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PubMed2005

Immunomodulatory effects of HSV-2 infection on immature macaque dendritic cells modify innate and adaptive responses.

Herpes simplex viruses (HSV) infect human and murine dendritic cells (DCs) and interfere with their immunostimulatory functions in culture. HSV-2 infection increases human immunodeficiency virus (HIV) spread in patients, and DCs also promote HIV infection. We have studied these topics in rhesus macaque monocyte-derived DCs (moDCs) to set the stage for future studies of these issues in animals. We provide the first evidence that macaque DCs become infected by HSV-2. Structural viral proteins (ICP5 [infected cell protein 5], glycoprotein D [gD], envelope) were detected in the cell periphery, and a functional protein (infected cell protein 8 [ICP8]) was predominantly found in the nucleus after infection. Infectious HSV-2 induced apoptotic death, decreased expression of HLA-DR, CD40, CD80, CD83, and CD86, and increased release of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha) (CCL3), and RANTES (regulated on activation normal T cells expressed and secreted) (CCL5) but not IL-12 or interferon-alpha (IFN-alpha) by macaque DCs. This coincided with HSV-2-infected DCs stimulating weak T-cell responses, including impaired SIV-specific responses. Comparable HSV-2 protein expression, DC apoptosis, as well as membrane immunophenotype and functional modifications were observed in HSV-2-exposed human moDCs. Such HSV-2-induced modifications of macaque and human DCs could augment DC-driven immunodeficiency virus infection. This work affords the basis for future macaque studies to explore how HSV-2 impacts the efficacy of strategies being developed to prevent HIV transmission.

Animals↗

PubMed2005

Kinetics and isotype profile of antibody responses in rhesus macaques induced following vaccination with HPV 6, 11, 16 and 18 L1-virus-like particles formulated with or without Merck aluminum adjuvant.

BACKGROUND: Human papillomaviruses (HPV) are the most common sexually transmitted viruses. Infection of the cervical epithelium by HPVs can lead to the development of cervical cancer. Recent advances in vaccine research have shown that immunization with papillomavirus-like particles (VLPs) containing the major structural viral protein, L1 from HPV 16 can provide protection from the establishment of a chronic HPV 16 infection and related cervical intraepithelial neoplasia (CIN) in baseline HPV 16 naive women. METHODS: To better understand the quantitative and qualitative effects of aluminum adjuvant on the immunogenic properties of an HPV 6, 11, 16 and 18L1 VLP vaccine, we used an HPV-specific, antibody isotyping assay and a competitive immunoassay that measures antibodies to neutralizing epitopes to profile sera from rhesus macaques immunized with the HPV L1 VLP vaccine formulated with or without aluminum adjuvant. RESULTS: Immunization with VLPs formulated with the aluminum adjuvant elicited a significantly stronger immune response with higher peak antibody titers both at four weeks post vaccination (12.7 to 41.9-fold higher) as well as in the persistent phase at week 52 (4.3 to 26.7-fold higher) than that of VLPs alone. Furthermore, the aluminum adjuvant formulated HPV VLP vaccine elicited a predominantly T helper type 2 response, with high levels of IgG1 and IgG4 and low levels of IgG2. The vaccine also elicited high levels of serum IgA, which may be important in providing mucosal immunity to impart protection in the anogenital tract. CONCLUSION: These results show that the HPV 6, 11, 16 and 18 L1-VLP vaccine formulated with Merck aluminum adjuvant elicits a robust and durable immune response and holds promise as a vaccine for preventing cervical cancer.

Journal Article↗

PubMed2004

RNA interference silencing the transcriptional message: aspects and applications.

RNA interference (RNAi) is silencing of gene expression by double-stranded RNA (dsRNA) having complementary sequence to the target gene to be silenced. This phenomenon has transformed into a complete technology for functional genomic studies. Small interfering RNAs (siRNAs) are 21- to 23-nucleotide dsRNAs, in which the sense strand is the same as the target mRNA and the antisense strand is the complement of the target mRNA sequence. These are the effector molecules for inducing RNAi, leading to posttranscriptional gene silencing with RNA-induced silencing complex. Besides siRNA, which can be chemically synthesized, various other systems in the form of potential effector molecules for posttranscriptional gene silencing are available, such as short hairpin RNAs (shRNAs), long dsRNAs, short temporal RNAs, and micro RNAs (miRNAs). These effector molecules either are processed into siRNA such as in the case of shRNA or directly aid gene silencing as in the case of miRNA. RNAi for various unknown genes may facilitate to elucidate inherited genetic diseases and provide drug candidates for viral and oncogenic diseases. This can be achieved by targeting mRNA from oncogenic genes or mRNA for viral cellular receptor and viral structural proteins for RNAi. In this article, we evaluate various aspects and applications of RNAi technology and provide comprehensive information for the system currently available for inducing RNAi.

Agriculture↗

PubMed1997

New developments in the treatment of viral respiratory tract infections.

Most respiratory tract infections are viral in origin, yet until recently only a few effective therapies had been developed. This reflected the large number of causative agents and the generally benign course of most infections. However, increasing numbers of serious respiratory infections have been seen in recent years, due to the rising prevalence of immunodeficient patients and the emergence of previously unrecognised pathogens. Better understanding of viral structure, and novel methods of drug design and discovery are leading to the development of potentially valuable new treatments, particularly for influenza and respiratory syncytial virus infection.

Journal Article↗

PubMed2000

Cell-free synthesis and affinity isolation of proteins on a nanomole scale.

The performance of conventional cell-free gene expression systems based on the Escherichia coli S30 extract can be significantly improved by using expression vectors that encode viral structural elements known to enhance translation in vivo and to protect mRNA from ribonuclease action. The expression vectors reported here are designed to produce a functionally active protein carrying the Strep-tag oligopeptide at its C-terminus. They can be used in translation, transcription-translation or replication-translation reactions. Depending on its type, the reaction yields up to 40 micrograms per mL, or about 1 nmol of a standard protein. The presence of Strep-tag allows the synthesized protein to be easily isolated on a streptavidin-agarose column under mild conditions and the entire procedure to be completed within one working day. The results show that standard low-cost, cell-free systems can serve for rapid preparation of purified proteins in amounts that can satisfy a number of needs of a research laboratory.

Amino Acid Sequence↗

PubMed2002

T-lymphocyte epitope identification and their use in vaccine development for HIV-1.

Cellular immune responses mediated by CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes (HTL) are needed to effectively control and clear many viral pathogens, including HIV-1. Thus, vaccines for HIV-1 capable of inducing CTL and HTL responses are now the focus of multiple academic and industry-based research and development programs. The use of defined, minimal CTL and HTL epitopes in vaccines has several potential advantages. Firstly, it is possible to use epitopes that are conserved thus targeting the majority of viral variants within a given clade or across clades. Secondly, epitopes from multiple viral structural or accessory gene products can be included in vaccines, which supports the induction cellular immune responses with significant breadth. Finally, dominance relationships between epitopes can be altered to increase immune recognition of subdominant epitopes. HTL and CTL epitopes from HIV-1 have recently been identified and characterized in numbers that are large enough to support their use in experimental vaccines. Initial studies with prototype DNA vaccines encoding epitopes indicate the need to include intracellular targeting sequences, to direct the encoded gene products to different cellular compartments, and amino acid spacer sequences between epitopes to optimize the processing, and subsequent presentation, of individual epitopes. Vaccines composed of CTL or HTL epitopes are now being developed for clinical testing.

AIDS Vaccines↗

PubMed1988

Clinical characteristics of papillomavirus-vulvovaginitis. A new entity with oncogenic potential.

The purpose of this paper is to describe the clinical characteristics of HPV-vulvovaginitis. Clinical symptoms were recorded in 74 women with the diagnosis of papillomavirus vulvovaginitis. The diagnosis was established by colposcopic examination, immunological detection of viral structural antigen, and selected biopsies. Patient data were obtained from medical records and by interviews. Discharge, itching, burning, fissures and dyspareunia were typical symptoms. Discharge was more frequent in women with vaginal localization of the HPV infection, whereas itching and burning were the predominant complaint when the HPV lesions were present on the vulva. However, 14 women were asymptomatic. Thirty-nine women had atypical Pap smears. In half of these women, there was no evidence of intra-epithelial neoplasia. In 15 women with atypical Pap smears there was no clinical affection of the cervix uteri. But manifestations of wart virus infection in the vagina and/or vulva. Papillomavirus vulvovaginitis may be a subclinical infection, but many women suffer from distinct symptoms related to the location of the specific lesions. This infection of the vulva and vagina may be the sole cause of atypical Pap smears. The clinical recognition of this condition is a necessary prerequisite for a rational therapeutic approach.

Adolescent↗

PubMed2004

TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses.

TLR signaling leads to dendritic cell (DC) maturation and immunity to diverse pathogens. The stimulation of TLRs by conserved viral structures is the only described mechanism leading to DC maturation after a virus infection. In this report, we demonstrate that mouse myeloid DCs mature normally after in vivo and in vitro infection with Sendai virus (SeV) in the absence of TLR3, 7, 8, or 9 signaling. DC maturation by SeV requires virus replication not necessary for TLR-mediated triggering. Moreover, DCs deficient in TLR signaling efficiently prime for Th1 immunity after infection with influenza or SeV, generating IFN-gamma-producing T cells, CTLs and antiviral Abs. We have previously demonstrated that SeV induces DC maturation independently of the presence of type I IFN, which has been reported to mature DCs in a TLR-independent manner. The data presented here provide evidence for the existence of a novel intracellular pathway independent of TLR-mediated signaling responsible for live virus triggering of DC maturation and demonstrate its critical role in the onset of antiviral immunity. The revelation of this pathway should stimulate invigorating research into the mechanism for virus-induced DC maturation and immunity.

Adaptor Proteins, Signal Transducing↗

PubMed1984

Yellow fever monoclonal antibodies: type-specific and cross-reactive determinants identified by immunofluorescence.

Monoclonal antibodies directed against the envelope glycoprotein and the NV3 non-structural viral protein of yellow fever (YF) were tested by the indirect fluorescent antibody technique against a variety of YF virus strains and heterologous flaviviruses. Monoclonal antibodies directed against the envelope glycoprotein exhibited YF strain-specificity, YF type-specificity, broad group cross-reactivity, or limited subgroup reactivity (YF + Banzi or YF + Koutango + Zika + Usutu + Uganda S). Monoclonal antibodies directed against NV3 reacted either with YF + Koutango or with YF + Banzi. These findings generally correlated with the results of biological tests reported previously. Monoclonal antibodies that were type-specific to YF will be useful for the rapid specific identification of YF virus isolates and are available from the Centers for Disease Control on request.

Animals↗

PubMed1999

Antiviral and hemolytic activities of surfactin isoforms and their methyl ester derivatives.

Inactivation of enveloped viruses (VSV, SFV, and SHV-1) by surfactin lipopeptides was dependent on the hydrophobicity, i.e. the number of carbon atoms of the fatty acid, and on the charge of the peptide moiety as well as on the virus species. Surfactins with fatty acid chains of 13 carbon atoms showed very low antiviral activity in comparison to C14 and C15 isoforms. C15 surfactin monomethyl ester also inactivated SFV which was resistant to the mixture of surfactin isoforms as produced by Bacillus subtilis. In contrast, the dimethyl ester showed no virus-inactivation capacity. Disintegration of viral structures as determined by electron microscopy after inactivation of VSV and SFV was comparable to the titer reduction. The effect of the surfactin isoforms and methyl esters on erythrocyte hemolysis correlated with the virus-inactivation capacity. Surfactins with a fatty acid chain moiety of 15 carbon atoms and one negative charge showed the highest antiviral activity.

Animals↗

PubMedDate not supplied

[Anatomoclinical study of 29 cases of acute necrotizing encephalitis. Demonstration of herpes virus in 24 cases].

The authors studied the cerebral lesions in 29 cases of acute necrotizing encephalitis. Electron microscopy showed the presence of typical herpes virus particles in 24 cases. In 16 of them the virus had been isolated from specimens of the brain taken by biopsy and in 8 other cases from autopsy specimens. In 3 acute cases the search for the virus was negative and it was not carried out in the two cases with prolonged evolution. Only 6 patients have survived. Some peculiar varieties have beeen observed, i.e. two adolescents had temporal and almost entirely unilateral lesions, and two aged females had severely hemorrhagic necrotic areas which could have been confounded with vascular lesions. In these two later cases typical particles were present. Finally, one case showed within the same nuclei at once typical herpes virus particles and other viral structures of vermicular form, the origin of which could not be precised.

Adolescent↗

PubMed2002

Animal models for development of therapeutic HPV16 vaccines (review).

In several types of human tumours a close association with oncogenic viruses has been established. Animal models mimicking these tumours with regard to their aetiology and expression of virus-related molecules have been developed. The rationale for development of the animal models was to create experimental systems allowing us to compare the efficacy of immunological and gene therapy protocols, with the final aim to optimize these therapeutic procedures prior to clinical trials. Anogenital carcinomas and particularly cervical carcinomas (CC) represent one of the aforementioned human oncogenic virus-associated tumour types. High-risk human papilloma viruses (HPV), particularly HPV16, 18, 31, 33, 45, and 56, are associated with nearly one hundred percent of CC. The only HPV proteins expressed in CC and representing the potential therapeutic targets are the non-structural viral gene products E6 and E7. The E6/E7 oncoproteins inactivate p53 and pRb tumour suppressor genes, they are required for maintenance of the malignant phenotype and their expression correlates with the transforming potential of HPV. Since the various HPV types do not cross-react with regard to the induction of both, humoral and cell-mediated immunity, the research of therapeutic vaccines is focused primarily on the HPV type 16, which is expressed in the majority, nearly 60%, of human squamous CC, and on the HPV16 E6/E7 oncogene products, which represent a target of choice for the therapeutic vaccination. The purpose of this review is to discuss the animal models of HPV-associated human tumours and the results obtained in these models with therapeutic vaccination against HPV-associated tumours. The prospects and limitations of the vaccination against HPV-associated tumours are also addressed.

Animals↗

PubMed1998

Cloning, Expression and Identification of Matrix Protein Gene of Wheat Rosette Stunt Virus (WRSV).

cDNA fragment located downstream of the WRSV NS protein gene was sequenced. Following an 80 nt untranslated region at the 5 'terminus, there is a 453 nt open reading frame(ORF) encoding a 17 kD protein, which was allowed to be expressed in E. coli using bacterial expression vector pGEX-3X and produced a 43 kD fusion protein. The result of Western blot showed that the fusion protein was able to react strongly with antibody raised against the purified WRSV particles. According to the similarities between the gene organizations of VSV and WRSV and between the molecular weights of deduced and expressed proteins, as well as the viral structural M protein, and to the result of Western blot, the 453 nt ORF was identified as WRSV M protein gene.

Journal Article↗

PubMed1992

Recombinant interferon-alpha 2 inhibits HIV replication in chronically infected promonocytic cells.

Promonocytic cells U937 with previously established HIV-1 persistent infection, were treated with increasing doses of the recombinant INF-alpha 2. This resulted in a significant decrease of virion-associated reverse transcriptase levels in medium of the cultures studied, most pronounced by the highest interferon doses, but depending on this cytokine presence. In spite of the marked restrictive effect of the interferon on the infectious virus production the synthesis, of viral structural proteins by the U937 cells, as detected by immunofluorescence, was not affected. The therapeutic index of interferon was considerably high.

Cell Line↗

PubMed1992

Antibodies to non-structural hepatitis C virus antigens: a link with liver disease activity?

OBJECTIVES: The aim of our study was to evaluate the aetiopathogenetic role of hepatitis C virus (HCV) in the genesis of chronic liver disease and hepatocellular carcinoma and the relationship between presence of circulating antibodies against non-structural HCV antigens and disease activity. METHODS: Using a new enzyme-immunoassay capable of detecting, either separately or together, circulating antibodies to structural and non-structural hepatitis C virus antigens, we tested 208 chronic hepatitis B surface antigen (HBsAg) carriers and 144 patients suffering from chronic liver disease. RESULTS: Among the chronic HBsAg carriers with normal transaminase activity, there were 4% who proved to be anti-HVC positive, compared with 14.5% among those with high serum transaminase. Among subjects with chronic liver disease, 20% of patients with chronic persistent hepatitis, 54% with chronic active hepatitis, 35% with liver cirrhosis and 47% with hepatocellular carcinoma proved to be anti-HCV positive. With regard to the aetiology of liver disease, 13% and 25% of chronic HBV infected patients, with or without anti-delta virus superinfection respectively, had anti-hepatitis C virus antibody. This prevalence was 22% among alcoholic liver disease and 89% among patients with cryptogenic liver diseases. The percentage of subjects with circulating antibodies against non-structural HCV proteins was higher among HBsAg chronic carriers with raised alanine aminotransferase and among patients with chronic active hepatitis and hepatocellular carcinoma. CONCLUSIONS: Many subjects with chronic liver disease have circulating anti-HCV antibodies. Anti-HCV positive subjects, especially those with antibodies to non-structural antigens, are more frequently found among patients with aggressive liver diseases. Among HBsAg chronic carriers the prevalence of anti-HCV was lower in "healthy carriers" and HBeAg positive rather than in HBeAg negative subjects with high alanine aminotransferase. We therefore suggest that there may be a relation between HCV replication, activeness of the liver disease and presence of antibodies to non-structural viral antigens.

Carcinoma, Hepatocellular↗

PubMed1992

Modulatory effects of Epstein-Barr, herpes simplex, and human herpes-6 viral infections and coinfections on cytokine synthesis. A comparative study.

Herpesviruses such as EBV, HSV, and human herpes virus-6 (HHV-6) have a marked tropism for cells of the immune system and therefore infection by these viruses may result in alterations of immune functions, leading at times to a state of immunosuppression. We report the results of a comparative study in which we found that EBV, HSV-1, and HHV-6 act differentially on the immune system with regard to their effect on the synthesis of IL-1 beta, IL-6, and TNF-alpha, i.e., three immunoregulatory cytokines mainly secreted by activated monocytes/macrophages. Using the polymerase chain reaction technique, analyses of the mRNA levels for each of the three monokines after viral infection indicated that the effect exerted by each of these herpesviruses on cytokine synthesis by human PBMC was detectable at the transcriptional level. Different amounts of IL-1 beta protein were detected in infected PBMC cultures, HHV-6 being the strongest IL-1 beta up-regulatory among these three herpesviruses. Spontaneous releases of IL-6 and TNF-alpha were found reduced after infection by HHV-6 and EBV, respectively. In comparison to EBV and HHV-6, HSV-1 proved to be a weak monokine enhancer. Results of coinfection studies indicated that virus-induced suppressive effects on cytokine synthesis are dominant. In fact, EBV inhibited TNF-alpha synthesis even in the presence of HHV-6, a strong up-regulator of TNF-alpha synthesis. Similarly, EBV was unable to stimulate IL-6 production in the presence of HHV-6. Viral structural component(s) appeared to be responsible for the up-regulation of IL-6 by both EBV and HSV-1, and of TNF-alpha by HSV-1. Taken together, our observations illustrate that herpesviruses can selectively regulate cytokine synthesis thereby disturbing immune homeostasis; this effect may favor pathogenic events, including the reactivation and/or spread of other infectious agents within the host.

Base Sequence↗

PubMed1990

[Dynamics of the antibody response and p24 antigenemia in HIV-1 infected individuals in Czechoslovakia].

In a group of 83 anti HIV-1 positive subjects the antibody response against different structural viral proteins was investigated concurrently with assessment of p 24 antigenaemia. Disappearance of antibodies against the capsidal antigen p 24 was recorded in 12% of 42 patients with ARC and AIDS. On the other hand, these antibodies persisted in all 41 asymptomatic infections throughout the three-year investigation period. Disappearance of antibodies against p 17 antigen was proved in 41% of the patients and in 22 subjects without clinical symptoms. The authors found a rising trend of antigenaemia p 24 in the course of HIV infection. The free p 24 antigen was detected in 62% patients with AIDS and only in 10% asymptomatic infections. The investigation confirmed the importance of investigations of the antibody response and p 24 antigenaemia in the prognosis of development of HIV infection and in monitoring of the effect of therapy.

AIDS-Related Complex↗

PubMed1990

[Virologic diagnosis of HIV infection in the pregnant woman and newborn infant].

The virological diagnosis of HIV infection in pregnant women mainly consists of detecting antibodies to structural viral antigens. The difficulty lies more in the interpretation of the confirmatory assay than in technical problems. The result is critical since the continuation or interruption of pregnancy is dependent upon it. The diagnosis of HIV infection in newborns has been hampered by the presence of passively acquired maternal antibodies. The diagnosis at birth therefore must include culture of peripheral blood mononuclear cells for virus isolation and detection of serum antigen. However, due to the difficulty or lack of sensitivity of these tests new diagnostic procedures, such as the polymerase chain reaction, must be developed to improve the accuracy of the early diagnosis. Such new approaches must be evaluated very carefully before being introduced in routine diagnosis.

AIDS Serodiagnosis↗