The molecular biology of HIV integrase

Published on Jul 1, 2012in Future Virology0.73
· DOI :10.2217/fvl.12.56
Robert Craigie52
Estimated H-index: 52
Integration of viral DNA into cellular DNA is an essential step in the replication cycle of HIV and other retroviruses. The first antiviral drugs that target integrase, the viral enzyme that catalyzes DNA integration, have recently been approved and more are in the pipeline. These drugs bind to an intermediate in DNA integration called the intasome, in which a pair of viral DNA ends are synapsed by a tetramer of integrase, rather than free integrase enzyme. We discuss the biochemical mechanism of integration, which is now quite well understood, and recent progress towards obtaining atomic-resolution structures of HIV intasomes in complex with inhibitors. Such structures are ultimately required to understand the detailed mechanism of inhibition and the mechanisms by which mutations in integrase confer resistance. The path from early biochemical studies to therapeutic inhibitors of integrase highlights the value of basic science in fighting human diseases.
  • References (79)
  • Citations (19)
📖 Papers frequently viewed together
1 Author (Alan Engelman)
1 Citations
5 Authors (Stephen Hare, ..., Peter Cherepanov)
481 Citations
10 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of c...
109 CitationsSource
#1K. D. BeareH-Index: 1
#2Mark J. CosterH-Index: 17
Last. Peter J. RutledgeH-Index: 18
view all 3 authors...
HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified; of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FDA) for HIV-1 therapy, while elvitegravir (Gilead Sciences/ Japan Tobacco) ...
11 CitationsSource
#1Min Li (NIH: National Institutes of Health)H-Index: 10
#2Vassili Ivanov (NIH: National Institutes of Health)H-Index: 2
Last. Robert Craigie (NIH: National Institutes of Health)H-Index: 52
view all 5 authors...
Integration of viral DNA into the host genome is an essential step in retroviral replication that is mediated by a stable nucleoprotein complex comprising a tetramer of integrase bridging the two ends of the viral DNA in a stable synaptic complex (SSC) or intasome. Assembly of HIV-1 intasomes requires several hundred base pairs of nonspecific internal DNA in addition to the terminal viral DNA sequence that is protected in footprinting experiments. We find that only one of the viral DNA ends in t...
6 CitationsSource
#1Krishan K. PandeyH-Index: 14
#2Sibes BeraH-Index: 12
Last. Duane P. GrandgenettH-Index: 26
view all 3 authors...
The assembly mechanism for the human immunodeficiency virus type 1 (HIV) synaptic complex (SC) capable of concerted integration is unknown. Molecular and structural studies have established that the HIV SC and prototype foamy virus (PFV) intasome contain a tetramer of integrase (IN) that catalyzes concerted integration. HIV IN purified in the presence of 1 mM EDTA and 10 mM MgSO4 was predominately a monomer. IN efficiently promoted concerted integration of micromolar concentrations of 3′-OH rece...
29 CitationsSource
#1Laura De LucaH-Index: 28
#2Stefania FerroH-Index: 16
Last. Alba ChimirriH-Index: 37
view all 5 authors...
The replication cycle of human immunodeficiency virus type 1 (HIV-1) is a complex multistep process that depends on both viral and host cell factors. The nuclear protein lens epithelium-derived growth factor (LEDGF/p75) is a multidomain protein, present in host cells, which plays an important role in the integration process. LEDGF/p75 not only binds HIV-1 integrase (IN) at its IN binding domain (IBD) but also contains several motifs that function in DNA and chromatin binding. The demonstrated im...
30 CitationsSource
#1Zhiqi Yin (NIH: National Institutes of Health)H-Index: 2
#2Robert CraigieH-Index: 1
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome. Infection is aborted in the absence of integration, making integrase an attractive antiviral target. Recently approved inhibitors of integrase bind tightly to integrase assembled in a nucleoprotein complex with the viral DNA ends (intasome), but have only low affinity for free integrase. High-resolution structures of HIV-1 intasomes are therefore required to understand the detailed mechanisms of inhib...
10 CitationsSource
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with first- and second-generation INSTIs at res...
197 CitationsSource
#1Goedele N. Maertens (Imperial College London)H-Index: 21
#2Stephen Hare (Imperial College London)H-Index: 17
Last. Peter Cherepanov (Imperial College London)H-Index: 38
view all 3 authors...
Insertion of retrovirus genome into host genome to replicate is mediated by a tetramer of the virus-encoded integrase protein. The structure of a related integrase from prototype foamy virus bound to the cleaved viral DNA ends, a complex called the intasome, was previously revealed. These authors solve the structure of the intasome interacting with the target host DNA both before and after it is cleaved, revealing new details of the integration process that may help in designing improved inhibit...
213 CitationsSource
#1Laura De Luca (UNIME: University of Messina)H-Index: 28
#2Stefania Ferro (UNIME: University of Messina)H-Index: 17
Last. Alba Chimirri (UNIME: University of Messina)H-Index: 37
view all 8 authors...
Abstract The search of small molecules as protein–protein interaction inhibitors represents a new attractive strategy to develop anti-HIV-1 agents. We previously reported a computational study that led to the discovery of new inhibitors of the interaction between enzyme HIV-1 integrase (IN) and the nuclear protein lens epithelium growth factor LEDGF/p75. 1 Herein, we describe new findings about the binding site of LEDGF/p75 on IN employing a different computational approach. In this way further ...
55 CitationsSource
#1Jan De Rijck (Katholieke Universiteit Leuven)H-Index: 24
#2Koen Bartholomeeusen (Katholieke Universiteit Leuven)H-Index: 3
Last. Rik Gijsbers (Katholieke Universiteit Leuven)H-Index: 36
view all 5 authors...
Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a transcriptional coactivator involved in stress response, autoimmune disease, cancer and HIV replication. A fusion between the nuclear pore protein NUP98 and LEDGF/p75 has been found in human acute and chronic myeloid leukemia and association of LEDGF/p75 with mixed-lineage leukemia (MLL)/menin is critical for leukemic transformation. During lentiviral replication, LEDGF/p75 tethers the pre-integration complex to the host chromatin result...
57 CitationsSource
Cited By19
#1Nabab Khan (UND: University of North Dakota)H-Index: 1
#2Xue-SongChen (UND: University of North Dakota)H-Index: 14
Last. Jonathan D. Geiger (UND: University of North Dakota)H-Index: 45
view all 3 authors...
Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication and pathogenicity. Homeostatic regulation of divalent cations’ levels and actions appear to change as HIV-1 infection progresses and as changes occur between HIV-1...
#1Clinton G. L. Veale (UKZN: University of KwaZulu-Natal)H-Index: 6
#2Ronel Müller (UKZN: University of KwaZulu-Natal)
Global advancements in biological technologies has vastly increased the variety of and accessibility to bioassay platforms, while simultaneously improving our understanding of druggable chemical space. In the South African context, this has resulted in a rapid expansion in the number of medicinal chemistry programmes currently operating, particularly on university campuses. Furthermore, the modern medicinal chemist has the advantage of being able to incorporate data from numerous related discipl...
Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the u...
#1Mahdieh Safakish (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 1
#2Zahra Hajimahdi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 6
Last. Afshin Zarghi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 25
view all 5 authors...
BACKGROUND: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. OBJECTIVE: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. METHODS: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared usi...
#1Robyn Waters (UCT: University of Cape Town)
#2Mthawelanga Ndengane (UCT: University of Cape Town)
Last. Anna K. CoussensH-Index: 15
view all 6 authors...
: Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized....
#1Thompho J. Rashamuse (Mintek)H-Index: 1
#2Angela T. Harrison (Mintek)H-Index: 1
Last. Moira L. Bode (University of the Witwatersrand)H-Index: 9
view all 6 authors...
Abstract We describe here the synthesis of libraries of novel 1-subtituted-5-aryl-1H-imidazole, 5-aryl-4-tosyl-4,5-dihydro-1,3-oxazole and 5-aryl-1,3-oxazole fragments via microwave (MW)-assisted cycloaddition of para-toluenesulfonylmethyl isocyanide (TosMIC) to imines and aldehydes. The compounds obtained were biologically evaluated in an AlphaScreen HIV-1 IN-LEDGF/p75 inhibition assay with six imidazole-based compounds (16c, 16f, 17c, 17f, 20a and 20d) displaying more than 50% inhibition at 10...
3 CitationsSource
#1Xiaozhuo RanH-Index: 2
#2Zhujun AoH-Index: 15
Last. Xiaojian YaoH-Index: 25
view all 4 authors...
To date, a series of histone deacetylases have been documented to restrict HIV-1 replication at different steps. In this study, we identified histone deacetylase 10 (HDAC10) as an inhibitory factor against HIV-1 replication. Our results showed that endogenous HDAC10 is downregulated at the transcriptional level during HIV-1 replication. By knocking down HDAC10 in CD4+ T cells with specific shRNAs, we observed that the downregulation of HDAC10 significantly facilitates viral replication. Moreover...
#1Zahra Hajimahdi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 6
#2Rezvan Zabihollahi (Pasteur Institute of Iran)H-Index: 8
Last. Afshin Zarghi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 25
view all 4 authors...
BACKGROUND: Although major efforts have been devoted to the effective treatment of HIV-1 infection, it has remained one of the leading causes of deaths around the world. So, development of anti-HIV-1 agents featuring novel structure is essential. OBJECTIVE: To synthesize novel quinazolinone derivatives and evaluate their anti-HIV-1 activity. METHOD: In this study, we designed and synthesized a series of novel 2,3-diaryl-4-quinazolinone derivatives using a one-pot multicomponent reaction. Then, t...
#1Muhammad Shoaib Ali Gill (Monash University Malaysia Campus)H-Index: 1
#2Sharifah Syed Hassan (Monash University Malaysia Campus)H-Index: 13
Last. Nafees Ahemad (Monash University Malaysia Campus)H-Index: 2
view all 3 authors...
Abstract HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti -HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti -HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting thr...
1 CitationsSource
#1Mosab Yahya Al-Nour (Omdurman Islamic University)H-Index: 1
#2Musab Mohamed Ibrahim (Omdurman Islamic University)H-Index: 1
Last. Tilal Elsaman (Omdurman Islamic University)H-Index: 5
view all 3 authors...
The pharmacological activity of Acacia nilotica’s phytochemical constituents was confirmed with evidence-based studies, but the determination of exact targets that they bind and the mechanism of action were not done; consequently, we aim to identify the exact targets that are responsible for the pharmacological activity via the computational methods. Furthermore, we aim to predict the pharmacokinetics (ADME) properties and the safety profile in order to identify the best drug candidates. To achi...