Stephen E. Straus

THE CHRONIC FATIGUE SYNDROME - A COMPREHENSIVE APPROACH TO ITS DEFINITION AND STUDY

We have developed a conceptual framework and a set of research guidelines for use in studies of the chronic fatigue syndrome. The guidelines cover the clinical and laboratory evaluation of persons with unexplained fatigue; the identification of underlying conditions that may explain the presence of chronic fatigue; revised criteria for defining cases of the chronic fatigue syndrome; and a strategy for dividing the chronic fatigue syndrome and other unexplained cases of chronic fatigue into subgroups. Background The chronic fatigue syndrome is a clinically defined condition [1-4] characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairments in concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Diagnosis of the chronic fatigue syndrome can be made only after alternative medical and psychiatric causes of chronic fatiguing illness have been excluded. No pathognomonic signs or diagnostic tests for this condition have been validated in scientific studies [5-7]; moreover, no definitive treatments for it exist [8]. Recent longitudinal studies suggest that some persons affected by the chronic fatigue syndrome improve with time but that most remain functionally impaired for several years [9, 10]. Issues in Chronic Fatigue Syndrome Research The central issue in chronic fatigue syndrome research is whether the chronic fatigue syndrome or any subset of it is a pathologically discrete entity, as opposed to a debilitating but nonspecific condition shared by many different entities. Resolution of this issue depends on whether clinical, epidemiologic, and pathophysiologic features convincingly distinguish the chronic fatigue syndrome from other illnesses. Clarification of the relation between the chronic fatigue syndrome and the neuropsychiatric syndromes is particularly important. The latter disorders are potentially the most important source of confounding in studies of chronic fatigue syndrome. Somatoform disorders, anxiety disorders, major depression, and other symptomatically defined syndromes can manifest severe fatigue and several somatic and psychological symptoms and are diagnosed more frequently in populations affected by chronic fatigue [11-13] and the chronic fatigue syndrome [14, 15] than in the general population. The extent to which the features of the chronic fatigue syndrome are generic features of chronic fatigue and deconditioning due to physical inactivity common to a diverse group of illnesses [16, 17] must also be established. A Conceptual Framework for Studying the Chronic Fatigue Syndrome In the United States, 24% of the general adult population has had fatigue lasting 2 weeks or longer; 59% to 64% of these persons report that their fatigue has no medical cause [18, 19]. In one study, 24% of patients in primary care clinics reported having had prolonged fatigue ( 1 month) [20]. In many persons with prolonged fatigue, fatigue persists beyond 6 months (defined as chronic fatigue) [21, 22]. We propose a conceptual framework Figure 1 to guide the development of studies relevant to the chronic fatigue syndrome. In this framework, in which the chronic fatigue syndrome is considered a subset of prolonged fatigue ( 1 month), epidemiologic studies of populations defined by prolonged or chronic fatigue can be used to search for illness patterns consistent with the chronic fatigue syndrome. Such studies, which differ from casecontrol and cohort studies based on predetermined criteria for the chronic fatigue syndrome, will also produce much-needed clinical and laboratory background information. Figure 1. A conceptual framework of abnormally fatigued populations, including those with the chronic fatigue syndrome (CFS) and overlapping disorders. This framework also clarifies the need to compare populations defined by the chronic fatigue syndrome with several other populations in casecontrol and cohort studies. The most important comparison populations are those defined by overlapping disorders, by prolonged fatigue, and by forms of chronic fatigue that do not meet criteria for the chronic fatigue syndrome. Controls drawn exclusively from healthy populations are inadequate to confirm the specificity of chronic fatigue syndrome-associated abnormalities. Need for Revised Criteria To Define the Chronic Fatigue Syndrome The possibility that chronic fatigue syndrome study populations have been selected or defined in substantially different ways has made it difficult to interpret conflicting laboratory findings related to the chronic fatigue syndrome [23]. For example, the North American chronic fatigue syndrome working case definition [1] has been inconsistently applied by researchers [24]. This case definition is frequently modified in practice because some of the criteria are difficult to interpret or to comply with [25] and because opinions differ about the classification of chronic fatigue cases preceded by a history of psychiatric illnesses [26, 27]. Current criteria for the chronic fatigue syndrome also do not appear to define a distinct group of cases (28; Reyes M, et al. Unpublished data). For example, participants in the Centers for Disease Control and Prevention (CDC) chronic fatigue syndrome surveillance system [29] who met the chronic fatigue syndrome case definition did not substantially differ by demographic characteristics, symptoms, and other illness features from those who did not meet the definition (except by criteria used to place patients into one of our predetermined surveillance classification categories [Reyes M, et al. Unpublished data]). These findings indicate that additional subgrouping or stratification of study cases into more homogeneous groups is necessary for comparative studies. Need for Clinical Evaluation Standards Our experience suggests that fatigued persons often receive either inadequate or excessive medical evaluations. In the CDC chronic fatigue syndrome surveillance system, all participants were clinically evaluated by a primary physician before enrollment. Subsequently, 18% were found to have a preexisting medical condition that plausibly accounted for their chronic fatiguing illness (Reyes M, et al. Unpublished data). These medical conditions were identified either from a single battery of routine laboratory tests done on blood specimens obtained at enrollment or from review of available medical records. We believe that inappropriate tests are often used to diagnose the chronic fatigue syndrome in chronically fatigued persons. This practice should be discouraged. Need for a Comprehensive and Integrated Approach The complexities of the chronic fatigue syndrome and the existence of several obstacles to our understanding of it make a comprehensive and integrated approach to the study of the chronic fatigue syndrome and similar illnesses desirable. The purpose of the following proposed guidelines Figure 2 is to facilitate such an approach. Figure 2. Evaluation and classification of unexplained chronic fatigue. Guidelines for the Clinical Evaluation and Study of the Chronic Fatigue Syndrome and Other Illnesses Associated with Unexplained Chronic Fatigue Definition and Clinical Evaluation of Prolonged Fatigue and Chronic Fatigue Prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month or longer. Chronic fatigue is defined as self-reported persistent or relapsing fatigue lasting 6 or more consecutive months. The presence of prolonged or chronic fatigue requires clinical evaluation to identify underlying or contributing conditions that require treatment. Further diagnosis or classification of chronic fatigue cases cannot be made without such an evaluation. The following items should be included in the clinical evaluation. 1. A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements. 2. A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done. 3. A thorough physical examination. 4. A minimum battery of laboratory screening tests including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis. Routinely doing other screening tests for all patients has no known value [20, 30]. However, further tests may be indicated on an individual basis to confirm or exclude another diagnosis, such as multiple sclerosis. In these cases, additional tests or procedures should be done according to accepted clinical standards. The use of tests to diagnose the chronic fatigue syndrome (rather than to exclude other diagnostic possibilities) should be done only in the setting of protocol-based research. The fact that such tests are investigational and do not aid in diagnosis or management should be explained to the patient. In clinical practice, no additional tests, including laboratory tests and neuroimaging studies, can be recommended for the specific purpose of diagnosing the chronic fatigue syndrome. Tests should be directed toward confirming or excluding other etiologic possibilities. Examples of specific tests that do not confirm or exclude the diagnosis of the chronic fatigue syndrome include serologic tests for Epstein-Barr vi

Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome

Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.

Inherited Human Caspase 10 Mutations Underlie Defective Lymphocyte and Dendritic Cell Apoptosis in Autoimmune Lymphoproliferative Syndrome Type II

Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II.

Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.

Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense.

To further understand the role of cytokine responses in symptom formation and host defenses in influenza infection, we determined the levels of IL-1beta, IL-2, IL-6, IL-8, IFN-alpha, TGF-beta, and TNF-alpha in nasal lavage fluid, plasma, and serum obtained serially from 19 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) and correlated these levels with various measures of infection and illness severity. We found that IL-6 and IFN-alpha levels in nasal lavage fluids peaked early (day 2) and correlated directly with viral titers, temperature, mucus production, and symptom scores. IL-6 elevations were also found in the circulation at this time point. In contrast, TNF-alpha responses peaked later (day 3 in plasma, day 4 in nasal fluids), when viral shedding and symptoms were subsiding. Similarly, IL-8 peaked late in the illness course (days 4-6) and correlated only with lower respiratory symptoms, which also occurred late. None of IL-1beta, IL-2, or TGF-beta levels increased significantly. These data implicate IL-6 and IFN-alpha as key factors both in symptom formation and host defense in influenza.

Persisting Illness and Fatigue in Adults with Evidence of Epstein-Barr Virus Infection

Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.

A Prospective Study of New Infections with Herpes Simplex Virus Type 1 and Type 2

BACKGROUND AND METHODS Herpes simplex virus (HSV) infections are endemic, but the clinical characteristics of newly acquired HSV type 1 (HSV-1) and HSV type 2 (HSV-2) infections in adults have not been rigorously defined. We monitored 2393 sexually active HSV-2-seronegative persons for clinical and serologic evidence of new HSV infection. Of the participants, 1508 were seropositive for HSV-1 and 885 were seronegative. Charts were reviewed in a blinded manner for classification of those with genitourinary or oropharyngeal symptoms. Charts were also reviewed for all 174 persons with HSV seroconversion. RESULTS The rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years, respectively. Of the 155 new HSV-2 infections, 57 (37 percent) were symptomatic, 47 of which (82 percent) were correctly diagnosed at presentation. Among the 74 patients given a clinical diagnosis of genital HSV-2 during the study, 60 were given a correct diagnosis and 14 were given an incorrect diagnosis of genital herpes, for a ratio of true positive results to false positive results of 4:1. Among the 98 persons with asymptomatic HSV-2 seroconversion, 15 percent had genital lesions at some time during follow-up. Women were more likely than men to acquire HSV-2 (P<0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion, as compared with symptomatic seroconversion, by a factor of 2.6 (P<0.001). Of the 19 new HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years). CONCLUSIONS Nearly 40 percent of newly acquired HSV-2 infections and nearly two thirds of new HSV-1 infections are symptomatic. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.

Epstein-Barr Virus Infections: Biology, Pathogenesis, and Management

Dr. Stephen E. Straus (Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health [NIH], Bethesda, Maryland): Epstein-Barr virus (EBV) is a ubiquitous pathogen that has evolved an effective strategy for infection, persistence, and spread; EBV infection occurs in more than 90% of the population, most often without evident consequences [1, 2]. The clinical outcome of infection rests on the compromise struck between the virus and the hosta fragile interplay of competing forces. Epstein-Barr virus, for its part, unswervingly pursues a genetic mission to infect B lymphocytes, to endow them with an endless potential to pass the virus on to their progeny, and to do so while evading immune clearance. The host response is less predictable and determines whether an EBV infection becomes symptomatic. An ineffectual response, which occurs in persons with congenital or acquired immunodeficiency, permits the unbridled proliferation of virus-infected B cells. In contrast, the curious predilection of adolescents and adults to experience symptomatic infection and the features of the mononucleosis syndrome that ensues suggests that an excessive host response to EBV can also lead to illness. The biology of EBV, the diseases it provokes, the nature of the virus-host interaction and how it is controlled or subverted, and the limited means available to manage EBV infections are the subjects of this conference. Epidemiology The paradigmatic disease associated with EBV is infectious mononucleosis. The description and epidemiology of infectious mononucleosis predated by decades the recognition of EBV as its dominant cause; cytomegalovirus, human immunodeficiency virus (HIV), and Toxoplasma gondii are infrequent causes of mononucleosis-like illness [3, 4]. Infectious mononucleosis occurs at all ages, but most cases occur during adolescence and early adulthood [5]. It is now understood that the restricted age distribution of infectious mononucleosis is delimited at the lower end by the greater capacity of children to resolve a primary EBV infection with few or no symptoms. Although adults do not handle EBV as well as children, by the age of 25 years most are already seropositive and not susceptible to reinfection. In developing countries, EBV infection occurs early in life. Nearly the entire population of a developing country becomes infected before adolescence. Thus, symptomatic infectious mononucleosis is uncommon in such countries. In areas with high standards of hygiene, such as the United States and western Europe, where EBV infection may be delayed until adulthood, infectious mononucleosis is more prevalent. The increase in the incidence of infectious mononucleosis with improved sanitary conditions may explain why this disease was not described until the latter half of the nineteenth century [3]. Mononucleosis-like infections may occur more than once, but such episodes are generally not caused by a resurgence of viral activity. Reactivation disease appears exclusively in transplant recipients and similarly impaired persons [6]; there has never been a confirmed case of symptomatic reactivation EBV disease in a healthy person. Most serial mononucleosis-like episodes are caused by sequential infections with different pathogens. Thus, EBV infection stands in stark contrast to other herpesvirus infections, which have a definite proclivity toward recurrences. Salivary tissues are the recognized repositories of EBV, and periodic shedding from such tissue is a necessary feature of this viruss biology. Shedding is sustained for months after infection and then falls gradually; in 15% to 20% of all attempts, the virus can be recovered from saliva [7]. Immune compromise in transplant recipients and patients with the acquired immunodeficiency syndrome (AIDS) leads to higher rates of shedding (average, 50% to 80%) [8]. Evidence of the viruss presence in cervical epithelium and semen has emerged, but sexual transmission has not been proved [9]. Exchange of saliva would appear sufficient to explain EBV transfer to partners and the corresponding difficulty of transmitting this virus in the home, in the hospital, or in other confined quarters where the issue has been carefully examined [5, 10]. The virus can be transmitted to susceptible recipients by blood transfusion or bone marrow transplantation [11, 12], but such transmission is rare. Studies of natural or experimental transmission of infectious mononucleosis documented an incubation period of 3 to 7 weeks [13]. Clinical Spectrum Infectious Mononucleosis The classic syndrome of mononucleosis is defined as a clinical triad of fever, pharyngitis, and adenopathy [14], although many other symptoms and signs also occur (Table 1). The diagnosis of acute EBV infectious mononucleosis is based on clinical presentation and supportive laboratory findings, including an absolute lymphocytosis in which more than 10% of cells are atypical, as well as heterophile antibody titers of at least 1:56 by the traditional Paul-Bunnell-Davidsohn test or positive rapid slide assays such as the Mono-Latex test (Wampole Laboratories, Cranbury, New Jersey) [15]. About 93% of patients who fulfill the above criteria have primary EBV infection; if the criteria are relaxed, the proportion decreases [16]. Table 1. The Most Common Symptoms and Signs of Infectious Mononucleosis* The fortuitous discovery in 1967 that EBV causes infectious mononucleosis led quickly to the development of virus-specific antibody tests that, despite broad misunderstanding and overinterpretation, remain useful serologic tools, primarily for the diagnosis of primary illness but also as adjuncts in the evaluation of chronic or malignant sequelae of EBV infection (Table 2) [4, 17]. Table 2. Serologic Responses of Patients with Epstein-Barr Virus-associated Diseases Immunoglobulin M antibodies to the EBV viral capsid antigen (anti-VCA) evolve quickly with infection, persist for weeks to months, and do not reappear. Thus, their detection is presumptive evidence of recent primary infection. Analysis of paired acute and convalescent sera shows a rise, a subsequent fall, and a lifelong persistence of IgG anti-VCA, usually in titers ranging from 1:40 to 1:2560. Measurement of IgA anti-VCA is not useful except in the diagnosis and management of nasopharyngeal carcinoma. Antibodies to viral early (pre-DNA synthesis) antigens (anti-EA) of the diffuse or restricted types develop in most primary infections, peak in titers of less than 1:640, and wane with time. They persist frequently enough, though, that their presence in low titers is of no diagnostic significance [18]. Antibodies to EBV nuclear antigen (anti-EBNA) are detected in traditional assays relatively late after the onset of symptoms in infectious mononucleosis, so that their absence in a previously well person who develops acute illness suggests an ongoing EBV infection. The EBV-specific serologic tests were all originally done by immunofluorescence microscopy. The titers discussed above apply only to those assays. Newer tests involving enzyme-linked techniques, Western blots, or other immunoassays yield results that are not directly comparable to these standard methods. Moreover, even for a given assay, performance standards differ considerably from laboratory to laboratory, making the scrutiny of results acquired at different times in different places a fruitless exercise. Infectious mononucleosis is, with rare exceptions, a self-limited disease. Adenopathy or splenomegaly can persist for weeks and provoke some anxiety about their cause, but unless symptoms or signs progress well beyond the period of the acute illness, further workup is not warranted. Primary EBV infections, with or without the features of infectious mononucleosis, have many recognized complications (Table 3) that fall into various categories mostly dependent on immunopathologic responses to the virus. Ominous complications such as severe autoimmune hemolysis, airway obstruction from grossly enlarged tonsils, splenic rupture, and encephalitis, among others, are seen in otherwise healthy patients. Agranulocytosis, aplastic anemia, and other rare but grave features of acute, progressive EBV infection can arise in healthy patients but may indicate a demonstrable deficiency of cellular immunity [19]. Table 3. Complications of Infectious Mononucleosis Lymphoproliferative Disorders Many EBV-associated lymphoproliferative lesions are recognized in persons with congenital or acquired cellular immune deficiency [20]. X-linked lymphoproliferative disease is a rare disorder of young boys who develop fulminant mononucleosis after EBV infection. The disease is characterized by B- and T-cell infiltration of organs with displacement of bone marrow elements [21]. Over two thirds of affected patients die of hemorrhage or infection within weeks, and 100% die by 40 years of age. Survivors of the acute infection experience aplastic anemia, hypo-or hypergammaglobulinemia, opportunistic infections, or lymphomas. Epstein-Barr virus-associated lymphoproliferative disease also occurs in 1% to 3% of bone marrow, kidney, or liver transplant recipients. About 5% to 10% of heart or heart-lung transplants have developed EBV-associated B-cell tumors [20]. The marked degree of immunosuppression in these patients may allow outgrowth of EBV-infected B cells, resulting in lymphoproliferative lesions. The reversal of some of these lesions after a reduction in immunosuppressive therapy emphasizes the role of the immune system in controlling EBV infection in the normal host. In transplant recipients, as well as in patients with AIDS, EBV-associated B-cell tumors may have either polyclonal, monoclonal, or mixed phenotypes. Death from progressive expansion of tumors, immunodeficiency, and opportunistic infections is frequent. Chronic infectious mononucleosis is a rare, heter

Roles for Endocytosis and Low pH in Herpes Simplex Virus Entry into HeLa and Chinese Hamster Ovary Cells

ABSTRACT Herpes simplex virus (HSV) infection of many cultured cells, e.g., Vero cells, can be initiated by receptor binding and pH-neutral fusion with the cell surface. Here we report that a major pathway for HSV entry into the HeLa and CHO-K1 cell lines is dependent on endocytosis and exposure to a low pH. Enveloped virions were readily detected in HeLa or receptor-expressing CHO cell vesicles by electron microscopy at <30 min postinfection. As expected, images of virus fusion with the Vero cell surface were prevalent. Treatment with energy depletion or hypertonic medium, which inhibits endocytosis, prevented uptake of HSV from the HeLa and CHO cell surface relative to uptake from the Vero cell surface. Incubation of HeLa and CHO cells with the weak base ammonium chloride or the ionophore monensin, which elevate the low pH of organelles, blocked HSV entry in a dose-dependent manner. Noncytotoxic concentrations of these agents acted at an early step during infection by HSV type 1 and 2 strains. Entry mediated by the HSV receptor HveA, nectin-1, or nectin-2 was also blocked. As analyzed by fluorescence microscopy, lysosomotropic agents such as the vacuolar H+-ATPase inhibitor bafilomycin A1 blocked the delivery of virus capsids to the nuclei of the HeLa and CHO cell lines but had no effect on capsid transport in Vero cells. The results suggest that HSV can utilize two distinct entry pathways, depending on the type of cell encountered.

NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention.

During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled with the aid of new molecular technologies. Varicella, usually a benign manifestation of primary infection, and zoster, a result of reactivation of latent virus, can cause considerable morbidity in patients with immune impairment. Antiviral drugs, especially acyclovir, ameliorate severe infections but still have little role in the treatment of most normal patients with varicella or zoster. Varicella can be prevented when necessary by patient isolation and passive prophylaxis with varicella-zoster immune globulin. An experimental live vaccine also prevents varicella, but problems regarding its virulence for immunosuppressed patients and the durability of the protective response are still being addressed.Abstract During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled wi...