Biomedical subjects

Hartmut Hengel

Publications and source records attributed to Hartmut Hengel.

12 recordsLinked to original sources

PubMed2004

Herpesviral Fcgamma receptors: culprits attenuating antiviral IgG?

Production of IgG in response to virus infection is central to antiviral immune effector functions and a hallmark of B cell memory. Antiviral antibodies (Abs) recognising viral glycoproteins or protein antigen displayed on the surface of virions or virus-infected cells are crucial in rendering the virus noninfectious and in eliminating viruses or infected cells, either acting alone or in conjunction with complement. In many instances, passive transfer of Abs is sufficient to protect from viral infection. Herpesviruses (HV) are equipped with a large array of immunomodulatory functions which increase the efficiency of infection by dampening the antiviral immunity. Members of the alpha- and beta-subfamily of the Herpesviridae are distinct in encoding transmembrane glycoproteins which selectively bind IgG via its Fc domain. The Fc-binding proteins constitute viral Fcgamma receptors (vFcgammaRs) which are expressed on the cell surface of infected cells. Moreover, vFcgammaRs are abundantly incorporated into the envelope of virions. Despite their molecular and structural heterogeneity, the vFcgammaRs generally interfere with IgG-mediated effector functions like antibody (Ab)-dependent cellular cytolysis, complement activation and neutralisation of infectivity of virions. vFcgammaRs may thus contribute to the limited therapeutic potency of antiherpesviral IgG in clinical settings. A detailed molecular understanding of vFcgammaRs opens up the possibility to design recombinant IgG molecules resisting vFcgammaRs. Engineering IgG with a better antiviral efficiency represents a new therapeutic option against herpesviral diseases.

Animals↗

PubMed2004

Laboratory investigations are indispensable to monitor the progress of measles elimination--results of the German Measles Sentinel 1999-2003.

BACKGROUND: The elimination of measles is a goal set by the World Health Organisation to be reached by 2010 in the European region. OBJECTIVES: To enhance the measles surveillance in Germany, a country-wide laboratory supported a sentinel was established. STUDY DESIGN: A network of >1200 representatively distributed practitioners reported detailed data on all clinically diagnosed cases and provided specimens for laboratory diagnosis. RESULTS: A total of 3225 suspected cases were reported between October 1999 and December 2003. The incidence in Western Germany decreased from >15 cases per 100,000 population to one case in 2003, while in Eastern Germany <1 case per 100,000 population was observed during these years. Laboratory investigations were undertaken in 40% of cases in 2000/2001. This rate increased to 79% in 2003. Simultaneously, the rate of confirmed cases dropped from 60% in the former years to 23% in 2003. Measles virus (MV) detection by serology and by PCR revealed concordant results in 92%. Most suspected cases (85%) were unvaccinated with 66% being laboratory confirmed. Only 10% of suspected cases occurred in vaccinated individuals and very few (22%) could be confirmed. Analyses of confirmed measles in vaccinated patients (n = 49) revealed 24.5% primary vaccine failures, 24.5% reinfections after successful vaccination and 31% MV infection before or shortly after vaccination. The genetic characterisation of 389 MV isolates identified eight genotypes: B3, C2, D4, D5, D6, D7, G2 and H1. Only the C2, D6 and D7 MV genotypes circulated endemically in Western Germany. The newly emerged MV D7 almost completely replaced the pre-existing C2 and D6 MVs in 2001. The few measles cases detected in Eastern Germany were mostly caused by imported MVs. CONCLUSION: The data demonstrate that laboratory investigations including molecular methods are an indispensable tool for surveillance in all countries advanced in measles elimination.

Adolescent↗

PubMed2004

A cytomegalovirus inhibitor of gamma interferon signaling controls immunoproteasome induction.

Both human and mouse cytomegaloviruses (HCMV and MCMV) avoid peptide presentation through the major histocompatibility complex (MHC) class I pathway to CD8(+) T cells. Within the MHC class I pathway, the vast majority of antigenic peptides are generated by the proteasome system, a multicatalytic protease complex consisting of constitutive subunits, three of which can be replaced by enzymatically active gamma interferon (IFN-gamma)-inducible subunits, i.e., LMP2, LMP7, and MECL1, to form the so-called immunoproteasomes. Here, we show that steady-state levels of immunoproteasomes are readily formed in response to MCMV infection in the liver. In contrast, the incorporation of immunoproteasome subunits was prevented in MCMV-infected, as well as HCMV-infected, fibroblasts in vitro. Likewise, the expression of the IFN-gamma-inducible proteasome regulator PA28 alpha beta was also impaired in MCMV-infected cells. Both MCMV and HCMV did not alter the constitutive-subunit composition of proteasomes in infected cells. Quantitative assessment of LMP2, MECL1, and LMP7 transcripts revealed that the inhibition of immunoproteasome formation occurred at a pretranscriptional level. Remarkably, a targeted deletion of the MCMV gene M27, encoding an inhibitor of STAT2 that disrupts IFN-gamma receptor signaling, largely restored transcription and protein expression of immunoproteasome subunits in infected cells. While CMV block peptide transport and MHC class I assembly by posttranslational strategies, immunoproteasome assembly, and thus the repertoire of proteasomal peptides, is controlled by pretranscriptional mechanisms. We hypothesize that the blockade of immunoproteasome formation has considerable consequences for shaping the CD8(+)-T-cell repertoire during the effector phase of the immune response.

Animals↗

PubMed2004

Expansion of protective CD8+ T-cell responses driven by recombinant cytomegaloviruses.

CD8(+) T cells are critical for the control of many persistent viral infections, such as human immunodeficiency virus, hepatitis C virus, Epstein-Barr virus, and cytomegalovirus (CMV). In most infections, large CD8(+)-T-cell populations are induced early but then contract and are maintained thereafter at lower levels. In contrast, CD8(+) T cells specific for murine CMV (MCMV) have been shown to gradually accumulate after resolution of primary infection. This unique behavior is restricted to certain epitopes, including an immunodominant epitope derived from the immediate-early 1 (IE1) gene product. To explore the mechanism behind this further, we measured CD8(+)-T-cell-mediated immunity induced by recombinant MCMV-expressing epitopes derived from influenza A virus or lymphocytic choriomeningitis virus placed under the control of an IE promoter. We observed that virus-specific CD8(+)-T-cell populations were induced and that these expanded gradually over time. Importantly, these CD8(+) T cells provided long-term protection against challenge without boosting. These results demonstrate a unique pattern of accumulating T cells, which provide long-lasting immune protection, that is independent of the initial immunodominance of the epitope and indicates the potential of T-cell-inducing vaccines based on persistent vectors.

Animals↗

PubMed2004

Hepatitis C virus mutation affects proteasomal epitope processing.

The high incidence of hepatitis C virus (HCV) persistence raises the question of how HCV interferes with host immune responses. Studying a single-source HCV outbreak, we identified an HCV mutation that impaired correct carboxyterminal cleavage of an immunodominant HLA-A2-restricted CD8 cell epitope that is frequently recognized by recovered patients. The mutation, a conservative HCV nonstructural protein 3 (NS3) tyrosine to phenylalanine substitution, was absent in 54 clones of the infectious source, but present in 15/21 (71%) HLA-A2-positive and in 11/24 (46%) HLA-A2-negative patients with chronic hepatitis C. In order to analyze whether the mutation affected the processing of the HLA-A2-restricted CD8 cell epitope, mutant and wild-type NS3 polypeptides were digested in vitro with 20S constitutive proteasomes and with immunoproteasomes. The presence of the mutation resulted in impaired carboxyterminal cleavage of the epitope. In order to analyze whether impaired epitope processing affected T cell priming in vivo, HLA-A2-transgenic mice were infected with vaccinia viruses encoding either wild-type or mutant HCV NS3. The mutant induced fewer epitope-specific, IFN-gamma;-producing and fewer tetramer(+) cells than the wild type. These data demonstrate how a conservative mutation in the flanking region of an HCV epitope impairs the induction of epitope-specific CD8(+) T cells and reveal a mechanism that may contribute to viral sequence evolution in infected patients.

Amino Acid Sequence↗

PubMed2003

Memory inflation: continuous accumulation of antiviral CD8+ T cells over time.

CD8+ T lymphocytes play an important role in the control of intracellular pathogens during both acute and persistent infections. This is particularly true in the case of persistent herpesviruses such as human CMV, which are typified by large virus-specific CD8+ T cell populations during viral latency. To understand the origin of these populations and the factors shaping them over time, we investigated the CD8+ T cell response after murine CMV (MCMV) infection. The kinetics of the acute response were characterized by rapid expansion of activated T cells, followed by a contraction phase. Thereafter, we observed a striking pattern, where MCMV-specific memory CD8+ T cells steadily accumulated over time, with 20% of all CD8+ T cells at 1 year specific for one MCMV epitope. Accumulation of MCMV-specific CD8+ T lymphocytes was seen in all organs tested and was associated with continuous activation of specific CD8+ T lymphocytes, primarily within lymph nodes. The pattern of accumulation was observed in only two of five epitopes tested, and was accompanied by a gradual restriction in usage of the variable region of the TCR beta-chain over time. This novel pattern of a virus-specific CD8+ T cell response suggests that continuous or repetitive exposure to Ag can slowly mold memory T cell populations over time. This may be relevant for understanding the evolution of the large human CMV-specific CD8+ T cell populations seen in humans.

Animals↗

PubMed2003

HCMV glycoprotein US6 mediated inhibition of TAP does not affect HLA-E dependent protection of K-562 cells from NK cell lysis.

Human cytomegalovirus has evolved multiple strategies to interfere with immune recognition by the host. A variety of mechanisms affect antigen presentation by major histocompatibility complex class I molecules resulting in a reduced class I cell-surface expression. This downregulation is expected to trigger natural killer (NK) cytotoxicity, requiring counteraction by the virus to establish long-term infection. Here we describe that the human cytomegalovirus gpUS6 protein, which has been demonstrated to downregulate the expression of human leukocyte antigen (HLA) class I and the presentation of cytotoxic T lymphocyte epitopes by blocking transporter associated with antigen presentation (TAP function), does not affect the ability of HLA-E to inhibit NK cell mediated lysis of K-562 cells by interaction with CD94/NKG2A expressed on NK cells. Cell surface expression and function of HLA-E is not altered although gpUS6 inhibits TAP-dependent peptide transport by 95%. Moreover, HLA-E molecules presenting HLA class I signal sequence-derived peptides are functionally detectable on transfected TAP-deficient RMA-S cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Combinatorial immunotherapies for infectious diseases.

Combating pathogenic organisms by combinatorial approaches involving appropriate immune response molecules and antimicrobial drugs represents a progessively more apparent and successful therapeutic paradigm for the treatment of acute and chronic persistent infectious diseases. This review explores areas of current innovation and provides an update of the present state of knowledge concerning combination of chemotherapy with several immune-based interventions in infections. In the future, a better understanding of microbial immune modulation and evasion may continue to open new avenues of inquiry and carefully targeted application of adjunctive immunotherapies.

Animals↗

PubMed2002

MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo.

The susceptibility of certain inbred mouse strains to murine cytomegalovirus (MCMV) is related to their inability to generate a strong natural killer (NK) cell response. We addressed here whether the MCMV susceptibility of the BALB/c strain is due to viral functions that control NK cell activation in a strain-specific manner. MCMV expresses two proteins, gp48 and gp40, that are encoded by the genes m06 and m152, respectively; they down-regulate major histocompatibility complex (MHC) class I expression at the plasma membrane. Using MCMV deletion mutants and revertants, we found that gp40 but not gp48 controls NK cell activation. Absence of gp40 improved antiviral NK cell control in BALB/c, but not C57BL/6, mice. Down-regulation of H-60, the high-affinity ligand for the NKG2D receptor, was the mechanism by which gp40 modulates NK cell activation. Thus, a single herpesvirus protein has a dual function in inhibiting both the adaptive as well as the innate immune response.

Animals↗

PubMed2002

Rapid replacement of endemic measles virus genotypes.

Although vaccination campaigns have significantly reduced the number of measles cases worldwide, endemic transmission of measles virus (MV) continues to occur in several continents, including Europe. To obtain current information on measles incidence and molecular data on circulating MVs in Germany, a nationwide measles sentinel was established. Phylogenetic analysis based on the variable part of the N gene from 80 MVs isolated between November 1999 and October 2001 revealed the presence of at least six distinct MV genotypes: B3, C2, D4, D6, G2 and a new variant of D7. Both the incidence and the pattern of MV genotypes differed markedly between the former East and West Germany. In the eastern part, few measles cases, mainly caused by genotypes originating from other countries (B3, D4, G2), were detected. In the western and southern parts, genotypes C2, D6 and D7 were associated with endemic transmission. Surprisingly, the indigenous genotypes predominant during the 1990s - C2 and D6 - disappeared simultaneously over the period of observation coinciding with the emergence and the wide spread of D7 viruses. While the incidence of measles remained constant, all MVs isolated in 2001 were assigned to D7. We note that the haemagglutinin (H) sequence of D7 viruses shows distinct exchanges of certain amino acids in the stem and propeller domain compared to C2, D6 and the MV vaccine strains used. This raises the possibility of a selective advantage of D7 viruses transmitted in the presence of H-specific antibodies.

Adolescent↗

PubMed2002

Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcgamma receptor homologs.

Cellular receptors for the Fc domain of immunoglobulin G (IgG) (FcgammaRs) comprise a family of surface receptors on immune cells connecting humoral and cellular immune responses. Several herpesviruses induce FcgammaR activities in infected cells. Here we identify two distinct human cytomegalovirus (HCMV)-encoded vFcgammaR glycoproteins of 34 and 68 kDa. A panel of HCMV strains exhibited a slight molecular microheterogeneity between Fcgamma-binding proteins, suggesting their viral origin. To locate the responsible genes within the HCMV genome, a large set of targeted HCMV deletion mutants was constructed. The mutant analysis allowed the identification of a spliced UL119-UL118 mRNA to encode vFcgammaR gp68 and TRL11/IRL11 to encode vFcgammaR gp34. Both vFcgammaRs are surface resident type I transmembrane glycoproteins. Significant relatedness of sequences in the extracellular chain of gpUL119-118 and gpTRL11 with particular immunoglobulin supergene family domains present in FcgammaR I and FcgammaRs II/III, respectively, indicates a different ancestry and function of gpUL119-118 and gpTRL11. The HCMV-encoded vFcgammaRs highlight an impressive diversification and redundancy of FcgammaR structures.

Amino Acid Sequence↗

PubMed2001

Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus.

Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV), causing severe disease in affected organs of immunocompromised patients. CMV downregulates major histocompatibility complex class I (MHC-I) molecule expression in fibroblasts in order to avoid lysis by CD8(+) cytotoxic T lymphocytes. However, MHC-I expression in human cytomegalovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-I expression in epithelial cells, new cell culture models for HCMV infection of differentiated hepatobiliary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early and late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2, gpUS3, gpUS6 and gpUS11, that downregulate MHC-I expression were synthesized with temporal kinetics and in a similar quantity to that seen in fibroblasts. As a result, HCMV infection led to a drastic and selective downregulation of MHC-I expression in epithelial cells and was uniformly observed irrespective of the hepatic or biliary origin of the cells. The new models document for the first time a stealth function of HCMV in epithelial cells and indicate that the downregulation of MHC-I expression by HCMV can occur in the virtual absence of virus replication.

Bile Ducts↗