Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 11, Issue 5, 2011

This special issue of Infectious Disorders-Drug Targets focuses on human cytomegalovirus (CMV) infection from a pediatric standpoint, presenting state-of-the-art reviews by experts in the field, with whom I have been privileged to collaborate. This issue will cover congenital infections in general, congenital CMV infection specifically, infection in the compromised host, CMV genetics and pathogenesis, diagnostic approaches, antiviral treatment and resistance, and CMV vaccine development. Many of these authors participate in the National Institute on Deafness and Other Communication Disorders CMV and Hearing Multicenter Screening (CHIMES) Study, which is providing invaluable information on the incidence, detection, and sequelae of congenital CMV infection by screening more than 100,000 newborns for congenital CMV infection and following those infected for hearing outcomes [1, 2]. While this issue was in preparation, Andrei, De Clercq, and Snoeck published an extraordinary overview of drug targets in CMV infection in this journal [3]. This special issue both expands on that foundation and emphasizes the importance of CMV infection in the pediatric population. CMV is the most common intrauterine infection in the United States and, likely, the rest of the world [4-6] in addition to being the leading infectious cause of psychomotor impairment and sensorineural hearing loss in infants and children [7, 8]. In fact, in 1999, the Institute of Medicine assigned CMV the highest priority in its assessment of targets for vaccine development based upon “the cost and human suffering that would be alleviated by reducing the disease burden of congenital CMV infection” [4]. More than 50 years after discovery of the virus, progress toward a vaccine is being made [9-11], but much remains to be done [6]. CMV infection has been reviewed frequently [6, 12, 13] and the state-of-the-art reviews in this issue supplement and update previous work. To review CMV disease burden and contextualize congenital CMV, Joseph Cantey and Pablo Sánchez have provided a broad overview of congenital infections [14]. Focusing on CMV specifically, Sean Elliott has narrowed the purview, thoughtfully describing congenital infection [15]. Finally, Marsha Russell, April Palmer, and Marian Michaels have cogently reviewed non-congenital CMV infection in the compromised host, including post-natally acquired CMV in the premature baby, oncology patient, solid organ and hematopoietic stem cell transplant recipient, and human immunodeficiency virus-infected individual [16]. In an excellent review of CMV-host interactions, Mark Schleiss has covered the pathogenesis of infection, including mechanisms for evasion of the immune response and suggesting possible targets for therapeutic intervention [17]. Current methods for diagnosing CMV infection in a variety of populations are thoroughly elucidated by Shannon Ross, Zdenek Novak, Sunil Kumar Pati, and Suresh Boppana [18]. Amina Ahmed has provided an encyclopedic assessment of treatment issues [19] which is complemented by a thorough overview of the genetic basis and current evaluation of antiviral resistance by Scott James and Mark Prichard [20]. Finally, David Bernstein has written a superior treatise on the status of vaccines to prevent CMV infection [21]. Space limitations do not allow inclusion of many important and interesting aspects of CMV biology and disease, such as the increasingly described, severe manifestations of CMV infection in apparently immunocompetent children [22] or the role of passive immunoprophylaxis for infected pregnant women [23-25]. The interplay between the immune system and CMV latency and reactivation is another topic worthy of further study and review [26, 27]. Finally, the role of CMV infection in cancer [28] (among many other diseases and conditions) is fascinating, but addressing these interactions is just beginning. Any of these areas (and many others) could have been included in this issue. In addition to the remarkable proficiency and expertise of the authors of these reviews, the following colleagues generously contributed to this issue's quality and success by serving as peer reviewers of the articles: Doctors Janet Chen, Jeffrey Cies, Irini Daskalaki, Gail Demmler-Harrison, Kristina Feja, Lawrence Frenkel, Jane Gould, Paul Griffiths, Hemant Kesarwala, David Kimberlin, Sarah Long, Robert Pass, Swetha Pinninti, Mobeen Rathore, Judy Scala, Sunil Sood, Greg Storch, and Jennifer Vodzak. The opportunity to interact with colleagues of this caliber is extraordinarily gratifying and the results of their hard work and dedication are reflected in the reviews comprising this special issue of Infectious Disorders-Drug Targets.....

Congenital infections are those that are acquired transplacentally by the fetus from an infected mother. They constitute a major public health burden, affecting millions of infants and children worldwide. Despite significant advances in medical diagnostics, the majority of newborns with congenital infections are not recognized, since many of these infections may not cause clinically - apparent disease in the newborn period. Nonetheless, these infections - whether they are apparent or silent - have the potential to adversely impact the neurodevelopmental outcomes of these vulnerable children.

Cytomegalovirus (CMV) remains the most common cause of congenitally-acquired infection in the United States and is a leading infectious cause of sensorineural hearing loss, cognitive delay, and permanent neurologic sequelae. Although most cases of congenital CMV infection are asymptomatic, significant morbidity and mortality exist for symptomatic infants and may also occur in asymptomatic ones. Diagnosis remains relatively straightforward, but treatment options are limited and associated with some toxicity. Efforts at prevention via vaccination, screening, and improved epidemiology deserve high priority to limit the impact of this common infection.

Disease caused by cytomegalovirus (CMV) infection can clinically manifest in a variety of ways in the immunodeficient host and lead to significant morbidity and mortality. Infections can be primary, occur as a result of reactivation of latent virus, or infection with a new strain of CMV. Cell-mediated immunity is the main defense against CMV disease. This component of the immune system is frequently affected in children who are born prematurely, have undergone solid organ transplantation or hematopoietic stem cell transplantation, or have infection with human immunodeficiency virus. Accordingly, these children are at increased risk for severe disease due to CMV. In addition, CMV itself alters cell-mediated immunity and may predispose hosts to other bacterial, fungal, or viral infections as well as predispose to graft rejection. The importance of CMV in these special populations of children, emphasizing epidemiology, risk factors, and preventive strategies, is reviewed.

Human cytomegalovirus (CMV) is responsible for approximately 40,000 congenital infections in the United States each year. Congenital CMV disease frequently produces serious neurodevelopmental disability, as well as vision impairment and sensorineural hearing loss. Development of a CMV vaccine is therefore considered to be a major public health priority. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal injury induced by pathologic virally-encoded gene products, an inability of the maternal immune response to control infection, and the direct impact of infection on placental function. CMV encodes gene products that function, both at the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; interfere with apoptosis; induce an inflammatory response; mediate vascular injury; induce site-specific breakage of chromosomes; promote oncogenesis; dysregulate cellular proliferation; and facilitate evasion of host immune responses. This minireview summarizes current concepts regarding these aspects of the molecular virology of CMV and the potential pathogenic impact of viral gene expression on the developing fetus. Areas for potential development of novel therapeutic intervention are suggested for improving the outcome of this disabling congenital infection.

Cytomegalovirus (CMV) is recognized as the most common congenital viral infection in humans and an important cause of morbidity and mortality in immunocompromised hosts. This recognition of the clinical importance of invasive CMV disease in the setting of immunodeficiency and in children with congenital CMV infection has led to the development of new diagnostic procedures for the rapid identification of CMV. Diagnosis of acute maternal CMV infection by the presence of immunoglobulin (Ig)M and low-avidity IgG requires confirmation of fetal infection, which is typically performed using polymerase chain reaction (PCR) assays for CMV on amniotic fluid. Viral culture of the urine and saliva obtained within the first two weeks of life continues to be the gold standard for diagnosis of congenitally-infected infants. PCR assays of dried blood spots from newborns have been shown to lack sufficient sensitivity for the identification of most neonates with congenital CMV infection for universal screening purposes. However, saliva PCR assays are currently being assessed as a useful screening method for congenital CMV infection. In the immunocompromised host, newer rapid diagnostic assays, such as phosphoprotein 65 antigenemia and CMV real-time PCR of blood or plasma have allowed for preemptive treatment, reducing morbidity and mortality. However, lack of standardized real-time PCR protocols hinders the comparison of data from different centers and the development of uniform guidelines for the management of invasive CMV infections in immunocompromised individuals.

Cytomegalovirus (CMV) is an opportunistic pathogen associated with significant morbidity and mortality in immunocompromised hosts. Antiviral agents specifically targeting CMV were initially developed during the human immunodeficiency virus (HIV) epidemic to treat end-organ disease in patients with acquired immunodeficiency syndrome (AIDS). There are currently four antiviral drugs licensed for the treatment of CMV infections: ganciclovir (GCV), valganciclovir (VGCV), foscarnet (FOS), and cidofovir (CDV). The role of these agents has evolved from the treatment of disease to include prevention of CMV infection and disease, primarily in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. The potential use of these drugs is being explored for the treatment of congenital CMV infection, another CMV-associated disease with significant morbidity. The availability of antiviral therapy has provided major advances in the treatment and prevention of CMV infection and has resulted in dramatically improved outcomes for immunocompromised hosts. At the same time, the clinical utility of most of these agents is limited by poor oral bioavailability, associated toxicities, and the potential for development of resistance with extended use. Novel therapeutic agents are needed to address these limitations. In this article, currently available anti-CMV agents will be described. An overview of the clinical syndromes caused by CMV will be provided, with specific reference to the role of antiviral agents in treating and preventing these infections. Antiviral resistance in CMV will be reviewed and novel therapeutic agents that may address resistance will be briefly discussed.

Infections due to resistant human cytomegalovirus (CMV) are an emerging problem, particularly in immunocompromised hosts. When managing such patients, clinicians should be aware of the possibility of developing CMV antiviral resistance, especially while on prolonged therapy or if severe immunosuppression is present. CMV resistance to current antiviral agents is mediated by alterations in either the UL97 kinase or DNA polymerase, encoded by the UL97 and UL54 genes, respectively. UL97 mutations are capable of conferring resistance to ganciclovir, while UL54 mutations can impart resistance to ganciclovir, cidofovir, and foscarnet. If treatment failure is suspected to be due to antiviral resistance, CMV resistance analysis should be obtained. Phenotypic resistance assays performed on clinical isolates measure antiviral susceptibilities directly, but are laborious and time-consuming. Therefore, genotypic resistance analysis has become the more common means of diagnosing CMV resistance. Mutations in UL97 or UL54 may be clinically associated with resistance, but their effect on antiviral susceptibility must be confirmed by marker transfer techniques such as recombinant phenotyping.

Cytomegalovirus (CMV) is a leading cause of congenital infection worldwide and therefore is recognized as an important target for vaccine development. Data from natural infections and work done with animal models, including models of congenital infection, provide the rationale for their development. CMV vaccine evaluations were begun in the mid-1970's with an attenuated live virus vaccine, Towne, but this vaccine has not consistently provided protection. Most recently, data from a trial with a subunit glycoprotein B (gB) vaccine administered with the adjuvant MF59 became available. This trial, conducted in post-partum women, demonstrated that the vaccine decreased CMV infections, increasing optimism that a protective CMV vaccine could be developed. Other approaches for CMV that have entered clinical trials include replicons, DNA vaccines, prime boost strategies, and chimeric live viruses. The replicon vaccine included gB and the T cell targets phosphoprotein (pp)65 and Immediate Early (IE)1 while the DNA vaccine was given with a new adjuvant and included gB and pp65. The optimal composition for a CMV vaccine remains to be defined but trials continue with the gB vaccine and others.