et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000; 287: Dayam R, Al-Mawsawi LQ, Neamati N. HIV-1 integrase inhibitors: an emerging clinical reality. Drugs R D 2007; 8: Hazuda DJ, Anthony NJ, Gomez RP, et. al. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc Natl Acad Sci U S A 2004; 101: Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303/GS th Interscience Conference on Antimicrobial Agents and Chemotherapy September 27 30, 2006, San Francisco, CA, USA. Abstract H Grinsztejn B, Nguyen, BY, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy September , San Francisco CA, USA. Abstract H1670b. 22. Bonnenfant S, Thomas CM, Vita C, et al. Styrylquinolines, integrase inhibitors acting prior to integration: a new mechanism of action for anti-integrase agents. J Virol 2004; 78: Mousnier A, Leh H, Mouscadet JF, Dargemont C. Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives. Mol Pharmacol 2004; 66: Di Santo R, Costi R, Roux A, et al. Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action. J Med Chem 2006; 49: Marchand C, Johnson AA, Karki RG, et al. Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S). Mol Pharmacol 2003; 64: Lee DJ, Robinson WE Jr. Human immunodeficiency virus type 1 (HIV-1) integrase: resistance to DKA integrase inhibitors impairs HIV replication and integration and confers cross resistance to L-chicoric acid. J Virol, 2004; 78: Barreca ML, Lee KW, Chimirri A, Briggs JM. Molecular dynamics of the wild type and double mutant HIV-1 integrase complexed with 5-CITEP inhibitor: mechanism for inhibition and drug resistance. Biophys J 2003; 84: Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Top HIV Med 2005; 13: Kozal MJ, Shah N, Shen N, et al. Extensive polymorphisms observed in HIV-1 clade B protease gene using high-density oligonucleotide arrays. Nat Med 1996; 2: De Meyer S, Hill A, De Baere I, et al. Effect of baseline susceptibility and on-treatment mutations on TMC114 and control PI efficacy: preliminary analysis of data from PI-experienced patients from POWER 1 and POWER 2. 13th Conference on Retroviral and Opportunistic Infections 2006, Denver, CO, USA. Abstract # Kozal MJ, Huppler Hullsiek K, Leduc R, et al. Prevalence and impact of HIV-1 protease codon 33 mutations and polymorphisms in treatment-naïve and treatment- Antiviral Therapy 12:4 569
8 M Lataillade et al. experienced patients enrolling in clinical trials. Antivir Ther 2006; 11: Fikkert V, Van Maele B, Vercammen J, Hantson A, Van Remoortel B, Michiels M. Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations. J Virol 2003; 77: Fikkert V, Hombrouk A, Van Remoortel B, et al. Multiple mutations in HIV-1 IN confer resistance to the clinical trial drug S AIDS 2004; 18: Jones G, Ledford R, Yu F, Miller M, Tsiang M, McColl D. Resistance Profile of HIV-1 Mutants in vitro Selected by the HIV-1 Integrase Inhibitor, GS-9137 (JTK-303). 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abstract Wai J, Fisher T, Embrey M, et al. Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: structural diversity and resistance profiles. 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abstract 87. Accepted for publication 16 March Hackett J, Jr, Swanson P, Harris B, Holzmayer V, Yamaguchi J, Bodelle P, Brennan C, Schochetman G, and Devare S. Comprehensive evaluation of HIV-1 integrase gene diversity in group M, N, and O viruses. 12th Conference on Retroviral and Opportunistic Infections, February 2005, Boston MA, USA. Abstract LB# Zioni, R, Rhee S, Liu T, Shafer R. Natural variation of HIV-1 group M integrase: implications for integrase inhibitor therapy. 14th Conference on Retroviral and Opportunistic Infections February 2007, Los Angeles CA, USA. Abstract Lu R, Limon A, Ghory HZ, Engelman A. Genetic analyses of DNA-binding mutants in the catalytic core domain of human immunodeficiency virus type 1 integrase. J Virol 2005; 79: Llano M, Saenz DT, Meehan A, et al. An essential role for LEDGF/p75 in HIV integration. Science 2006; 314: Emiliani S, Mousnier A, Busschots K, Maroun M, Van Maele B, Tempe D. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV- 1 replication. J Biol Chem 2005; 280: International Medical Press
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