Viruses Of Human Origin Research Articles

The rapidly expanding family of human polyomaviruses: recent developments in understanding their life cycle and role in human pathology.

Since their discovery in 1971, the polyomaviruses JC (JCPyV) and BK (BKPyV), isolated from patients with progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy, respectively, remained for decades as the only known members of the Polyomaviridae family of viruses of human origin. Over the past five years, the application of new genomic amplification technologies has facilitated the discovery of several novel human polyomaviruses (HPyVs), bringing the present number to 10. These HPyVs share many fundamental features in common such as genome size and organization. Infection by all HPyVs is widespread in the human population, but they show important differences in their tissue tropism and association with disease. Much remains unknown about these new viruses. In this review, we discuss the problems associated with studying HPyVs, such as the lack of culture systems for the new viruses and the gaps in our basic understanding of their biology. We summarize what is known so far about their distribution, life cycle, tissue tropism, their associated pathologies (if any), and future research directions in the field.

Viral Tropism and the Pathogenesis of Influenza in the Mammalian Host

Influenza viruses, single-stranded negative-sense RNA viruses within the family Orthomyxoviridae, remain an important cause of human morbidity and mortality worldwide. Despite effective vaccines, more than 200,000 individuals in the United States are hospitalized each year for influenza, and approximately 35,000 succumb to disease.1 Seasonal epidemics arise through antigenic variation and recombination events from existing and currently circulating human strains, which initially target the upper respiratory tract with extension to a bronchointerstitial pneumonia in a subset of affected individuals. Disease is often more severe in older and debilitated patients, producing a characteristic distribution in age-related mortality within the affected population.2 In contrast to seasonal epidemics, pandemics arise when antigenically novel viruses emerge and are readily transmissible within the naive human population. Such events are rare and occur after zoonotic transmission of viruses through recombination events between established human and avian strains or possibly through direct adaptation of avian strains for efficient human to human transmission.3 Concerns over an avian influenza pandemic have risen since 1997 with the recognition of H5N1 as a cause of fulminant disease in humans.4,5 Pathologically fatal H5N1 causes diffuse alveolar damage and progression to multiple organ dysfunction with a case fatality rate estimated at more than 50%. Although H5N1 disease is severe, transmission rates have been low, and viral adaptation to efficient human to human transmission has not occurred. Understanding viral and host barriers that prevent transmission may be critical in establishing rational control measures as well as predicting and stratifying risk for individual strains of influenza. In this issue of The American Journal of Pathology, van Riel et al6 examine the viral binding distribution in pulmonary tissue of a number of avian and human influenza strains to elucidate the role of tropism in transmission and pathogenesis.

The fingerpad protocol to assess hygienic hand antiseptics against viruses

Many types of viruses can be spread by the hands of caregivers and food handlers, and regular and proper decontamination of hands is crucial in interrupting such spread. Standardized methods to assess the virus-eliminating potential of handwash and handrub agents have not been available and this test method addresses this gap. Each fingerpad of an adult subject receives 10 μl of the test virus suspension and the inoculum allowed to dry. The contaminated area is then exposed to 1 ml of a control or test agent for the desired contact time and virus remaining on the fingerpad is eluted, and the eluates are titrated for infectious virus along with the required controls. The method can also allow the determination of further virus removal due to post-treatment rinsing of the fingerpads with water and/or their subsequent towel- or air-drying. Percent reductions in the amounts of infectious virus after treatment with the control and test agents are then determined. The method gives results that are comparable to those obtained using the whole-hand. The activities of all major classes of germicidal chemicals used in hygienic hand antiseptics have been tested against several enveloped and non-enveloped viruses of human origin.

Complete nucleotide sequence of a strain of coxsackie B4 virus of human origin that induces diabetes in mice and its comparison with nondiabetogenic coxsackie B4 JBV strain

The E2 strain of coxsackie B4 virus (CB4), which is of human origin, can induce a diabetes-like syndrome in mice. The cDNA of the genome of the E2 strain was cloned and sequenced. The E2 viral genome was found to comprise 7,396 bases, which appear to encode a polyprotein of 2,183 amino acids with an overall similarity of 94.91% to nondiabetogenic CB4 prototype JBV strain. The E2 genome is organized like other enteroviruses. It has a 5' noncoding region of 744 nucleotides, a single long open translational reading frame starting at nucleotide 745 and extending to nucleotide 7293, a 3' noncoding region of 100 nucleotides, and a poly (A) tract. Genomic sequence comparison of the E2 and JBV strains showed 1,369 nucleotide substitutions in the genome of the E2 strain, most of which are single and silent. There were 111 resultant amino acid changes arising from some of these substitutions, including 82 amino acid changes in the noncapsid proteins, and 29 amino acid changes in the capsid proteins VP1, VP2, VP3, and VP4, which showed 11, 13, 4, and 1 substitution(s), respectively. Noncapsid protein P2-C showed eight amino acid substitutions. On the basis of the sequence comparison of E2 and JBV strains of CB4, we suggest that some of the amino acid changes in the capsid and noncapsid proteins of the E2 strain may be involved in the determination of its diabetogenicity.

Viral strain dependent differences in experimental Argentine hemorrhagic fever (Junin virus) infection of guinea pigs.

Guinea pigs infected with low-passage Junin virus of human origin showed viral strain dependent differences in mortality, LD50, time to death, and in viral spread and distribution. Different Junin strains appeared to cause at least two broad patterns of Argentine hemorrhagic fever in guinea pigs. A number of strains of Junin virus caused a viscerotropic type of illness in which virus replicated predominantly in lymph nodes, spleen, and bone marrow. With the most severe visceral forms of Argentine hemorrhagic fever, the guinea pigs became viremic, developed necrosis of spleen, lymph nodes, and bone marrow, showed gastric hemorrhages, and all animals died within 13-15 days. Other Junin strains induced a neurological type of illness with transient viral replication in and lymphocyte depletion of spleen and lymph nodes, with no detectable viremia or viral replication in bone marrow. Subsequently, virus was found in the brain with varying severities of polioencephalitis, and the guinea pigs frequently showed rear leg paralysis before death occurred 28-34 days after inoculation. Not all animals infected with a neurotropic strain developed all these signs. One viral strain induced some signs characteristic of both patterns of illness. Although the disease forms in the guinea pig model did not strictly correlate with those observed in the humans from which these strains were obtained, the different strains of Junin virus consistently caused very different patterns of illness in infected guinea pigs.

Specific enzyme-linked immunoassay for rotavirus serotypes 1 and 3.

We prepared monoclonal antibodies against two serotypically distinct rotavirus strains: Wa, a serotype 1 virus of human origin, and rhesus rotavirus, a simian serotype 3 virus. Monoclonal antibodies which react specifically with VP7 of each serotype were identified by hemagglutination inhibition tests, plaque reduction neutralization studies, and solid-phase immunoassays which used wild-type and reassortant strains of rotavirus. An enzyme-linked immunoassay was designed which utilizes two of these antibodies to correctly identify serotype 1 and serotype 3 viruses.

Enteric Viruses of Nonhuman Primates

The phylogenetic relationship of nonhuman primates to man implies that many of these animals could serve as surrogates for studies of diseases of man. Many nonhuman primate species are susceptible not only to viruses of human origin but also to nonhuman primate viruses that are counterparts of viruses of man. All monkeys and great apes do not respond similarly to an antigenic stimulus. Some agents are highly pathogenic for one species and completely innocuous for another. For example, poliovirus causes disease and fatalities in great apes, but picornaviruses given orally cause few lesions in most nonhuman primates. Other enteroviruses (coxsackie-, echoviruses) have caused disease in nonhuman primates. It is difficult to separate viruses into distinct categories according to their anatomic affinities. Many viruses not considered to be enteric may be recovered from the intestinal tract. Adenoviruses, both human and nonhuman strains, which are not considered enteric viruses, nonetheless are recovered frequently from the intestinal tract. Adult animals show little evidence of disease, with the possible exception of diarrhea, after adenovirus infection. Newborns, however, may respond with a fatal pneumoenteritis. Adenovirus may be associated with diseases in organs other than the intestines. The reoviruses, which may be recovered from the intestinal tract, also are generally innocuous. Rotaviruses as pathogens in nonhuman primates are presently under study, and it is suspected that rotaviruses of man may produce experimental disease in nonhuman primates. Production of diabetes by several of the enteric viruses has been suggested but not demonstrated conclusively.

An outbreak of hepatitis in marmosets in a zoological collection.

12 marmosets of 3 different species died of hepatitis during a period of 5 months. The lesions closely resembled those of virus hepatitis in man but material from these animals and from in-contact marmosets failed to reveal the presence of hepatitis A. This together with certain aspects of the epidemiology of the disease suggests that the outbreak was not caused by a virus of human origin but possibly by a virus indigenous to the marmoset or tamarin.

Triplication of a unique genetic segment in a simian virus 40-like virus of human origin and evolution of new viral genomes

The non-defective (heavy) virions from a simian virus 40-like virus (DAR virus) isolated from human brain have been serially passaged at high input multi-plicities in primary monkey kidney cells. The 32P-labeled, progeny DAR-viral genomes have been purified and tested for sensitivity to the R I restriction endouclease from Escherichia coli ( Eco RI‡ restriction nuclease). The parental DAR-viral genomes share many physical properties with “standard” simian virus 40 DNA and are cleaved once by the Eco RI restriction nuclease. After the fourth serial passage, three populations of genomes could be distinguished: Eco RI resistant, Eco RI sensitive (one cleavage site) and Eco RI “supersensitive” (three, symmetrically-located, cleavage sites). The Eco RI cleavage product of the “supersensitive” form is one-third the physical size (10.4 S) of simian virus 40 DNA and reassociates about three times more rapidly than sheared, denatured simian virus 40 DNA. From the fourth to the eighth serial passages, the genomes containing this specific triplication of viral DNA sequences were selected for and became the predominant viral DNA species.

Antibodies to viruses of human origin in monkeys from Uganda.

SummarySera from 52 red-tail (wild) and 31 African green (captive) monkeys were examined for the prevalence of viral antibodies. Antibodies to Herpesvirus hominis, mumps virus, certain human enteroviruses, and M. pneumoniae occurred at a greater frequency in captive monkeys, suggesting that nonhuman primates acquire these infections through contact with humans. Antibodies to parainfluenza viruses, adenoviruses, coronaviruses, influenza A and B viruses, and respiratory syncytial virus occurred as often in captive as in wild monkeys. All sera were negative for neutralizing antibodies to poliovirus types 1, 2, and 3, Coxsackie B-3 virus, and ECHO-virus type 6. Wild monkeys from the Bwamba region were found to have a high rate of hepatitis B infections; few captive monkeys were positive for this infection.

A Description of Two Newly-Recognized Rhinoviruses of Human Origin

SummaryProperties of 2 new viruses of human origin recovered from the human oro-pharynx are described. These agents were found to be less than 30 mμ in size and ether resistant. By inference they were found to contain RNA. These properties are consistent with their classification as picornaviruses.Both agents were unstable in acid pH; thus they were designated as rhinoviruses. The viruses were immunologically distinct from each other and from all previously characterized rhinoviruses. Nineteen other virus strains serologically related to the prototype viruses were recovered from recruits at a military training camp. Statistical analysis suggested that viruses similar to prototype strain 1200 were associated with occurrence of mild “cold-like” illnesses. These studies also indicated that homologous neutralizing antibodies protected against infection by these viruses.The authors take pleasure in acknowledging the capable technical assistance of Mrs. Carol Uhlendorf, Mrs. Lena Wetherall, Mr. Conard Davis, Mr...

Adenovirus Type 12 Infection

IN 1962, Trentin and others 1 reported that adenovirus type 12 produced undifferentiated sarcoma when injected into newborn hamsters after an interval of 33 days or more. This was the first report of malignancies produced in animals by inoculation of virus of human origin. Reports of recovery of this virus from specimens taken from ill children have been few. The prototype strain (Huie) was recovered from the stool specimen of a child with suspected nonparalytic poliomyelitis. 2 Further isolations have been made from the anal swabs of apparently well children. 3,4 Recent reports have described the recovery of this virus from specimens from children with central nervous system (CNS) disease 5,6 and illnesses resembling acute lymphocytosis. 7 This report describes illnesses of three infants and one child from whom adenovirus type 12 was recovered, the serologic responses of the patients to the infection, and studies of the incidence of neutralizing

Inactivation of hemagglutinating capacity of type A influenza virus by trypsin treatment.

SummaryThe effect of trypsin on hemagglutinating capacity of 6 type A strains of influenza virus of human origin has been determined under different experimental conditions. With both virus and enzyme in tris-Cl buffer and incubation at 37°C the hemagglutinating capacity of all strains was rapidly inactivated. Minimum concentration of enzyme and minimum time required for inactivation was not the same for all strains. However, with all strains, lowering the incubation temperature or adding sodium or calcium chloride to the trypsin-virus mixtures either reduced the rate of the reaction or completely inhibited it. These changes in test conditions did not in all instances affect all strains to the same extent. With 5 of the 6 strains the effect of added salt appeared to be more closely associated with the concentration than the type of ion present, whereas with the sixth strain the type of ion was a significant factor. The findings illustrate the importance of both the strain examined and the experimental con...

Use of Complement Fixation Screening Technique to Identify Poliovirus in Enterovirus Isolates

SINCE the introduction of tissue culture methods for isolation of viruses, many previously unknown viruses of human origin have been characterized. Of these, the largest number classified to date fall into the enterovirus group. The usual procedure for identification of these viruses by neutralization test (NT) is a timeconsuming, expensive task. Less expensive and less time-consuming complement fixation (CF) techniques have been reported for identification of certain enterovirus isolates (1-4). Few laboratories performing diagnostic tests on viruses have incorporated a CF procedure into their routine identification of enterovirus isolates. At the beginning of the 1961 poliomyelitis season, a screening procedure by CF for identification of the three types of poliovirus was initiated by the Immuno-Serology Unit, Communicable Disease Center, to simplify typing of suspected enteroviruses. This report presents the findings obtained with the procedure, and correlates these results with identification by NT or by history of the type of oral vaccine fed.

Electron Microscopy of Purified Lansing Virus.

ConclusionsThe results mentioned in the preceding paper as well as those given here lead to the conclusion that the Lansing virus, unlike Theiler's virus and probably the SK mouse virus, is a relatively spherical or slightly asymmetrical particle of about 25 mμ average particle diameter. It may be recalled that a somewhat similar conclusion was reported for the MV virus.5 It appears to the present authors that such values for the size of these strains of poliomyelitis virus of human origin are also more in accord with the filtration end-point data and the conditions that have been found necessary for sedimentation in the ultracentrifuge.Presented at, the Symposium of the Division of Biologieal Chemistry of the American Chemical Society on Biochemical and Biophysical Studies on Viruses at Atlantie City on April 12, 1946.

Studies on Measles

Summary Simultaneous inoculation of children and monkeys with measles virus of human origin produces in both, after a like incubation period, a syndrome which is similar except in point of severity. The syndrome in the children is that of typical measles; that in the monkeys is what we and others have regarded as typical of measles in this species. An examination of the results obtained in some 80 monkeys receiving in certain instances human and in others egg-derived measles virus, reveals no evidence of any difference in the picture produced by either of the materials. Both appear to be typical of measles in this species. Inoculation of 36 children with active egg-passage virus produced in 4 mild but definite measles, and in 7 others coryza with or without leucopenia and questionable Koplik spots appearing between the 8th and 15th days after inoculation.