Showing papers on "Viral pathogenesis published in 1996"

Host factors and the pathogenesis of HIV-induced disease

Abstract: The level of human immunodeficiency virus (HIV) replication in patients reflects a balance between stimulatory and inhibitory host factors (particularly endogenous cytokines). New information concerning the cellular co-receptors for HIV and the cellular tropism of different strains of virus will advance our understanding of HIV-induced pathogenesis and suggests new therapeutic and preventive strategies.

ONE STEP AHEAD OF THE GAME: Viral Immunomodulatory Molecules

Abstract: For decades cell biologists have relied on viruses to facilitate the study of complex cellular function. More recently, the tragedy of the AIDS epidemic has focused considerable human and financial resources on both virology and immunology, resulting in the generation of new information relating these disciplines. As the miracle of the mammalian immune system unfolds in the laboratory, the elegance of the mechanisms used by co-evolving viruses to circumvent detection and destruction by the host becomes inescapably obvious. Although many observations of virus-induced phenomena that likely contribute to the virus's escape of immune surveillance are still empirical, many other such phenomena have now been defined at the molecular level and confirmed in in vivo models. Immune modulators encoded within viral genomes include proteins that regulate antigen presentation, function as cytokines or cytokine antagonists, inhibit apoptosis, and interrupt the complement cascade. The identification of such gene products...

In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression.

Abstract: Human papillomavirus (HPV) types 16, 18, 31, and 51 are the etiologic agents of many anogenital cancers including those of the cervix. These "high risk" HPVs specifically target genital squamous epithelia, and their lytic life cycle is closely linked to epithelial differentiation. We have developed a genetic assay for HPV functions during pathogenesis using recircularized cloned HPV 31 genomes that were transfected together with a drug resistance marker into monolayer cultures of normal human foreskin keratinocytes, the natural host cell. After drug selection, cell lines were isolated that stably maintained HPV 31 DNA as episomes and underwent terminal differentiation when grown in organotypic raft cultures. In differentiated rafts, the expression of late viral genes, amplification of viral DNA, and production of viral particles were detected in suprabasal cells. This demonstrated the ability to synthesize HPV 31 virions from transfected DNA templates and allowed an examination of HPV functions during the vegetative viral life cycle. We then used this system to investigate whether an episomal genome was required for the induction of late viral gene expression. When an HPV 31 genome (31E1*) containing a missense mutation in the E1 open reading frame was transfected into normal human keratinocytes, the mutant viral sequences were found to integrate into the host cell chromosomal DNA with both early and late regions intact. While high levels of early viral gene transcription were observed, no late gene expression was detected in rafts of cell lines containing the mutant viral genome despite evidence of terminal differentiation. Therefore, the induction of late viral gene expression required that the viral genomes be maintained as extrachromosomal elements, and terminal differentiation alone was not sufficient. These studies provide the basis for a detailed examination of HPV functions during viral pathogenesis.

Bc1-2 protects mice against fatal alphavirus encephalitis.

Abstract: Virus-induced apoptosis has been well characterized in vitro, but the role of apoptosis in viral pathogenesis is not well understood. The suicide of a cell in response to viral infection is postulated to be an important host defense for the organism, leading to a reduction in its total viral burden. However, virus-induced death of nonregenerating cells in the central nervous system may be detrimental to the host. Therefore, to investigate the role of apoptosis in the pathogenesis of fatal encephalitis, we constructed a recombinant alphavirus chimera that expresses the antiapoptotic gene, bcl-2, in virally infected neural cells. Infection of neonatal mice with the alphavirus chimera expressing human bcl-2 [Sindbis virus (SIN)/bcl-2] resulted in a significantly lower mortality rate (7.5%) as compared with infection with control chimeric viruses containing a chloramphenicol acetyltransferase (CAT) reporter gene (SIN/CAT) (78.1%) or bcl-2 containing a premature stop codon (SIN/bcl-2stop) (72.1%) (P < 0.001). Viral titers were reduced 5-fold 1 day after infection and 10-fold 6 days after infection in the brains of SIN/bcl-2-infected mice as compared to SIN/CAT or SIN/bcl-2stop-infected mice. In situ end labeling to detect apoptotic nuclei demonstrated a reduction in the number of foci of apoptotic cells in the brains of mice infected with SIN/bcl-2 as compared with SIN/bcl-2stop. The reduction in apoptosis was associated with a reduction in the number of foci of cells expressing alphavirus RNA. Thus, the antiapoptotic gene, bcl-2, suppresses viral replication and protects against a lethal viral disease, suggesting an interaction between cellular genetic control of viral replication and cell death.

Decreased Susceptibility to Viral Disease of [beta]-1,3-Glucanase-Deficient Plants Generated by Antisense Transformation.

Abstract: Antifungal class I [beta]-1,3-glucanases are believed to be part of the constitutive and induced defenses of plants against fungal infection. Unexpectedly, mutants deficient in these enzymes generated by antisense transformation showed markedly reduced lesion size, lesion number, and virus yield in the local-lesion response of Havana 425 tobacco to tobacco mosaic virus (TMV) and of Nicotiana sylvestris to tobacco necrosis virus. These mutants also showed decreased severity of mosaic disease symptoms, delayed spread of symptoms, and reduced yield of virus in the susceptible response of N. sylvestris to TMV. The symptoms of disease in the responses of both plant species were positively correlated with [beta]-1,3-glucanase content in a series of independent transformants. Taken together, these results provide direct evidence that [beta]-1,3-glucanases function in viral pathogenesis. Callose, a substrate for [beta]-1,3-glucanase, acts as a physical barrier to the spread of virus. Callose deposition in and surrounding TMV-induced lesions was increased in the [beta]-1,3-glucanase-deficient, local-lesion Havana 425 host, suggesting as a working hypothesis that decreased susceptibility to virus resulted from increased deposition of callose in response to infection. Our results suggest novel means, based on antisense transformation with host genes, for protecting plants against viral infection. These observations also raise the intriguing possibility that viruses can use a defense response of the host against fungal infection[mdash]production of [beta]-1,3-glucanases[mdash]to promote their own replication and spread.

Analysis of hepatitis B virus genotypes and pre-core region variability during interferon treatment of HBe antigen negative chronic hepatitis B

Abstract: The clinical importance of hepatitis B virus (HBV) genome variability has been reported recently. One example is the occurrence of hepatitis B virus pre-core mutants, which arise during spontaneous or interferon-induced seroconversion from HBeAg to anti-HBe and are thought to be selected by immune pressure. A survey of HBV pre-core mutants and viral genotypes in 35 HBeAg negative patients during interferon therapy was carried out to understand viral pathogenesis in this form of chronic hepatitis B. Seventeen patients responded to interferon therapy as assessed by the sustained normalization of serum ALT levels and the significant decrease of viremia levels. The response rate to interferon was independent of both initial serum viral DNA level and interferon doses. During interferon therapy, a significant decrease of M0 (wild-type pre-core sequence at pos. 1887–1908), M1 (TGG to TAG at pos. 1896) or M2 (TGG to TAG at pos. 1896, and GGC to GAC at pos. 1899) positive viral genomes was found in 48%, 42%, and 33% of patients, respectively. A higher response rate to interferon therapy was observed in patients infected with HBV genotype A (70%) or M0 positive strains (75%) as compared to patients infected with genotype D/E (40%) or M1/M2 positive strains (44%). The data support the hypothesis that pre-core defective HBV represent viral mutants with an increased capacity to resist exogenous alpha interferon. These findings emphasize that characterization of HBV genome variability prior to interferon therapy may help to predict antiviral response in HBeAg negative patients. © 1996 Wiley-Liss, Inc.

The Regulation of Human Immunodeficiency Virus Type-1 Gene Expression

Abstract: Despite 15 years of intensive research we still do not have an effective treatment for AIDS, the disease caused by human immunodeficiency virus (HIV). Recent research is, however, revealing some of the secrets of the replication cycle of this complex retrovirus, and this may lead to the development of novel antiviral compounds. In particular the virus uses strategies for gene expression that seem to be unique in the eukaryotic world. These involve the use of virally encoded regulatory proteins that mediate their effects through interactions with specific viral target sequences present in the messenger RNA rather than in the proviral DNA. If there are no cellular counterparts of these RNA-dependent gene-regulation pathways then they offer excellent targets for the development of antiviral compounds. The viral promoter is also subject to complex regulation by combinations of cellular factors that may be functional in different cell types and at different cell states. Selective interference of specific cellular factors may also provide a route to inhibiting viral replication without disrupting normal cellular functions. The aim of this review is to discuss the regulation of HIV-1 gene expression and, as far as it is possible, to relate the observations to viral pathogenesis. Some areas of research into the regulation of HIV-1 replication have generated controversy and rather than rehearsing this controversy we have imposed our own bias on the field. To redress the balance and to give a broader view of HIV-1 replication and pathogenesis we refer you to a number of excellent reviews [Cullen, B. R. (1992) Microbiol. Rev. 56, 375–394; Levy, J. A. (1993) Microbiol. Rev. 57, 183–394; Antoni, B. A., Stein, S. & Rabson, A. B. (1994) Adv. Virus Res. 43, 53–145; Rosen, C. A. & Fenyoe, E. M. (1995) AIDS (Phila.) 9, S1–S3].

Decreased Susceptibility to Viral Disease of b-1,3-Glucanase-Deficient Plants Generated by Antisense Transformation

Abstract: Antifungal class I P-1,3-glucanases are believed to be part of the constitutive and induced defenses of plants against fungal infection. Unexpectedly, mutants deficient in these enzymes generated by antisense transformation showed markedly reduced lesion size, lesion number, and virus yield in the local-lesion response of Havana 425 tobacco to tobacco mosaic virus (TMV) and of Nicotiane sylvestris to tobacco necrosis virus. These mutants also showed decreased severity of mosaic disease symptoms, delayed spread of symptoms, and reduced yield of virus in the susceptible response of N. sylvestris to TMV, The symptoms of disease in the responses of both plant species were positively correlated with p-l,3glucanase content in a series of independent transformants. Taken together, these results provide direct evidence that ~-1,3-glucanases function in viral pathogenesis. Callose, a substrate for &l,&glucanase, acts as a physical barrier to the spread of virus. Callose deposition in and surrounding TMV-induced lesions was increased in the p-l,3-glucanase-deficient, local-lesion Havana 425 host, suggesting as a working hypothesis that decreased susceptibility to virus resulted from increased deposition of callose in response to infection. Our results suggest nove1 means, based on antisense transformation with host genes, for protecting plants against viral infection. These observations also raise the intriguing possibility that viruses can use a defense response of the host against fungal infection-production of ~1,3-glucanases-to promote their own replication and spread.

Iron withholding: a defense against viral infections.

Abstract: A variety of laboratory and clinical investigations during the past 15 years have observed that one of the dangers of excessive iron is its ability to favor animal viral infections. The metal is essential for host cell synthesis of virions and can also impair defense cell function and increase oxidative stress. In both animal models and humans, viral infections cause upregulation of the iron withholding defense system. Factors that suppress the system enhance viral progression; factors that strengthen the system augment host defense. Procedures designed to reinforce the system are being developed and tested; some of these may become useful adjuncts in prevention and management of viral diseases.

Anatomy of viral persistence : Mechanisms of persistence and associated disease

Abstract: Publisher Summary The knowledge that viruses can persist is as important finding in virology. Indeed, the puzzle for a virus to solve is how to live within a host over the lifetime of the host. Viruses that persist in a host are ultimately successful by virtue of their abilities to (1) survive within cells that provide their sustenance, and (2) avoid recognition by the host immune system. Viruses that persist must remain within a cell for a prolonged time without disturbing the transcription or translation of genes necessary for survival of the infected cell or altering lysosomal or plasma membranes. It is reported that a number of current diseases affecting differentiated systems such as the nervous, endocrine, immune, and cardioskeletal muscle systems as yet of unknown etiology may likely be caused by infectious agents such as viruses, which have evolved to persist and replicate in differentiated cells without causing lysis of the cell they infect. With the availability of highly sensitive molecular techniques to identify limited amounts of materials, this hypothesis can be adequately tested in the coming decades. From the evidence that is evolving, the study of such persistent viruses may dominate virology in the 21st century.

Virus-Induced Immunopathology

Abstract: Publisher Summary Several viruses cause damage to the tissue by immunopathological mechanisms This chapter presents the principal examples of immunopathogenesis caused by the viruses, accompanied by speculations about its management The most common mechanism of lesion development in virus induced immunopathology involves T cells Usually, it seems that when CD8 + T cells act as the controlling cell type, lesions are acute and the outcome is decided quickly The classic example is provided by LCM in mice The newest candidate may turn out to be SNV infection in humans Lesions orchestrated primarily by CD4 + T cells can be either acute or long-lasting Curiously, in the LCMV example, if CD8 + T cells are removed from the scene, immunopathological responses may still occur and these involve CD4 + T cells Such responses are far more chronic and of lower grade than those mediated by CD8 + T lymphocytes One possible sequel to chronic inflammatory responses to viruses is that autoreactive inflammatory reactions are initiated and an autoimmune disease occurs The adage that an ounce of prevention is worth a pound of cure is certainly true in the field of viral pathogenesis Preventing viral infection or manipulating immune processes during the initial phases of infection is far more successful than attempting to counteract pathological events once underway

Soluble interferon-γ receptors encoded by poxviruses

Abstract: Poxviruses encode a broad range of proteins that counteract the formidable attack of the immune response initiated in the host after infection, among which are proteins that mimic the extracellular binding domain of host cytokine receptors and are secreted from virus-infected cells. A soluble interferon-gamma receptor (IFN-gamma R) is produced early after infection and efficiently blocks the binding of IFN-gamma to cellular receptors, thus inhibiting both the anti-viral and immune functions of IFN-gamma. An IFN-gamma R is highly conserved among members of the poxvirus family, suggesting a major role in viral pathogenesis. The highly species-specific nature of the IFN system enables questions concerning the evolutionary relationship between poxviruses and their hosts to be addressed. The IFN-gamma R encoded by myxoma virus, a natural pathogen of rabbits, is specific for rabbit IFN-gamma. However, the IFN-gamma R encoded by orthopoxviruses (vaccinia, cowpox, camelpox, ectromelia) shows a novel, broad species specificity suggesting that these viruses have evolved in several species. The implications for the unknown origin and natural host(s) of vaccinia virus are discussed.

The role of nutrition in viral disease

Abstract: Malnutrition has been associated with a decrease in immune function. Impairment of immune function may lead to increased susceptibility to infection with viruses. Although there are many studies documenting the effect of host nutritional status on immune functions, fewer studies have examined the effect of host nutritional status on viral pathogenesis. This review examines the relationship between viral infection and the nutritional status of the host, and documents that not only can the nutritional status of the host affect immune function, but can have profound effects on the virus itself. One mechanism by which nutritional status affects the virulence of the viral pathogen involves selection for virulent viral genotypes. Other mechanisms remain to be elucidated.

Molecular basis of immune evasion strategies by adenoviruses.

Abstract: Human adenoviruses have provided valuable insights into virus-host interactions at the clinical and experimental levels. In addition to the medical importance of adenoviruses in acute infections and the ability of the virus to persist in the host, adenovirus-based recombinants are being developed as potential vaccine vectors. It is now clear that adenoviruses employ various strategies to modulate the innate and the adaptive host immune defences. Adenovirus genome-coded products that interact with the immune response of the host have been identified, and to a large extent the molecular mechanisms of their functions have been revealed. Such knowledge will no doubt influence our approach to the areas of viral pathogenesis, vaccine development and immune modulation for disease management.

Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and multiple sclerosis.

Abstract: Transgenic technology has been used by virologists for two main purposes. One has been to evaluate cell-specific expression and function in vivo of specific viral proteins. Of the many such studies performed, one prominent example is the work of Levine and colleagues (MARKS et al. 1989) on the expression of SV40 T antigen that resulted in choroid plexus papillomas; these experiments led to identification of p53 bound to T antigen. As another example, Nerenberg et al. (1987) used transgenic expression of the TAT protein of HTLV-1 to establish the oncogenic potential of TAT. Lastly, Nelson and colleagues (unpublished data) probed expression of the immediate early 72 KDa protein of human cytomegalo- virus and located this early regulatory protein in the islets of Langerhans, smooth muscle wall of large arteries, retina and salivary gland. All of these studies were similar in that the authentic promoter of the particular viral gene being expressed was employed. The second major avenue followed by virologists utilizing transgenic technology has been to create animal models of viral pathogenesis. Examples of this application are described in separate chapters of this volume and include, first, the isolation and expression of the gene encoding the human poliovirus receptor in mice by Ren and Racaniello (1992), REN ET AL. (1990), and independently by Horie et al. (1994) and KOIKE et al. (1991), allowing study of the virus’ tropism, pathogenesis of the disease it causes, and design of new protective vaccines. Second, CHISARI et al. (1987,1989) utilized the albumin promoter to express hepatitis B virus surface antigen in the liver to study virus-induced chronic liver disease, hepatocellular carcinoma, and the role of the immune system in either clearing virus of causing immunopathology. The third example is that of TOGGAS et al. (1994) who used an astrocyte-specific promoter to express HIV-1 gp120 in transgenic mice. The brain lesions of these mice closely mimic those of AIDS neuropathology in humans including neuronal injury, microglia activation and gliosis.

Effect of E2 envelope glycoprotein cytoplasmic domain mutations on Sindbis virus pathogenesis.

Abstract: The cytoplasmic domain of the E2 envelope glycoprotein is important in Sindbis virus assembly, but little is known about its role in the pathogenesis of Sindbis virus encephalitis. To investigate its role in viral pathogenesis, we constructed six recombinant viruses containing site mutations in the E2 cytoplasmic domain, using the neurovirulent background strain, TE12. Our findings demonstrate that the E2 cytoplasmic domain is a determinant of Sindbis virus growth and neurovirulence in suckling mice as well as persistent infection in weanling scid mice. They also suggest that the tyrosine, serine, or threonine residues are not essential for replication in mouse brain or anti-E2 monoclonal antibody-mediated restriction of Sindbis virus replication.

Virus‐induced autoimmune disease: transgenic approach to mimic insulin‐dependent diabetes mellitus and other autoimmune diseases:

Abstract: The technology of cloning viral genes and expressing them in vivo under cell-specific promoters allows to dissect the role of viruses, host self proteins, host genetics and immune responses in the complex etiology of autoimmune disease. Expression of a viral transgene, that is really a marker for a host "self" protein per se in beta cells of the islets of Langerhans, need not cause disease. In our model, expression of a viral gene was not associated with disease over the lifetime of the animal. However, when the host becomes infected with a virus encoding the same gene as the transgene or one closely related to it, a resultant immune response directed against the virus also recognizes the transgene leading to progressive T-cell-mediated response and destruction of the tissue expressing the viral ("self") gene, leading to autoimmune disease. This multifactorial process is influenced by whether the viral transgene is expressed in the thymus as well as in the disease-related cell or target tissue. Thymic expression influences negative selection of responder lymphocytes and thus delays the onset of the autoimmune disorder. Further, the MHC haplotype or other background genes of an individual undergoing autoimmune dysfunction play a role in the affinity of binding of the transgene products to the MHC molecule and influence the degree of negative selection that occurs, thereby influencing the vigor of the resulting immune response. The current ability to express host or viral genes in unique cell populations, and to make double- or triple-tg mice in which various cytokine genes or lymphocyte activation genes can be expressed along with the viral gene, offers a unique possibility for molecular dissection of autoimmunity. With the information on hand, approaches to the prevention and treatment of human autoimmune disease are likely to be uncovered. Finally, animal models are available in which the onset, progression and control of molecular mimicry can be evaluated. Future studies should define roles played by cytokines, bystander and immune-specific cross-reactivity to viruses and other microbes in several autoimmune diseases.

Effect of HIV type 1 Tat protein on butyric acid-induced differentiation in a hematopoietic progenitor cell line.

Abstract: The trans-activator protein (Tat) of HIV-1 plays an important role in viral pathogenesis. Since Tat has been shown to alter expression of a number of host cellular genes, we have investiga...