Current status and challenges of antiretroviral research and therapy

Esté, José A.; Cihlář, Tomáš

doi:10.1016/j.antiviral.2009.10.007

Cited by 235 publications

(194 citation statements)

References 90 publications

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“…M any viruses exhibit a high mutation rate when replicating their genomes, enabling quick adaptation to both changing cellular environments and therapeutics (1)(2)(3)(4)(5). Mammalian innate immune systems have developed a mechanism to exploit this high mutation rate against the virus; in a phenomenon termed "lethal mutagenesis," (6)(7)(8)(9)(10)(11)(12)(13)(14) the immune system employs nucleic acid-modifying enzymes (e.g., APOBEC and ADAR) to increase the viral mutation rate sharply, stressing the functional gene product repertoire of the virus to the point that the viral population collapses (15)(16)(17).…”

mentioning

confidence: 99%

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Fedeles

Singh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.

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mentioning

confidence: 99%

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Fedeles

Singh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite the improved quality of life, HAART has a number of limitations including high cost, drug toxicity and interactions, emergence of virus resistance, and the need for indefinite treatment, necessitating alternative therapeutic approaches. 3,4 Highly potent human monoclonal antibodies that recognize HIV envelope component gp120 or gp41 of a broad range of virus clades have been identified. These broadly neutralizing antibodies (bNAbs) have a number of unusual characteristics, including a high degree of somatic mutation, extended CDR H3 regions, and poly-and autoreactivity, making them difficult to elicit by immunization or natural infection.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

et al. 2015

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{The first three authors contributed equally to this manuscript.Despite nearly three decades of research, a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) has yet to be achieved. More recently, the discovery of highly potent anti-gp160 broadly neutralizing antibodies (bNAbs) has garnered renewed interest in using antibody-based prophylactic and therapeutic approaches. Here, we encoded bNAbs in first-generation adenoviral (ADV) vectors, which have the distinctive features of a large coding capacity and ease of propagation. A single intramuscular injection of ADV-vectorized bNAbs in humanized mice generated high serum levels of bNAbs that provided protection against multiple repeated challenges with a high dose of HIV-1, prevented depletion of peripheral CD4 + T cells, and reduced plasma viral loads to below detection limits. Our results suggest that ADV vectors may be a viable option for the prophylactic and perhaps therapeutic use of bNAbs in humans. INTRODUCTIONSince its emergence more than three decades ago, human immunodeficiency virus type 1 (HIV-1) remains a pandemic, with more than 60 million infected individuals to date and more than 32 million acquired immunodeficiency syndrome (AIDS)-related deaths.1,2 Despite intense research efforts, a safe and effective vaccine remains elusive. At present, highly active antiretroviral therapy (HAART) constitutes the mainstay of treatment and has resulted in HIV-infected individuals with plasma viral RNA loads (VLs) below the limits of detection, increased peripheral CD4 + T cell counts, and decreased patient morbidity and mortality. Despite the improved quality of life, HAART has a number of limitations including high cost, drug toxicity and interactions, emergence of virus resistance, and the need for indefinite treatment, necessitating alternative therapeutic approaches.

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“…Section 2.2 presents a direct synthesis of tricyclic heterocycles by a regioselective S N Ar-type reaction of tetrahydropyrimidine-substituted haloarenes with heterocumulenes. The efficient synthetic route for pyrimido [1,2-c] [1,3] benzothiazin-6-imine such as PD 404182 is also described. Chapter 3 describes the SAR study of PD 404182 derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…This global health threat has triggered intensive drug discovery efforts and a number of anti-HIV drugs including azidothymidine [AZT; the first nucleoside reverse transcriptase inhibitor (NRTI)], saquinavir (the first protease inhibitor), and nevirapine [a non-nucleoside reverse transcriptase inhibitor (NNRTI)] has been approved for treatment of HIV infection ( Fig. 1.1) [3]. Highly active antiretroviral therapy (HAART) involving co-administration of these anti-HIV agents is a standard treatment regimen for HIV infection.…”

Section: Introductionmentioning

confidence: 99%

Introduction

Mizuhara

2013

Development of Novel Anti-Hiv Pyrimidobenzothiazine Derivatives

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Current status and challenges of antiretroviral research and therapy

Cited by 235 publications

References 90 publications

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

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