Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 12, Issue 2, 2012

This issue of Infectious Disorders - Drug Targets, with a series of important papers on respiratory syncytial virus, is dedicated to Dr. Robert Chanock. For about a half century, Robert Merritt Chanock (known universally as “Bob Chanock”, or occasionally as just “Chanock”), was a dominant figure in international virology, and arguably the dominant figure in the world of respiratory virology. Chanock’s many scientific achievements have been cataloged in numerous obituaries, notably those in the New York Times by Dr Larry Altman, the Washington Post by Emma Brown, and in the Journal of Infectious Diseases (2011; 203:3-5) by colleagues Al Kapikian, David Morens and Tony Fauci. His laboratory – often with external collaborators - contributed significantly to the field of mycoplasmology, and made seminal discoveries in relation to hepatitis, gastrointestinal and respiratory virology. He and his collaborators connected respiratory syncytial virus (RSV) with the infant bronchiolitis syndrome and Mycoplasma pneumonia with atypical pneumonia; he discovered the paramyxoviruses which caused croup and other respiratory illnesses, co-discovered (with David Tyrrell) many strains of the two major agents of “colds”, rhinoviruses and coronaviruses, and discovered noroviruses (originally named “Norwalk virus”) which are perhaps the commonest cause of gastrointestinal illness in humans. His laboratory developed unique, live adenovirus vaccines, attenuated by enteric coating, which were widely used by the US military for prevention of pneumonia due to adenovirus types 4, 7 and 21. Although his laboratory made major efforts to develop vaccines for influenza and RSV, and the principle of live, attenuated vaccines as protective agents for these respiratory infections was established by his lab, success ultimately evaded him (although a live, attenuated influenza vaccine was subsequently developed by others). Chanock’s group did, however, develop a neutralizing monoclonal antibody to the RSV fusion protein (palivizumab) which is now FDA approved to prevent RSV infection in high-risk infants, and his laboratory played an important role in the development of vaccines against hepatitis A and rotavirus infections. He co-authored over 500 publications and was a co-editor of Fields’ Virology, the principal textbook of virology. Many dozens of scientists – MDs and PhDs – passed through his laboratory and learned from him, sometimes staying and sometimes leaving to go on to distinguished careers in virology at other institutions. And his list of international collaborators would run to many dozens as well....

The discovery of respiratory syncytial virus and the connection between RSV infection and severe respiratory disease in children was made over a half-century ago by Bob Chanock and his colleagues. In the intervening decades it has become clear that RSV is a major respiratory pathogen – nearly equal or second only to influenza virus – of infants, children, adults, the elderly and immunosuppressed individuals of all ages. If the reader had any doubts about the clinical and public health importance of RSV infection, the manuscripts in this issue by Caroline Breese Hall, Edward Walsh and Anne Falsey would certainly dispel them. Studies reviewed in those papers report rates of complications including hospitalization and death from RSV that are highly significant, and at rates that are about a half or a third of those attributable to influenza. We developed this RSV Theme Issue of Infectious Disorders – Drug Targets because we felt that the time was ripe for an overview of the clinical importance of RSV infection and of the current research on the virus. It is this research which is now close to yielding the tools which will reduce RSV’s clinical importance through developing effective vaccines and chemotherapeutic agents. Development of vaccines to prevent or mitigate RSV infection began shortly after its discovery, but research virtually came to a halt for several decades after a large clinical trial of a formalin-inactivated whole-virus vaccine paradoxically worsened the disease (see Costello et al., paper in this issue for details). Over the past 15-20 years attempts have been made to develop liveattenuated vaccines for infants as well as protein-based vaccines for adults, and research has also at least partially elucidated the reasons for the paradoxical effects of the formalin-inactivated vaccine. The wide availability of a reverse genetics system for RSV has facilitated generation of attenuated variants, and will continue to do so. So far, these efforts have not been completely successful, with many candidate RSV vaccines failing because of an inability to achieve the required level of safety whilst retaining efficacy. However, the success of the neutralizing F protein monoclonal antibody, palivizumab, for passive immunoprophylaxis clearly shows that vaccines which generate protective antibodies will be effective. It is unfortunate that motavizumab, also developed by Medimmune/AstraZeneca, and which appeared more potent than palivizumab in vitro and in clinical trials, was dropped by AstraZeneca when the FDA expressed concerns about adverse reactions and other issues and requested additional clinical trials. Previous and ongoing work has clearly shown that attenuation through mutation of single genes, though effective in reducing RSV infection and spread, all too easily allows reversion to wild-type virus. A combination of mutations that inhibit several different stages in the RSV lifecycle without reducing its immunogenicity, we think, is a better approach. A major challenge for any RSV vaccine is the requirement that it be safe and immunogenic in infants and the elderly; two extremes of age where immune systems do not function optimally. Given the additional complication in infants of the presence of maternal antibodies, it is probable that two different vaccine formulations will need to be developed. This has been highlighted in recent trials with live attenuated candidates showing that strains attenuated in adults and RSV-seropositive children may not be similarly attenuated in infants. The multiplicity of additional attenuating mutations that come from an understanding of the function of the non-structural proteins and the matrix protein – discussed in the articles by Teng and Ghildyal et al., in this issue, combined with other approaches such as the use of recombinant vectors for antigen delivery – we think will result in successful attenuated vaccines suitable for use even in infants. Although some may disagree, our opinion is that we do not have an effective therapeutic for RSV infections. Ribavirin is FDA-approved for that indication, but the data supporting its efficacy would not allow approval by current standards, and it is rarely used by clinicians. Clearly better drugs are needed. Again, data reported in this Theme Issue indicate that there are many processes in the RSV replication cycle which could be targeted by novel antiviral drugs. Several drugs have been developed against the F protein which showed some efficacy in animal studies, but their development was discontinued because of toxicity and/or insufficient efficacy. The approval of the peptide antiviral enfuvirtide for treatment of HIV infection, despite its limitations of cost, the need for parenteral administration and toxicity, has shown that clinically-effective fusion inhibitors can be developed, and this success should spur commercial interest. Work by Costello et al., summarized in this issue, also supports development of an RSV F protein inhibitor. However, a myriad other targets are also worthy of development. Maybe it is time to adopt a multidrug / multifaceted approach to RSV, on the lines of the very successful multidrug therapy for HIV. A famous Roz Chast cartoon published in The New Yorker magazine many years ago shows four panels, and in each panel there is a person staring at a half-full glass of water on a table. In the first panel the person says, “half full – that’s great”; in the second, “half-full – that’s terrible”; in the third, “half-full; half-empty; I can’t make up my mind” and in the fourth he says, “what’s this? I ordered a Big Mac and a Coke”. Perhaps this cartoon reflects the RSV drug and vaccine landscape!

Respiratory syncytial virus (RSV) was first isolated from infants by Chanock and colleagues in 1957. However, control of this ubiquitous agent has yet to be achieved. RSV is recognized as the primary cause of hospitalization for acute lower respiratory tract illness (LRTI) among infants worldwide. Among children <5 years old, annual hospitalization rates in the United States (US) is 3/1000 children, and rates in Canada and European countries are similar. In the US the hospitalization rate is 3 times higher than that from influenza or parainfluenza viral infections. Much less appreciated is the clinical and economic burden from RSV outpatients, as few have specific diagnostic testing. Nevertheless, RSV in the US is estimated to cause 1 of 334 hospitalizations, 1 of 38 emergency department visits, but 1 of 13 private practice visits. These outpatient children tend to have moderate to severe illness with approximately three-fourths manifesting labored respirations. RSV burden among outpatients, therefore, is considerable both in size and severity. The global burden of RSV infection is unknown as few studies are from developing countries. Estimates indicate about one-fourth of all acute LRTI occur among children <5 years, and the greatest burden is among children in developing countries. Currently the only approved means of RSV prophylaxis is passive immunization with humanized F protein monoclonal antibody. Such prophylaxis, however, has limited availability, is expensive, and is recommended only for infants most at risk for severe RSV disease. Only widespread immunization of children is likely to diminish the current burden of RSV infection.

Respiratory Syncytial Virus, generally recognized for its role as the major respiratory pathogen in newborn infants and young children, is also a significant pathogen in adults. It is a frequent cause of upper and lower respiratory illness among all age groups, although it often goes unrecognized in adults unless highly sensitive molecular diagnostic tests are used. All RSV infections in adults represent re-infection and are generally mild to moderate in severity, although persons with certain high-risk conditions are susceptible to severe disease. These include the frail elderly living at home or in long term care facilities, those with underlying chronic pulmonary disease, and the severely immunocompromised. It is estimated that between 11,000-17,000 adults die of RSV infection annually in the U.S, with ˜ ten-fold more admitted to hospital with respiratory symptoms. As in infants, wheezing is often noted during RSV infections and chest radiographs are often normal despite significant lower respiratory symptoms and hypoxia. Treatment of RSV is directed at symptomatic relief, and only rarely is specific antiviral therapy recommended. Exceptions include the severely immunocompromised, in whom inhaled ribavirin has been recommended in hopes of reducing both mortality and long term pulmonary compromise, especially in lung transplant recipients. Immunity to RSV is incomplete. Although there does not appear to be a defect in humoral immunity, there is evidence that CD8+ T cell immunity may be impaired with age. Currently a vaccine for RSV is not available, and many challenges to developing a successful vaccine must be overcome.

Respiratory syncytial virus (RSV) is the major respiratory pathogen of infants and children worldwide, with no effective treatment or vaccine available. Steady progress has been made in understanding the respiratory syncytial virus lifecycle and the consequences of infection, but some areas of RSV still remain poorly understood. Although many of the interactions between virus proteins that are required for efficient RSV assembly have been elucidated, many questions still remain regarding viral assembly, as well as the mechanisms of RSV budding. This review will summarise the current understanding of RSV assembly, including the various interactions between virus proteins and the involvement of cellular factors with a view to identifying possible attenuation and/or drug targets within the assembly pathway.

Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.

Over fifty years have passed since the identification of respiratory syncytial virus (RSV) as an important pediatric pathogen. However, an effective vaccine is still lacking. Immunization with formalin-inactivated RSV resulted in vaccine-enhanced disease; thus, a greater focus has been placed more recently on developing live attenuated RSV vaccines. The difficulty in identifying a live attenuated vaccine candidate has been balancing appropriate attenuation with sufficient immunogenicity. With the advent of reverse genetics systems for RSV, researchers have been able to generate recombinint vaccine candidates by introducing specific mutations into the genome wild-type RSV. These systems provide a means to determine the effects of known attenuating mutations and identifying novel methods of attenuating the virus without decreasing immunogenicity. In addition, different mutations can be combined in a single genome to fine-tune the level of attenuation and immunogenicity to achieve the proper balance in a viable vaccine candidate. Among the targets for attenuation are the small RSV nonstructural (NS) proteins. The NS proteins have multiple functions during the virus life cycle, including antagonizing the antiviral effects of interferon and directly augmenting virus replication. This review will outline the progress in understanding the functions of the NS proteins and how altering these functions by reverse genetic manipulation can be a useful path toward rationally designing a safe and effective live-attenuated RSV vaccine.

Despite that pancreatic necrosis complicates only 15 % of cases of acute pancreatitis (AP), it is associated with high morbidity and considerable mortality. In an attempt to improve prognosis, many surgical strategies have been described during the last few decades. Currently, necrosectomy remains the cornerstone in the surgical treatment of infected pancreatic necrosis and in selected cases of sterile necrotizing pancreatitis. Following necrosectomy, continuous closed lavage is recommended by many authors, while closed abdominal packing /drainage and repeated planned necrosectomies- commonly using the zipper technique-are also acceptable alternative strategies. Open abdomen (laparostomy) is rarely indicated in carefully selected cases (typically in abdominal compartment syndrome associated with necrotizing AP). During the last decade, minimally invasive techniques (including percutaneous drainage, retroperitoneal endoscopic approach, transgastric endoscopic approach etc) have been extensively studied by some groups not only in the management of pancreatic abscesses and / or pseudocysts, but also as primary methods of treatment of necrotizing AP. Results have been impressive, but experience currently is limited to only a few centers around the world.

Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with antiprion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemicalbased treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.

Sepsis and septic shock are the major causes of death in intensive care units. Oxidative damage to mitochondria is involved in the development of organ dysfunction associated with sepsis. This syndrome is caused by an excessive defensive and inflammatory response characterised by a massive increases of reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria The consequences of sepsis is a systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, antioxidant depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O2 consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondria-targeted antioxidants and the future implications for such approaches in patients.