Virus-host Relationship Research Articles

Pathogenesis of experimental rhesus cytomegalovirus infection.

Human cytomegalovirus (HCMV) establishes and maintains a lifelong persistence following infection in an immunocompetent host. The determinants of a stable virus-host relationship are poorly defined. A nonhuman primate model for HCMV was used to investigate virological and host parameters of infection in a healthy host. Juvenile rhesus macaques (Macaca mulatta) were inoculated with rhesus cytomegalovirus (RhCMV), either orally or intravenously (i.v. ), and longitudinally necropsied. None of the animals displayed clinical signs of disease, although hematologic abnormalities were observed intermittently in i.v. inoculated animals. RhCMV DNA was detected transiently in the plasma of all animals at 1 to 2 weeks postinfection (wpi) and in multiple tissues beginning at 2 to 4 wpi. Splenic tissue was the only organ positive for RhCMV DNA in all animals. The location of splenic cells expressing RhCMV immediate-early protein 1 (IE1) in i.v. inoculated animals changed following inoculation. At 4 to 5 wpi, most IE1-positive cells were perifollicular, and at 25 wpi, the majority were located within the red pulp. All animals developed anti-RhCMV immunoglobulin M (IgM) antibodies within 1 to 2 wpi and IgG antibodies within 2 to 4 wpi against a limited number of viral proteins. Host reactivity to RhCMV proteins increased in titer (total and neutralizing) and avidity with time. These results demonstrate that while antiviral immune responses were able to protect from disease, they were insufficient to eliminate reservoirs of persistent viral gene expression.

Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?

Between 5 and 10% of adults infected with the hepatitis B virus (HBV) develop a chronic infection lasting longer than 6 months, which may lead to advanced liver disease. HBV can be classified into six genotypic families: A, B, C, D, E and F, but only genotypes A and D are significantly represented in western Europe, where they account for some 90% of cases of infection with HBV. In the present study, we investigated a possible association between HBV genotype A or D and clinical outcome of the infection. We compared the prevalence of these genotypes in a group of patients with chronic active hepatitis to that of a group with acute resolving hepatitis. In patients with chronic active hepatitis, genotype A was found in 28 of 35 patients and genotype D in only four. The remaining three patients were infected with genotype non-A, non-D. In contrast, genotype D was found in 24 of 30 patients with acute hepatitis, whilst genotype A was found in only three patients of this group. Three were infected with genotype non-A, non-D. Our results show a clear association between genotype A and chronic outcome (Ficher's exact test: two-sided P-value, P < 0.0001). They suggest that HBV genotypes may play a role in the virus-host relationship. Possible mechanisms for such a role are discussed.

Role of Outer Capsid Proteins in Transmission of Phytoreovirus By Insect Vectors

Publisher Summary This chapter focuses on the role of outer capsid protein in the transmission of Phytoreoviru s by insect vectors. Using current research systems combined with reliable traditional experimental systems, the chapter discusses the viral proteins responsible for infection by Phytoreovirus of vector cells, with the goal of defining the mechanism of the vector transmission of such viruses. Clarification of the molecular mechanisms of viral multiplication in distinct hosts and of interkingdom differences in the expression of specific proteins should provide new insights into the roles of proteins that function in the virus–host relationship. Such investigations of the viral molecules that are essential for virus transmission by vectors and of the ways in which these molecules function should help develop measures for controling plant viruses that are transmitted by vectors. It might even be possible to generate transgenic plants that express proteins that interfere with the normal interactions between a virus and its vector.

Low-Productive Alpha-Herpesviridae Infection in Chronic Lichenoid Dermatoses

Background: Herpes simplex virus (HSV) and Varicella-zoster virus (VZV) are responsible for various atypical mucocutaneous manifestations in the immunosuppressed population. One of the causative pathomechanisms suggests an altered virus-host cell relationship. Objective/Methods: This report investigates by histology, immunohistochemistry and in situ hybridization the histological and virological features of 6 protracted, indolent HSV infections and 2 prolonged zoster infections. Results: Histopathology revealed a lichenoid dermatitis in all patients. Specific HSV-1, HSV-2 and VZV in situ hybridization proved the viral origin of the cutaneous lesions. Immunohistochemical assessment demonstrated the intracellular presence of the HSV glycoproteins gB, gC and gD in epidermal keratinocytes which did not exhibit cytolysis. Similar findings were obtained for the VZV gE and gB. Conclusion: These results suggest that in some instances HSV and VZV infections may present a protracted disease course associated with a lichenoid inflammatory pattern and a non-cytolytic virus-host cell relationship.

The role of immune mechanisms in control of herpes simplex virus infection of the peripheral nervous system.

Underlying the recurrent cutaneous lesions caused by herpes simplex virus (HSV) is a sophisticated virus-host relationship involving primary sensory neurons. These cells may become productively infected, but sometimes virus replication is interrupted for long periods, producing a reservoir of latent herpes in the nervous system from which infection can periodically reactivate. How the balance is tipped in favor of either productive or latent infection and how productive infection of neurons is rapidly controlled (which, in general, it is) are prominent contemporary questions for herpes virologists. In this chapter, we critically review the clinical and experimental evidence suggesting that the host’s adaptive immune response makes a vital contribution to the control of established HSV replication in the nervous system, and we dwell on the controversial issue of the fate of productively infected neurons.

A quantifiable phenotype of viral propagation

A system has been identified where a virus, replicating continuously on its host, displays a distinct and quantifiable phenotype, and thereby continuously reports on the state of the virus-host relationship. When bacteriophage T7 is plated out with its host, Escherichia coli, it establishes a constant-velocity infection wave, which is driven by an autocatalytic reaction-diffusion mechanism. The velocity—which is easily measured—continuously reflects the infection environment. The simplicity of the system extends to the investigator an unprecedented ability to monitor and control a viral infection process.

The natural history of the major feline viral diseases

ABSTRACTThis paper discusses factors that are important in the natural history of five major feline viral diseases, namely, feline panleucopenia, feline viral rhinotracheitis, feline caliciviral disease, feline leukaemia virus infection, and feline infectious peritonitis. Each disease is considered in terms of the properties and infectivity of the infecting agent, the sources of infectious virus, the mode of transmission of the disease, and the methods by which the agent persists in the cat population. Finally, each disease is discussed in terms of immunity and the role of vaccination. All these factors affect the balance of the virus‐host relationship and are thus directly relevant to the epizootiology of these diseases and their control.

Vaccinia infection of the nervous system in animals with normal and altered immune reaction.

The outcome of viral infection appears to be the result of a complex interplay of both viral and host factors. The virus-host cell relationship as well as the host's immune response are the major factors determining the type of infection and the expression of the disease. Demyelination disease appears to be rare complication of a systemic viral infection. The mayor factor in its expression is an altered response to the virus favoring the establishment of a noncytocidal abortive infection of the glial cells, which in turn induce a complex of potentially pathogenic immune mechanisms.

Modulation by cell trypsinization of Sendai virus expression in African green monkey kidney cells: first infection and establishment of a carrier state.

Two African green monkey kidney (AGMK) cell lines, 37RC (interferon-producing) and Vero (non-interferon-producing), were infected by egg-grown Sendai virus passaged in eggs at high and low m.o.i. The appearance of haem-adsorption, and cytopathic effect (c.p.e.) as well as the presence of haemagglutinating virions in the supernates were much more pronounced with a virus seed obtained with 10(-3) diluted passages than with a seed obtained with undiluted inoculum. They were also independent of interferon production (data obtained in 37RC and Vero cells were almost superimposable). In studies carried out with the virus seed prepared at high dilution the establishment of infection was maximal when monolayers were infected as soon as 5 h after trypsinization and cell seeding, regardless of cell density. Virus in supernates obtained from cultures infected 5, 20 or 50 h after seeding exhibited a greatly reduced infectivity for monkey cells, but not apparently for chick embryos. Trypsin treatment of the virus supernates restored their infectivity for AGMK cells more efficiently for virus released from cells infected 5 h after seeding than for virus released from cells infected later after seeding. In keeping with these observations, virus in supernates from cultures infected 5, 20 or 50 h after seeding contained increasing amounts of auto-interfering virions. The decreased infectivity obtained in cell supernates was not accounted for by major differences in virus RNA synthesis. Similarly, the optimum infection established in cells seeded only for 5 h was not due to increased virus adsorption. Several lines of cells surviving first infection with egg-grown Sendai virus have been obtained and kept in cultures for 3 to 18 months. Virus release and c.p.e. apparently become reduced in the cells surviving the first infection until the newly repopulated monolayers must undergo trypsinization. Weekly protease treatments of the cells reactivate all parameters of virus infection which again will tend to disappear slowly and then reappear following each trypsinization ('intermittent' carrier state). The establishment and the 'intermittent' reactivation of these lines were not prevented by the inclusion in the medium of anti-Sendai virus serum. Temperature-sensitive ts functions do not seem to play an important role in this virus-host relationship.

Changes in the virus-host cell relationship in a stable non-virogenic cell line persistently infected with measles virus (BGM/MV).

A non-virogenic African green monkey kidney cell line BGM/MV persistently infected with a neurotropic mouse brain-adapted strain of measles virus, was found to have undergone significant changes in the virus-host cell relationship between passages 35 and 119. Rather than the stable non-cytopathic relationship previously reported in which approximately 100% of the cells contained measles antigens and less than 1% of the cells expressed cell surface measles antigen, we observed cyclic manifestations of c.p.e. together with changes in the percentage of cells expressing intracellular and cell surface measles antigens. Treatment of BGM/MV cells with actinomycin D effected an increase in the percentage of cells expressing cell surface virus haemagglutinin (HA) at times when the percentage of cells with surface HA was less than the percentage of cells with intracellular measles antigens. Superinfection studies employing measles virus and vesicular stomatitis virus revealed a consonant cyclic refractivity and essentially no refractivity, respectively. Endogenous, infectious measles virus was not detected nor was interferon. It was concluded that a host cell factor other than interferon was modulating the cyclic expression of the measles virus infection.

Characterization of infection and replication of Mason-Pfizer monkey virus in human cell cultures.

Human cells derived from both normal and neoplastic tissues can be infected by Mason-Pfizer monkey virus (MPMV) without accompanying cytopathology. Infection of cell cultures such as human rhabdomyosarcoma (A204) results in a persistenly infected cell line which can be subcultured over 30 sequential culture passages without significant change in phenotype properties according to reverse, transcriptase (RT), MPMV p27 antigen content, virus particle count and infectivity titre. Productive virus infections were established at relatively low virus particle (VP) input multiplicities (p.i.m.; about 0.06 VP/cell) In A204 cell cultures. At higher p.i.m. (about 600 to 6000 VP/cell) newly synthesized virus was detected within 4 days post infection. Although virus production was cumulative following primary infection, after subculture of infected cultures MPVM production was greater during active cell division. Using synchronization techniques, MPMV replication in persistently infected cultures was found to be cell cycle-dependent. The major internal antigen, p27, was synthesized in G2 and newly synthesized virus particles were released predominantly during mitosis and early G1. Colcemid arrest of cells during mitosis inhibited subsequent MPMV release. Consequently, production of extracellular virus depends upon the progression of cells through the mitotic stage. These data, which provided a basic understanding of the virus-host relationship that occurs in primate cells productively infected with MPMV, were used as a guideline for isolating MPMV-like viruses from experimentally and naturally infected Rhesus monkey.

Scrapie in the sheep and laboratory animals: Suitability of the sheep model for the study of slow virus diseases

After briefly summarizing the information available on sheep scrapie, the authors explain the value of using the sheep in the study of ‘slow virus’ diseases, since it is particularly prone to diseases of this type. It may be affected not only by scrapie but also by other similar diseases such as visna, maedi and jaagsiekte. These disorders may therefore be used as models to which the most recent pathogenic concepts can be applied. A study of them will lead to a better understanding of the virus-host relationship in the pathology of infection.

Demyelinating encephalomyelitis induced by a long-term corona virus infection in rats

SummaryAbout 30% of weanling rats inoculated with JHM virus developed a subacute demyelinating encephalomyelitis (SDE) 3 weeks after inoculation (a.i.). From the remaining animals, 5% displayed overt neurological signs 3,6, and 8 months a.i. Animals with and without clinical signs 6–8 months a.i. were morphologically examined.Fresh demyelinating lesions could be demonstrated in paralyzed animals. Viral antigen was demonstrated and infectious JHM virus could be recovered from one animal which developed clinical signs at 3 months a.i. In one animal with clinical onset of 8 months a.i., completely remyelinated areas as well as recent demyelinating lesions were observed, suggesting a recurrence of the disease process. Remyelinated areas were also found in 40% of clinically silent animals. The morphology of the late onset of the demyelination was similar to that occurring in SDE. Remyelination consisted of both CNS and PNS-type. This animal model offers the possibility to investigate the virus-host relationship which is responsible for the induction of a demyelinating process after a long incubation period.

Ultrastructural Study of Avian Synovium Infected with an Arthrotropic Reovirus

Three-week-old chicks were inoculated via the foot pad with the avian reovirus (strain WVU 2937) that has been proved to be the causative agent in avian viral arthritis. The initial stages of the avian reovirus infection in the synovium of the hock joint were studied by transmission electron microscopy to shed light on the early virus-host relationship of an arthrotropic virus and synovial tissue. At 48 hours postinoculation (PI), coated, partially coated, and uncoated virus particles were seen in a dense lysosome-like inclusion in the cytoplasm of subsynovial fibroblasts. Virus replication was demonstrated in fibroblasts of the subsynovium 4 days PI. Infiltration of leukocytes into the area of the virus replication was noted at the time of virus replication (4 days PI). By the second week of the infection (11 days PI), the subsynovium was heavily infiltrated with lymphocytes and plasma cells, and proliferative changes had occurred in the synovial lining cells.

Effect of Immune Manipulation on Natural Immune Responses to Murine Mammary Tumor Antigens2

The virus-host relationship in BALB/cfC3H virgin female mice neonatally infected with an oncogenic virus (mammary tumor virus) (MuMTV) was significantly altered by a brief immunosuppressive treatment during young adult life. Natural immune responses were augmented and changed. The ability of lymphoid cells to attack target cells expressing MuMTV-associated antigens was significantly increased, and a new component, a non-T-cell reactivity, was added to the T-cell reactivity found in normal females. Serum blocking factors were both quantitatively and qualitatively altered.

Studies of the epstein-barr virus-host relationship: Autochthonous and allogeneic lymphocyte stimulation by lymphoblast cell lines in mixed cell culture

The capacity of 21 established human lymphoblast cell lines to stimulate DNA synthesis in peripheral blood leukocyte populations of autochthonous or allogeneic origin was compared in one-way mixed lymphocyte cultures. Strong stimulation in the autochthonous combination was found in 20 out of 21 pairs, and weak but significant stimulation was observed in the exceptional pair. Allogeneic pairs gave additional increments of stimulation over that of the autochthonous pair in 21 out of 31 pairs tested. The observed stimulation was shown not to be due to a secreted blastogenic agent. The data support but do not prove that EBV-related antigens are responsible for the observed stimulation. This implies the existence of an EBV-immune cell population recognizing specific antigens in the target cell membrane.

A persistent and inapparent infection of L cells with the virus of lymphocytic choriomeningitis.

Summary L cells infected with the virus of lymphocytic choriomeningitis, strain armstrong, produced infectious progeny; this was unaccompanied by visible signs of cell damage. Serial cultivation of infected cells in a medium free of antibodies was easily accomplished. Initially, retardation of cell multiplication and of first subculture cytopathic effects were observed. Later, a state of equilibrium was attained in which the cells multiplied at a normal rate, while continually producing and releasing virus. Although almost every cell of these carrier cultures could be shown by immunofluorescence to be infected, morphologically and functionally pathological alterations were not found. After prolonged cultivation the carried virus was found to be incomplete; its ability to spread from cell to cell was greatly reduced; its ability to kill mice was abolished. These losses were not regained by passages in various hosts. Otherwise the carried virus resembled the original armstrong virus in conferring solid immunity to mice, reacting specifically with antibodies and sedimenting in the ultracentrifuge like lymphocytic choriomeningitis virus. To characterize more fully the virus-host relationship, the following facts have been established. No antigens, alien for L cells, were found on the cell surface. Most clones from single cells carried lymphocytic choriomeningitis-specific antigen in every cell. A few clones were evidently completely free of the virus. Some cultures derived from single cells consisted of a mixed population of infected and antigen-free cells. Homologous interference was absolute; heterologous interference against vesicular stomatitis, encephalomyocarditis and vaccinia viruses could not be demonstrated. Treatment of L (Arm) cultures with lymphocytic choriomeningitis-neutralizing antibodies slowly decreased the proportion of antigen-containing cells. This ‘cure’ was real, and, furthermore, not caused by the inhibition of multiplication of L (Arm) cells reacting with antibodies. This observation indicated that the persistent infection of L cells with the lymphocytic choriomeningitis virus, strain armstrong, was not only maintained by a vertical transfer of virus from parent to daughter cells but that horizontal spread played a role.

Interferon and host resistance to Rauscher virus-induced leukemia.

A random bred strain of mice (CD-1) was shown to develop resistance to Rauscher leukemia virus (RLV) as the animals matured. Resistant adult mice developed relatively high-serum levels of interferon (150 to 2,000 units per ml) in contrast to susceptible 21-day-old animals in which interferon levels were undetectable or low (less than 20 to 200 units per ml). A similar correlation between resistance and interferon levels was observed in comparisons between resistant CD-1 and susceptible BALB/c mice. The F(1) hybrids of CD-1 x BALB/c and BALB/c x CD-1 matings manifested an intermediate degree of susceptibility and interferon production. The difference in interferon production by CD-1 and BALB/c mice was specific for the RLV-host interaction, since both strains produced equal serum levels of interferon in response to Sindbis and Newcastle disease viruses. The mortality of CD-1 suckling mice infected with Rauscher leukemia virus was decreased by treatment with interferon. These data demonstrate an association between interferon production by the host and the observed relative resistance of the CD-1 strain of adult mice to the subsequent malignant transformation. This virus-host relationship provides an excellent model for further study of factors affecting the development of virus-induced leukemia.

Multiplication of Plant Viruses in Insect Vectors

Virus diseases of plants are, for the most part, arthropod-borne. The word vector is commonly used to indicate the invertebrate transmitter necessary for the successful passage of certain disease agents from the infected to the noninfected host. Most vectors of plant viruses are insects of the families aphididae (aphids), cicadellidae (leafhoppers), and aleyrodidae (white flies). Only a few viruses are transmitted by the insects of other families, like the coccidae (mealybugs) and the thysanoptera (thrips). Transmission of the plant viruses by acarina (mites), arthropods other than insects, was recently established. In order to ascertain that an arthropod is a vector of a given plant virus in nature, the infection must be reproducible experimentally by the use of the arthropod under controlled conditions through feeding it on susceptible plants with adequate uninfected controls. In practice, this test alone is generally considered sufficient for the establishment of a virus–vector relationship. Animal virologists usually require additional criteria, such as a close association of the arthropod with the infected host, regular visits to the healthy host under conditions suitable for the transfer of the virus and the presence of the virus in the arthropod host. In the transmission of plant viruses, two major types of virus–host relationship are usually recognized. Vectors of one type may acquire a virus in short feeding periods and transmit it almost immediately. Vectors of the second type may also acquire virus by feeding for short periods on infected plants, although generally longer acquisition feeding is required. This chapter focuses on the multiplication of these viruses in cicadellid leafhoppers.

Quantitative studies of the virus-host relationship in chimpanzees after inapparent infection with Coxsackie viruses. I. The virus carrier state and the development of neutralizing antibodies.

Following oral administration of Coxsackie viruses (C viruses) to susceptible chimpanzees, these agents can be isolated from the throat for a period of approximately a week, from the blood for a few days, and from the stools for 2 to 3 weeks or even longer. Animals so infected respond with the formation of specific neutralizing antibodies which are maintained for at least 1 to 2 years. Such chimpanzees are immune when challenged orally with homologous strains of virus. They then excrete virus in the stools for 3 or 4 days (passive transfer); no virus can be recovered from the throats and blood of these animals, and neutralizing antibody levels remain unchanged. Animals immune to one antigenic type of C virus can be infected by feeding a different antigenic type. Following such a heterotypic challenge, virus can again be isolated from the throat, blood, and stools; neutralizing antibodies develop to the new strain. Antibodies to the Texas-1 type of C virus were already present in four chimpanzees upon their arrival in the laboratory from Africa. It was possible to set up intestinal carriage of the Texas-1 virus in these animals and to demonstrate a 10- to 100-fold increase in titer of neutralizing, as well as complement-fixing, antibody. Quantitative titrations of the amount of virus present in the stools and throat were performed. Immediately after the first feeding of virus relatively large amounts can be detected in the stools; the titer drops, but may be maintained for as long as 25 days at 10(-2) to 10(-3), furnishing evidence that virus multiplication has taken place. Virus in the throat reached the same order of magnitude at first as in the stools but there was a rapid decline to zero in a few days. The Ohio-1 virus differed from the others in that it persisted in the throat as long as in the stools, and in several instances reached a higher titer in the throat. Following homotypic challenge with all types, virus could be detected in the stools for only a relatively short period of time and at low concentration. Virus-neutralizing substances could not be detected in the stools or throat swabs of convalescent animals, at a time when their serum-neutralizing antibody titers were high. Under the limited conditions of the present experiments, C viruses had no effect on the infection of chimpanzees with three different antigenic types of poliomyelitis virus. Both poliomyelitis and C viruses set up independent infections without apparent interaction between them. No enhancement of the poliomyelitis infection took place, as was plain from the fact that none of the infected chimpanzees became paralyzed. a titration of Texas-1 C virus in four chimpanzees revealed that a suspension of infected tissue diluted to 10(6.0) could cause the development of the carrier state; accidental infection of control animals with other Coxsackie types indicated also that very little virus may be necessary to initiate infection. Seven distinct antigenic types of C virus were inoculated subcutaneously and intramuscularly at the same time into four chimpanzees. The response was the same as that following feeding; virus could be recovered from the throat, blood, and stools, and the animals developed neutralizing antibodies to all seven types of C virus. There was no detectable interference among the viruses. Cortisone did not bring about the reappearance of the virus excretion in chimpanzees previously infected and shown to be intestinal carriers of poliomyelitis and Coxsackie viruses.