Current Opinion in Virology 2012, 2:569–571
For a complete overview see the Issue
Available online 29th September 2012
1879-6257/$ – see front matter, © 2012 Elsevier B.V. All rights reserved.
Introduction
Viruses have been known to exist as distinct entities for many years but efforts to understand and control these agents of disease only began in the 20th century. While methods for fighting viral diseases such as smallpox have been used with relative success over much of the last millennium, the first attenuated viral vaccine to combat rabies was only produced by Pasteur in 1885 and was followed over 50 years later by the discovery of vaccine approaches to combat yellow fever virus and influenza. Vaccines proved effective in preventing many viral diseases but were inefficient for the treatment of patients with existing viral infections. Progress in virology research and increasing knowledge of viral enzymes has set the stage for antiviral drug discovery. The first experimental antivirals were developed in the 1960s, mostly to block the replication of herpes viruses. Compounds were identified through traditional drug discovery methods by screening infected cells for chemicals that inhibit viral activity. In the 1980s, when the full genetic sequences of viruses were elucidated, researchers began to learn in detail how viruses worked, and the type of chemicals needed to thwart viral replication. Indeed, the last 30 years have seen the successful discovery of a wide array of antiviral drugs with therapeutic value for devastating diseases such as human immunodeficiency virus (HIV) infection. As highlighted in the article by E De Clercq, 26 drugs have been formally approved for the treatment of HIV infections as of 2011, and the antiviral drug area is in effervescence, with new drug regimens emerging against widely diverse viruses on a regular basis.
The fundamental characteristic of viruses is their absolute dependence on a living host organism for replication and propagation, making them absolutely reliant on interaction with host organisms. This led to different drug discovery paradigms targeting virus-specific functions, virus–host interfaces or/and functions essential for virus replication. Indeed, antiviral drug discovery is a wonderful illustration of successful targeted therapy approaches. As a basic mechanism, antiviral drugs specifically inhibit one step of virus replication without causing unacceptable side effects by acting on defined molecular targets. Many effective compounds, targeting viral proteins/enzymes, recently termed direct acting antivirals (DAAs), have been developed. DAAs have the advantages of inhibiting virus replication with greater selectivity for virus-specific functions, of being orally bioavailable with pharmacokinetics that permit drug combinations, and of having limited side effects. The availability of protein structures has further triggered structure-based and rational drug design approaches. With access to well characterized molecular targets, antiviral compounds are tailored on the basis of the molecular configuration and mode of action of the target proteins, allowing the conceptual design of potent antiviral compounds. The class of antiviral drugs known as HIV protease inhibitors revolutionized the treatment of HIV infection in the mid 1990s and represents one of the best examples of DAAs developed by rational design. With a rapidly increasing number of protein structures linked to advances in computing systems, experimental high-throughput screening can now be complemented by computational virtual screening to discover new antiviral drug molecules. Of course, the identification and validation of future antiviral targets remain crucial steps, which will gain from advances in antiviral drug discovery, spanning the conceptual design and chemical synthesis of new antiviral compounds, their structure–activity relationships, their mechanisms of action as well as their pharmacological behavior (better adherence and combination therapy). However, major limitations in ‘state of the art’ developments of antiviral drugs still include a narrow antiviral activity spectrum (addressed by novel antiviral approaches in three articles: de Chassey et al.; Ma-Lauer et al.; Es-Saad et al.), ineffectiveness against latent viruses (addressed in an article by Brumme et al. on HIV cure strategy), the development of drug-resistant virus mutants (four articles: Lessells et al.; Götte; Welsch and Zeusem; Wainberg et al.) and undesirable toxic side effects.
The first series of articles focuses on future targeted therapy with continued interest in the development of novel DAAs for treatment of HIV, in the absence of a cure, and of hepatitis C virus (HCV) infections. Malet, Calvez and Marcelin describe the potential of HIV integrase inhibitors (INIs), an attractive fourth HIV drug class, and of a novel class of allosteric inhibitors interfering with integrase-host factor LEDGF/75 interactions. Both classes of INIs prevent viral DNA from integrating into the genetic material of the host cell, thereby blocking HIV replication. The first drug in this class, Raltegravir (Isentress; Merck), received US Food and Drug Administration (FDA) approval in 2007, while Elvitegravir (Gilead) a second drug in this class also recently received FDA approval (2012); a third compound, Dolutegravir (GlaxoSmithKline) is now in advanced phase 3 clinical trials. The availability of two classes of INIs brings interesting potential for their use in future HIV strategies to eliminate or reduce latent HIV reservoirs.
Chatel-Chaix, Germain, Götte and Lamarre provide an in-depth overview of current and future directions in HCV inhibitors, by describing novel classes of either direct-acting or host-targeting inhibitors that will be developed. Despite huge progress that has been made in understanding HCV molecular virology and in developing HCV-specific antiviral drugs, the attrition rate remains high due to various toxicities. The review also addresses the limitations of the recently introduced NS3 protease inhibitors and makes the point that intense efforts will be required to generate future personalized interferon (IFN)-free combination therapies that will be orally bioavailable.
Then, Brumme, Chopera and Brockman address the role of host immunity in the control of HIV reservoirs through the clearance of reactivated cells. The article highlights the importance of better understanding HIV immunology and particularly protective cellular immunity. This information will be essential not only to develop effective vaccines, but also to design novel therapies to cure HIV.
Other papers are based on the value of a comprehensive knowledge of virus–host interactions for identification of cellular antiviral drug target candidates. Current strategies for antiviral therapeutics target the virus specifically and directly, but alternative approaches to drug discovery are described by the groups of Lotteau, von Brunn and Lamarre. These concepts call for identification of critical host targets and broad-spectrum targets that are common to numerous viral infections. While major challenges in developing molecularly host-targeted therapies are to minimize adverse effects, a main advantage of this approach is the potential to develop panviral therapeutics, based on strong biological hypotheses in the context of a novel drug development paradigm. Indeed, the groups of Lotteau and von Brunn provide an exhaustive overview of state-of-the-art methodologies applied to the comprehensive landscape of virus–host interactions in the prioritization of cellular targets. They also describe how viral and human interactome analyses can identify central human proteins that are targeted by different viruses, and how these constitute powerful broad-spectrum antiviral targets. The article by de Chassey, Meyniel-Schicklin, Aublin-Gex, André and Lotteau illustrates how targeting host proteins also offers a valuable advantage in drug repositioning strategy to expedite antiviral drug discovery. Ma-Lauer, Lei, Hilgenfeld and von Brunn further provide examples of members of the cyclophilin and FKBP protein families as prerequisites for coronavirus replication. Broad-spectrum anti-coronaviral targets could include cellular elements and they have identified both cyclosporin and FK506 as potential anti-coronaviral drugs.
The article of Es-Saad, Tremblay, Baril and Lamarre describes an alternative approach to drug discovery based on enhancement of the immune response to a broad range of viruses. The design of therapeutics acting on specific immune targets requires a comprehensive knowledge of innate immunity signaling pathways and regulators that are induced by and are common to numerous viral infections. Host proteins targeted by multiples viruses are key players in innate antiviral immunity and represent potential therapeutic targets to restore innate immune responses.
In another chapter, an article by Vladimir Beljanski and John Hiscott describes how viruses can be used to infect cancer cells and trigger strong anti-cancer and innate immune responsiveness that could potentially combat neoplastic disease. This is a growing area of investigation with specific viral approaches that have been designed to target many different types of cancer cells. This approach could further benefit from future identification of small-molecule regulators of antiviral innate immunity. Although this field of research is still in its infancy, great hope exists in regard to the possibility that viruses might be harnessed to have positive effects for disease eradication and/or therapy.
This notwithstanding, the field of HIV drug resistance and resistance against other DAAs remain daunting. In this context, Lessells, Katzenstein and de Oliveira have described evidence of subtype differences in drug resistance that can exist among different viral subtypes. The basis for such variability is varied but results indicate that the multiplicity of polymorphisms within the viral genetic code can govern such distinctiveness. This is clearly an important topic for both clinicians and scientists to work on in terms of better understanding the diversification of antiviral responsiveness as well as drug resistance.
Also in the area of drug resistance, the article by Götte provides a comprehensive and basic description of the reasons for variability in regard to genetic barrier to resistance and how considerations of viral fitness can impact on the development of drug resistance. This is an important area of research with applicability to a wide array of different viruses. In this context, the HIV and HCV examples used to illustrate the points made in this paper are important, given that these two viruses display high level variability and susceptibility to development of drug resistance.
It is noteworthy, as well, that the article in this compendium by Welsch and Zeusem describes data that are available to-date in regard to HCV drug resistance. Although two drugs are currently approved for the treatment of HCV disease, the fact is that drug resistance has been selected in replicon systems against all classes of anti-HCV drugs, and the expectation is that resistance will be a major problem in regard to HCV therapeutics. Of course, as was demonstrated with HIV, future DAAs targeting different enzymatic functions of HCV could be combined in such a way as to completely abolish virus replication and the possibility of drug resistance. Should this be the case, the potential for achieving a cure of HCV infection will be attainable, given that HCV, in contrast to HIV, does not integrate into host cell genomes. The reality of retroviral integration into host-cell chromosomes represents a clear obstacle to the potential for achieving HIV eradication in the near future.
Indeed, the article by Wainberg, Mesplède and Quashie on the development of novel HIV integrase inhibitors and drug resistance paints a realistic portrait of the occurrence of drug resistance against this newest class of antiretroviral drugs. Although numerous mutations that alter integrase structure and lead to resistance against integrase strand transfer inhibitors have been described, there is an active pipeline of new INIs continuously being developed. Moreover, as also pointed out in the article by Marcelin and colleagues, new classes of anti-integrase compounds that target the cellular element known as LEDGF may also be prone to resistance but by different mechanisms. One major hope is that LEDGF inhibitors that block HIV integrase may have a completely different resistance profile than integrase strand transfer inhibitors, potentially permitting these two types of compounds to be used synergistically or, at least, additively.
In summary, viruses have remained resilient to challenges and maintain the ability to evolve into new drug resistant forms despite the advent of new types of DAAs with the potential to antagonize viral replication. It is our hope that future research will point the way toward development of newer classes of antiviral drugs that will be more efficient than those developed until now, such that treatment and eradication of a wide array of viral diseases may be possible.
Biographies
Daniel Lamarre is a professor of Medicine at Université de Montréal and leads the Molecular Immunovirology Research Unit at IRIC. After many years in the pharmaceutical industry, he pursues an academic carrier integrating drug discovery and systems biology approaches applied to biomedical research. He continues to explore novel targets in infectious diseases by exploiting membrane protein–protein interactions, and to uncover novel regulators of innate immunity aimed at the development of panviral therapeutics.
Mark A. Wainberg is a Professor of Microbiology and Immunology at McGill University in Montreal where he also serves as Director of the McGill AIDS Centre that is based at the Jewish General Hospital. He is well recognized for his contributions to HIV drug development and to the study of HIV drug resistance. He continues to investigate these topics as well as the possibility that HIV might be eradicated from infected individuals.