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De novo design and synthesis of HIV-1 integrase inhibitors
Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently ava …
Structural basis for strand-transfer inhibitor binding to HIV …
The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intaso …
Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract …
2.1. Patient Demographics. We collected samples from 235 HIV-infected subjects in Cameroon, of which we successfully amplified and sequenced the integrase and/or nef genes in 130 samples (Table 1).This cohort of 130 patients included 39 males [mean age: 37.28 ± 9.94 years] and 91 females (35.43 ± 8.75 years).
Molecular dynamics studies on the HIV-1 integrase catalytic domain
The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome, thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transc …
Specific features of HIV-1 integrase inhibition by ...
The integration of viral DNA into the cell genome is one of the key steps in the replication cycle of human immunodeficiency virus type 1 (HIV-1). Therefore, the viral enzyme integrase (IN) catalyzing this process is of great interest as a target for new antiviral agents. We performed a structural-f …
Integrase deficient lentiviral vector: prospects for safe clinical ...
Introduction. Lentiviral vector (LV) or integrase-proficient lentiviral virus (IPLV) is a viral vector commonly derived from human immunodeficiency virus-1 (HIV-1) (Liu & Berkhout, 2014).The HIV-derived LV is first reported for its functions in in vivo gene delivery and stable transduction of non-dividing cells (Naldini et al., 1996).The vector is packaged by …
Sequence specificity of viral end DNA binding by HIV-1 ...
HIV-1 integrase specifically recognizes and cleaves viral end DNA during the initial step of retroviral integration. The protein and DNA determinants of the specificity of viral end DNA binding have not been clearly identified. We have used mutational analysis of the viral end LTR sequence, in vitro …
LEDGINs, Inhibitors of the Interaction Between HIV-1 Integrase …
A permanent cure remains the greatest challenge in the field of HIV research. In order to reach this goal, a profound understanding of the molecular mechanisms controlling HIV integration and transcription is needed. Here we provide an overview of recent advances in the field. Lens epithelium-derive …
HIV-1 Integrase Inhibitors: A Comparative Review of Efficacy
The newest class of antiretrovirals for all persons living with HIV are the integrase strand transfer inhibitors (INSTIs). Since 2007, five INSTIs have been introduced: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. The INSTIs have favorable pharmacokinetic and pharmacodynamic properties, which contribute to both their …
Integrase
1. Introduction. The Baltimore virus classification method, currently adopted from the International Committee on Taxonomy of Viruses (ICTV), organizes the ribonucleic acid (RNA) containing viruses within groups III–VI on the basis of genome pairing (i.e., single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA)) and sign [1], [2], …
INSTI Resistance Notes
References. 1.0 1.1 Quashie PK, Mesplède T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR and Wainberg MA. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir.
Mutations in the amino-terminal domain of lambda-integrase …
Lambda integrase (Int) forms higher-order protein-DNA complexes necessary for site-specific recombination. The carboxy-terminal domain of Int (75-356) is responsible for catalysis at specific core-type binding sites whereas the amino-terminal domain (1-70) is responsible for cooperative arm-type DNA …
Elvitegravir: a once-daily, boosted, HIV-1 integrase inhibitor
The development of HIV-1 integrase strand transfer inhibitors (INSTIs) has been a major therapeutic breakthrough in the management of HIV-1 infection. The first HIV-1 integrase inhibitor, raltegravir, was licensed in 2007 and was subsequently approved for use in treatment-naive patients. Since then, …
Impact of primary elvitegravir resistance-associated mutations ...
Elvitegravir (EVG) is an effective HIV-1 integrase (IN) strand transfer inhibitor (INSTI) in advanced clinical development. Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H.
Modeling the HIV-1 Intasome: A Prototype View of the Target of ...
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 comple …
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Elvitegravir: a once-daily inhibitor of HIV-1 integrase
Co-formulated EVG/COBI/FTC/TDF is an option for the treatment of antiretroviral naïve and experienced patients. Once-daily dosing offers an advantage over raltegravir, but the requirement for pharmacologic boosting increases regimen complexity. Dolutegravir in development offers a favorable resistan …
Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs
1. Introduction. Integrase strand transfer inhibitors (INSTIs) are important drugs that are currently used in efforts to control human immunodeficiency virus type one (HIV-1) infections and limit the spread of the virus (Figure 1).We will briefly consider the discovery, efficacy, mechanism of action, and resistance to the clinically relevant INSTIs.
Integration-deficient lentiviral vectors: a slow coming of age
Lentiviral vectors are very efficient at transducing dividing and quiescent cells, which makes them highly useful tools for genetic analysis and gene therapy. Traditionally this efficiency was considered dependent on provirus integration in the host cell genome; however, recent results have challeng …
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