Preface [Hot topic: HIV Drug Resistance and Approaches to New Therapies (Guest Editor: Chris Petropoulos)]

HIV DRUG RESISTANCE AND APPROACHES TO NEW THERAPIES In the absence of preventative or therapeutic vaccines for the foreseeable future, antiretroviral therapy is the most effective weapon in the fight against HIV / AIDS. Currently, there are 19 drugs that are commercially available for the treatment of HIV-1 infection, including eight nucleoside analog inhibitors of reverse transcriptase (NRTI), three allosteric (non-nucleoside) RT inhibitors (NNRTI), seven protease inhibitors (PI) and one recently approved entry inhibitor. In developed countries, treatments with combinations of these agents have proven highly effective at suppressing viral replication resulting in dramatic reductions in HIV morbidity and mortality. However, treatment failure is almost inevitable and is most frequently associated with the emergence of drug resistant virus. Efforts to reduce the occurrence and long-term clinical impact of treatment failures include the development of new and improved antiretroviral therapeutics and treatment strategies. The HIV / AIDS pandemic has emerged as the defining public health crisis of today's developing countries. The delivery of effective drug treatment to patient populations most in need is long overdue, but will require careful planning and implementation. These efforts can benefit from the many lessons learned since the approval of the first antiretroviral drug (AZT) in 1987. The collection of articles in this special issue address recent advancements in HIV-1 drug resistance research and the development of effective antiretroviral drug treatment strategies. A Review of Resistance to the Nucleoside and Nucleotide Reverse Transcriptase Inhibitors N. Shulman* and M. Winters Although members of the NRTI class were among the first antiretroviral drugs available for the treatment of HIV-1 infection, the field has only recently gained a firm understanding of the molecular mechanisms that confer reduced NRTI susceptibility. In this article, the authors describe an improved appreciation for the incidence and patterns of NRTI cross resistance, including the newer members of this drug class. With this new information, the field is better equipped to develop new candidates with more favorable / less extensive cross-resistance profiles and to optimize gene sequencing strategies for an important drug class that continues to serve as the cornerstone for most of today's HAART regimens. Resistance to HIV-1 Entry Inhibitors W.C. Olson* and P.J. Maddon Broad cross-resistance within the NRTI, NNRTI, and PI classes significantly limits the treatment options for a growing number of patients that have experienced multiple treatment regimen failures. This has prompted the search for drugs that target other steps in the HIV-1 replication cycle. The process of virus attachment / entry represents a promising target for antiretroviral drug development and the first member (enfuvirtide) of this new drug class is now available for the treatment of HIV / AIDS in the US and EU. In this review, the authors describe the preclinical and clinical characterization of each of the leading entry inhibitor candidates, and also discuss mechanisms of drug resistance. Members of this new drug family can be sub-classified as inhibitors of attachment, co-receptor binding, or fusion based on their ability to disrupt distinct steps in the entry process. The use of multiple entry inhibitors may offer advantages that include synergistic antiviral activity and non-overlapping resistance profiles. Is Resistance Futile? Victoria D. Kutilek, Dennis A. Sheeter, John H. Elder, and Bruce E. Torbett* In this article, the authors detail the structure and function of HIV-1 protease and discuss the limitations in the transition state design of existing protease inhibitors that have led to the widespread selection of viral variants exhibiting broad cross-resistance. These limitations include the structural rigidity of inhibitors and proteaseinhibitor binding interactions that are less reliant on backbone atoms and more sensitive to changes in side chain atoms than the normal protease-substrate complex. The authors discuss several new considerations for the design of second-generation competitive inhibitors, including inhibitor flexibility and inhibitor binding on rates that are more competitive with normal substrate binding. The authors also suggest the means for targeting other non-active site features, including the dimer interface, and entertain the attractive concept that viral evolution can be constrained in favor of drug resistant variants that are incapable of high rates of replication. Structural and Thermodynamic Basis of Resistance to HIV-1 Protease Inhibition: Implications for Inhibitor Design Adrian Velazquez-Campoy, Salman Muzammil, Hiroyasu Ohtaka, Arne Schön, Sonia Vega and Ernesto Freire* The available protease inhibitors were developed to inhibit the protease activity of wild-type (i.e. protease inhibitor naïve) HIV-1. Because the design of these first generation inhibitors was based on a constrained target, they are all vulnerable to resistance mutations that are capable of conferring broad cross-resistance to other members of this class. In this review, the authors discuss a paradigm shift in drug development strategy that includes the design of inhibitors that can structurally adapt to the binding site changes conferred by resistance mutations or polymorphisms without sacrificing binding specificity and affinity. Predicting the Impact of Antiretrovirals in Resource-Poor Settings: Preventing HIV Infections whilst Controlling Drug Resistance Sally Blower*, Li Ma, Paul Farmer, and Serena Koenig The introduction of antiretroviral drug treatment into resource limited settings that are in desperate need of HIV treatment intervention has been the subject of much debate. However, there are limited data to substantiate the beneficial and detrimental consequences of such a course of action, or how best to proceed. This will likely be the single most important decision that the world health community will make in the foreseeable future addressing this devastating global epidemic. In this article, the authors develop and apply newly developed mathematical models to estimate the impact of low to moderate levels of antiretroviral drug treatment in developing countries. The outcome of this endeavor stresses the importance and value of developing community specific AIDS prevention and care policies that carefully balance the prevention of new infections against the emergence and transmission of drug resistant strains. Mathematical Approaches in the Study of Viral Kinetics and Drug Resistance in HIV-1 Infection V. Muller* and S. Bonhoeffer The authors provide an in depth and comprehensive discussion of the application of mathematical modeling to the study of HIV dynamics. This work builds on earlier dynamic models in attempts to explain common treatment observations, including persistent low-level viremia and the emergence of drug resistant variants in the face of fully suppressive therapy. The authors also discuss the roles of viral “fitness”, recombination and intermittent drug pressure on the selection and outgrowth of resistant variants. The refined model further highlights the critical importance of treatment adherence to the durability of fully suppressive antiretroviral drug treatments. Fitness Variations and their Impact on the Evolution of Antiretroviral Drug Resistance Luis Menendez-Arias*, Miguel A. Martinez , Miguel E. Quinones-Mateu , and Javier Martinez-Picado Over the past several years, it has become increasingly apparent that many antiretroviral drug resistance mutations impair the normal function of the viral target protein, which in turn leads to attenuated viral replication. In this review, the authors describe the various methods that have been developed to measure the degree of impairment and also provide a comprehensive description of the contribution of specific NRTI, NNRTI and PI mutations to decreased viral “fitness”. The authors review several recent studies that have revealed associations between viruses with impaired replication and immune system preservation. More studies are needed to determine whether / how the impaired replication of drug resistant strains directly impacts pathogenesis, disease progression, and transmission. Variety of Interpretation Systems for Human Immunodeficiency Virus Type 1 Genotyping: Confirmatory Information of Additional Confusion M. Sturmer*, H. W. Doerr, and W. Preiser Genotyping assays are the most widely used form of antiretroviral resistance testing. The increasing complexities of mutational patterns that have emerged in response to the successive use of multi-drug treatment regimens have prompted the development of a wide variety of assay interpretation systems. In this article, the authors provide an overview of the most commonly used systems, followed by a drug by drug comparison of available interpretation algorithms. The authors also discuss the likely causes for common discordant interpretations and stress the importance of linking genotypic interpretations to clinical outcome data. Anti-HIV Inhibitors Based on Nucleic Acids: Emergence of Aptamers as Potent Antivirals P. J. Joshi, T. S. Fisher and V. R. Prasad* Cross resistance has not only prompted the search for new drug targets, but also new inhibitors that are structurally and mechanistically distinct from existing members of the NRTI, NNRTI, and PI classes. The authors provide an extensive review of nucleic acid-based inhibitors of HIV-1 replication. These versatile approaches can be applied to a wide variety of new (e.g. regulatory and structural proteins) and existing (enzymes) viral targets. Progress on the identification and development of inhibitory RNAs, referred to as “aptamers”, which exhibit impressive binding specificities and affinities is discussed in detail. The authors close with a discussion of several important technical obstacles, including delivery and intracellular expression, which will need to be addressed before this new therapeutic strategy can be fully exploited. I would like to close by thanking all of the authors for their excellent and thoughtful contributions, as well as Dr. Robert Goldman for his assistance and cooperation in the assembly of this special topics issue of CDT-ID.