共查询到20条相似文献,搜索用时 0 毫秒
1.
2.
3.
4.
5.
Meni Melek Jessica M Jones Mary H O'Dea Godwin Pais Terrence R Burke Yves Pommier Nouri Neamati Martin Gellert 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(1):134-137
Assembly of functional Ig and T cell receptor genes by V(D)J recombination depends on site-specific cleavage of chromosomal DNA by the RAG1/2 recombinase. As RAG1/2 action has mechanistic similarities to DNA transposases and integrases such as HIV-1 integrase, we sought to determine how integrase inhibitors of the diketo acid type would affect the various activities of RAG1/2. Both of the inhibitors we tested interfered with DNA cleavage and disintegration activities of RAG1/2, apparently by disrupting interaction with the DNA motifs bound specifically by the recombinase. The inhibitors did not ablate RAG1/2's transposition activity or capture of nonspecific transpositional target DNA, suggesting this DNA occupies a site on the recombinase different from that used for specific binding. These results further underscore the similarities between RAG1/2 and integrase and suggest that certain integrase inhibitors may have the potential to interfere with aspects of B and T cell development. 相似文献
6.
HIV整合酶可催化病毒复制周期中的整合过程,即将HIV反转录产物cDNA整合入宿主基因组,它是病毒复制过程不可缺少的酶。抑制该酶活性将能有效抗HIV,迄今尚未在人体内发现整合酶的功能类似物,故整合酶成为抗HIV的理想靶点。本文综述了近年来整合酶的结构、催化活性及影响因素、整合酶抑制剂的研究进展。 相似文献
7.
Little is known about the extent and predictors of polymorphisms potentially influencing susceptibility to HIV integrase inhibitors. HIV-1 genetic diversity and drug resistance are major challenges in patient management globally. To evaluate HIV genetic diversity and drug resistance-associated mutations within a Nairobi cohort, genetic analysis of the HIV-1 pol-integrase gene regions was performed on samples collected from 42 subjects and 113 Kenyan intergrase sequences deposited in the Los Alamos HIV database. From the partial pol-integrase sequences analyzed phylogenetically, it was shown that 26 (61.9%) were subtype A1, 9 (21.4%) were subtype D, 5 (11.9%) were subtype C, 1 (2.4%) was subtype A2 and 1 (2.4%) was subtype CRF. Integrase-associated mutations were found in 12 patients, and in all 113 sequences already deposited in GenBank. One sample from this study and five from previous Kenyan integrase sequences had mutations at T97A, which is associated with reduced susceptibility to raltegravir. 相似文献
8.
Trevon Fuller Maria Isabel Fragoso da Silveira Gouvêa Maria de Lourdes Benamor Teixeira Adriana Ferreira Medeiros Patricia Amorim da Silva Camile Medeiros Braga Miriam Constan Werneck Sant'anna Mariza de Mattos Salgueiro Clarisse da Silveira Bressan Wallace Mendes-Silva Esau C. João 《HIV medicine》2023,24(3):301-310
9.
The hunt for HIV-1 integrase inhibitors 总被引:5,自引:0,他引:5
10.
11.
Monleau M Aghokeng AF Nkano BA Chaix ML Peeters M;AC/AC ANRS Working Group 《AIDS research and human retroviruses》2012,28(9):1157-1160
The routine use of integrase inhibitors in sub-Saharan Africa where HIV-1 non-B viruses predominate is limited, but evaluating their effectiveness on HIV-1 subtypes and CRFs that circulate in this region is essential. We here analyzed 97 integrase sequences from HIV-1 non-B-infected individuals from African countries. Using currently available interpretation algorithms (ANRS, HIVdb, and Rega), we identified the presence of mutations at nine resistance-associated positions including L74M (3.1%), T97A (9.3%), K156N (2.1%), E157Q (5.2%), G163K (1.0%), T206S (48.5%), S230N (1.0%), D232N (1.0%), and R236K (1.0%). All but one (E157Q) were considered as accessory resistant mutation by the algorithms. E157Q identified in 5% of patients tested (5/97) was selected by the ANRS algorithm as a primary mutation, which alone can confer resistance to raltegravir. These results illustrated the need of further in vitro and clinical studies involving non-B viruses to better understand the real significance of observed mutations and harmonize interpretations. 相似文献
12.
13.
14.
W E Robinson Jr M G Reinecke S Abdel-Malek Q Jia S A Chow 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(13):6326-6331
HIV-1 replication depends on the viral enzyme integrase that mediates integration of a DNA copy of the virus into the host cell genome. This enzyme represents a novel target to which antiviral agents might be directed. Three compounds, 3,5-dicaffeoylquinic acid, 1-methoxyoxalyl-3,5-dicaffeoylquinic acid, and L-chicoric acid, inhibit HIV-1 integrase in biochemical assays at concentrations ranging from 0.06-0.66 microgram/ml; furthermore, these compounds inhibit HIV-1 replication in tissue culture at 1-4 microgram/ml. The toxic concentrations of these compounds are fully 100-fold greater than their antiviral concentrations. These compounds represent a potentially important new class of antiviral agents that may contribute to our understanding of the molecular mechanisms of viral integration. Thus, the dicaffeoylquinic acids are promising leads to new anti-HIV therapeutics and offer a significant advance in the search for new HIV enzyme targets as they are both specific for HIV-1 integrase and active against HIV-1 in tissue culture. 相似文献
15.
HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase 总被引:12,自引:0,他引:12
Espeseth AS Felock P Wolfe A Witmer M Grobler J Anthony N Egbertson M Melamed JY Young S Hamill T Cole JL Hazuda DJ 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(21):11244-11249
Diketo acids such as L-731,988 are potent inhibitors of HIV-1 integrase that inhibit integration and viral replication in cells. These compounds exhibit the unique ability to inhibit the strand transfer activity of integrase in the absence of an effect on 3' end processing. To understand the reasons for this distinct inhibitory profile, we developed a scintillation proximity assay that permits analysis of radiolabeled inhibitor binding and integrase function. High-affinity binding of L-731,988 is shown to require the assembly of a specific complex on the HIV-1 long terminal repeat. The interaction of L-731,988 with the complex and the efficacy of L-731, 988 in strand transfer can be abrogated by the interaction with target substrates, suggesting competition between the inhibitor and the target DNA. The L-731,988 binding site and that of the target substrate are thus distinct from that of the donor substrate and are defined by a conformation of integrase that is only adopted after assembly with the viral end. These results elucidate the basis for diketo acid inhibition of strand transfer and have implications for integrase-directed HIV-1 drug discovery efforts. 相似文献
16.
17.
Resistance to HIV protease inhibitors 总被引:4,自引:0,他引:4
J. H. CONDRA 《Haemophilia》1998,4(4):610-615
Summary. Resistance to the HIV-1 protease inhibitor indinavir involves the accumulation of multiple amino acid substitutions in the viral protease. A minimum of 11 amino acid positions have been identified as potential contributors to phenotypic resistance. Three or more amino acid substitutions in the protease are required before resistance becomes measurable (≥four-fold). Further losses in susceptibility follow the stepwise accumulation of additional amino acid substitutions, indicating that antiviral activity (selective pressure) is maintained despite the appearance of multiple amino acid substitutions in the viral protease. Importantly, the sequential nature of these changes indicates that the effects of these substitutions are additive, and that the evolution of resistance is driven by viral replication. This result has significant implications for therapy. It predicts that viral variants resistant to indinavir are unlikely to pre-exist in protease inhibitor-naive patients, and further, that high-level resistance can only develop if the virus is allowed to replicate in the presence of the drug. The use of indinavir in combination with other antiretroviral agents has been demonstrated to dramatically reduce the incidence of resistance mutations, suggesting that with maximal suppression of viral replication, long-term control of HIV-1 infection may be achievable. Thus, the goal of therapy must be to never to allow the virus to replicate. This can be best accomplished by initiating therapy with a maximally suppressive regimen, to reduce viral replication as much as possible, and by imposing a high genetic barrier to resistance. Previous use of other protease inhibitors or inadequate adherence to therapy may compromise the long-term benefit of indinavir by allowing the virus to gain a foothold through the development of resistance. An understanding of these issues will be critical in realizing the full potential of this potent new drug for the control of HIV-1 infection. 相似文献
18.
Charpentier C Karmochkine M Laureillard D Tisserand P Bélec L Weiss L Si-Mohamed A Piketty C 《HIV medicine》2008,9(9):765-770
Objectives
Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV‐infected patients failing RAL‐containing regimens.Methods
Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF.Results
At the time of VF, RAL‐resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi‐species. In addition, RAL‐resistance mutations were detected in HIV DNA in all patients.Conclusions
Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second‐generation integrase inhibitors. Moreover, RAL‐resistance mutations can be archived early in PBMC. 相似文献19.
Variation in HIV-1 genes within and between subtypes has been best defined in the env gene, however, other more conserved genes vary between subtypes. Integrase (IN) and other regions of the pol gene are highly conserved due to their integral role in HIV replication and therefore are targets for antiviral drugs. In this study 3 individuals, infected heterosexually with HIV-1 subtype A, were examined for IN polymorphisms. Two patients' sequences clustered phylogenetically with other subtype A sequences and one patient's sequence was most similar to the circulating recombinant form CRF_02. No polymorphisms were observed in either of the motifs containing residues critical residues for IN activity. Polymorphisms were observed in a residue associated with resistance to anti-integrase drugs. In addition, a number of unique polymorphisms were observed in one individual (WM1666). IN can vary significantly within a subtype as well as between subtypes, and mutations associated with resistance to anti-integrase compounds can be present in drug naive individuals. 相似文献
20.
Phuphuakrat A Pasomsub E Kiertiburanakul S Chantratita W Sungkanuparph S 《AIDS research and human retroviruses》2012,28(8):937-943
Integrase inhibitor (INI) is a novel antiretroviral drug recommended for both treatment-naive and treatment-experienced HIV-1-infected patients. Limited data are available on INI resistance in Thailand, where HIV-1 subtype A/E predominates. We aimed to investigate INI resistance-associated mutations (RAMs) among treatment-naive patients and patients who experienced treatment failure with NNRTI-based or PI-based antiretroviral therapy (ART) in Thailand. One hundred and eight plasma samples of 58 treatment-naive and 50 treatment-experienced HIV-1-infected individuals were collected. The HIV-1 integrase coding region was sequenced. Polymorphisms were compared between subtype A/E and B circulating in Thailand and between treatment-naive and treatment-experienced groups. Resulting amino acids were interpreted for drug resistance according to Stanford algorithms. Ninety-seven samples were HIV-1 subtype A/E, 10 were subtype B, and one was subtype C. Age, gender, and CD4 cell counts were similar between treatment-naive and treatment-experienced groups, while the treatment-failure group showed a statistically significant longer awareness time of HIV-1 infection and lower viral load than the treatment-naive group. Major INI-RAM was not found in this study, but some minor INI-RAMs, such asV54I, L68I, L74M, T97A, and S230N, were found. Comparing INI-RAMs between subtype A/E and B, the prevalence of V54I and V72I was higher in subtype B than subtype E, while V201I was found in all sequences of subtype A/E. In subtype A/E, integrase polymorphisms were not different between treatment-naive and treatment-experienced groups. However, the number of amino acid substitutions was significantly higher in the treatment-experienced group (p=0.009). One NNRTI-based ART-treated patient was found to have potential low-level INI-RAMs. INI-RAMs are rare in both treatment-naive and treatment-experienced patients in Thailand. This suggested that INI should be active in patients who are naive to INI in Thailand. 相似文献