Identification of two new HLA-A variants, HLA-A*2911 and HLA-A*6827.
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Alleles↗
Biomedical subjects
T F Schulz
Publications and source records attributed to T F Schulz.
Insertion of targeting domains into the envelope glycoprotein of Moloney murine leukemia virus (MoMLV)-based vectors modulates the route of mCAT-1-mediated viral entry.
Several groups have inserted targeting domains into the envelope glycoprotein (Env) of Moloney murine leukemia virus (MoMLV) in an attempt to produce targeted retroviral vectors for human gene therapy. While binding of these modified Envs to the target molecule expressed on the surface of human cells was observed, specific high-titer infection of human cells expressing the target molecule was not achieved. Here we investigate the initial steps in the entry process of targeted MoMLV vectors both in murine and human cells expressing the MoMLV receptor, the mouse cationic amino acid transporter-1 (mCAT-1). We show that insertion of a small ligand targeted to E-selectin and of a single chain antibody (scFv) targeted to folate-binding protein (FBP) into the N-terminus of MoMLV Env results in the reduction of the infectivity and the kinetics of entry of the MoMLV vectors. The use of soluble receptor-binding domain (sRBD), bafilomycin A1 (BafA1) and methyl-beta-cyclodextrin (MbetaC) increase the infectivity of the MoMLV vectors targeted to FBP (MoMLV-FBP) suggesting that the scFv targeted to FBP increases the threshold for fusion and might re-route entry of the targeted MoMLV-FBP vector towards an endocytic, non-productive pathway.
Animals↗
Increase in infectivity of targeted Moloney murine leukemia virus-based gene-delivery vectors through lowering the threshold for fusion.
Many research groups have developed targeted vectors for gene therapy based on Moloney murine leukemia virus (MoMLV). Despite proper binding of the targeted vector to the target molecule, little or no infectivity of human cells expressing the target molecule has been achieved in most studies. One of the reasons for this lack of infectivity may be steric hindrance within the targeted envelope glycoprotein (Env), impeding the conformational changes required for fusion and infection. Here, attempts were made to solve this problem by mutating key residues within Env of two targeted MoMLV-based vectors, MoMLV-E-Sel and MoMLV-FBP. Selection of key residues was based on an Env with reduced threshold for fusion, that of the CD4-independent human immunodeficiency virus type 2 isolate ROD/B. It was shown here that vectors bearing MoMLV-FBP Env with a V512M substitution had higher titres and faster kinetics of entry than vectors bearing parental targeted Env proteins. This could be due to the partial release of steric constraints that result in an Env with a reduced threshold for fusion.
Amino Acid Sequence↗
HHV-8 transmission via saliva to soothe blood-sucking arthropod bites.
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Adult↗
Reduced seroprevalence of Kaposi's sarcoma-associated herpesvirus (KSHV), human herpesvirus 8 (HHV8), related to suppression of Anopheles density in Italy.
In two formerly malarious parts of Italy, age-related seroprevalence rates of Kaposi's sarcoma-associated herpesvirus [human herpesvirus 8 (KSHV/HHV8)] were determined from local blood donors and correlated with periods of vector control during anti-malaria campaigns. In Veneto, decreased KSHV/HHV8 seroprevalence in the 1951-1955 birth cohort coincides with the peak of DDT house-spraying. In Sardinia, where larviciding augmented indoor DDT-spraying, a significant drop of KSHV/HHV8 seroprevalence between 1945 and 1950 and 1951-1955 birth cohorts (P = 0.0046) coincides with suppression of the malaria vector Anopheles labranchiae Falleroni (Diptera: Culicidae). These results are consistent with age-related association between KSHV/HHV8 seroprevalence rates in native/resident populations and the density of malaria vectors in Veneto and Sardinia. This example supports our 'promoter arthropod' hypothesis on the role of haematophagous insects [putatively blackflies (Simuliidae), sandflies (Phlebotominae) and biting midges (Ceratopogonidae), as well as mosquitoes] when their bites induce hypersensitivity and immunosuppression, potentiate KSHV/HHV8 transmission via human saliva (when insect bite lesions are licked by another person whose saliva carries the virus) and may facilitate Kaposi's sarcoma.
Animals↗
Kaposi's sarcoma and human herpesvirus 8 infection do not protect HIV-1 infected homosexual men from AIDS dementia complex.
OBJECTIVE: To examine the association between Kaposi's sarcoma (KS), human herpes virus 8 (HHV8) and AIDS dementia complex (ADC). DESIGN: A total of 599 HIV-1 infected homosexual men participated in a prospective cohort study (Amsterdam, 1984-1996). METHODS: The risk for ADC in patients with prior KS or HHV8 infection was estimated using the Cox proportional hazards method with adjustments for antiretroviral medication and low CD4 cell counts. RESULTS: Of the 599 participants, 290 (48.4%) had HHV8 antibodies, 99 (16.5%) had KS and 30 (5.0%) had ADC. ADC was diagnosed in 5.2% of participants with KS and 5.0% of those without KS, and in 4.8% of HHV8 seropositive compared to 5.2% seronegative individuals and thus was not associated with KS or HHV8 infection. Using a time-dependent Cox proportional hazards analysis with the date of KS as risk factor, the risk for ADC was 2.7 [95% confidence interval (CI), 0.92-7.96; P = 0.07) and when only definite ADC was considered it was 3.5 (95% CI, 1.00-12.26;P = 0.05). After adjusting for decreases in CD4 cell count and use of medication, the hazards ratio for participants with KS to develop ADC was 2.0 (95% CI, 0.66-5.77; P = 0.23) and 2.6 (95% CI, 0.73-9.12; P = 0.14), respectively. HHV8 seropositivity, adjusted for the same variables, showed a risk for ADC of 0.85 (95% CI, 0.41-1.77;P = 0.66) and for definite ADC 0.69 (95% CI, 0.27-1.73; P = 0.42). The expected neuroprotective effects of antiretroviral medication were observed. CONCLUSIONS: KS or HHV8 does not significantly influence the risk for developing ADC in a group with a uniform risk for developing KS therefore we recommend caution in searching for a KS-associated or HHV8-derived therapy for ADC.
AIDS Dementia Complex↗
No increased human herpesvirus 8 seroprevalence in patients with HIV-associated non-Hodgkin's lymphoma.
Human herpesvirus 8 (HHV-8) is closely associated with Kaposi's sarcoma (KS), HIV-associated Castleman's disease, and primary effusion lymphoma. As a high frequency of non-Hodgkin's lymphoma (NHL) has been reported in patients with HIV-associated KS, we hypothesized that HHV-8 infection could be indirectly implicated in the pathogenesis of NHL. We assessed the prevalence of HHV-8 antibodies in 63 patients with NHL compared with 126 HIV-infected matched control patients without NHL. Serum samples from cases and controls were assayed for antibodies to HHV-8 lytic and latent antigens using an indirect immunofluorescence assay. In patients with concordant serologic results, HHV-8 antibodies were detected in 41.5% of the NHL cases and 37% of the controls. This absence of a significant difference in HHV-8 seroprevalence between cases and controls (p =.73) does not support a possible role for HHV-8 infection in the development of NHL in HIV-infected patients.
Adolescent↗
A prospective seroepidemiological study of human herpesvirus-8 infection and the risk of multiple myeloma.
Presence of the Human Herpesvirus 8 (HHV8) genome has been reported in the bone marrow of multiple myeloma (MM) patients. So far, serological studies of HHV8 and MM have been inconsistent but have not included prospective epidemiological studies. We evaluated whether HHV8 infection is associated with increased risk for MM in a prospective population-based study of 39 000 Finnish subjects who donated serum samples in the period 1968-72. Serum samples from 47 subjects who developed MM during a 23-year follow-up and 224 age, area of residence and sex-matched subjects who remained healthy over a similar follow-up period were evaluated for HHV8 antibodies at enrollment, as assayed both with an immunofluorescence assay (IFA) for lytic and latent HHV8 antigens and by Western blot (WB) with three recombinant HHV8 proteins (ORFs 65, 73 and K8.1A). HHV8 seropositivity for at least one HHV8 protein on WB was found in 7% of the Finnish population and was not associated with the risk of developing MM (Relative Risk (RR) = 0.89, Confidence Interval (CI): 0.25-3.25). HHV8 seropositivity for lytic and latent antigens in the IFA was found in 16% and 0.4% of the Finnish population and tended to associate with risk of MM (RR = 2.02, CI: 0.94-4.33 and RR = 10.00, CI: 0.91-110.29, respectively). In conclusion, no statistically significant evidence for an association between HHV8 infection and the risk of future MM was found.
Antigens, Viral↗
KSHV/HHV8-associated lymphoproliferations in the AIDS setting.
Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is associated with two lymphoproliferative disorders in the AIDS setting, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). In PEL, KSHV persists in a latent form in most lymphoma cells, although viral production has been seen infrequently. In MCD, the viral gene expression pattern is less restrictive, virus production appears to occur and to correlate with the severity of this disease. Several viral genes may contribute to the particular features of these two disorders: among them a viral homologue of interleukin 6 (vIL6) has attracted much attention and been shown to promote the growth of plasma cells. It is thought that its activity is important in the pathogenesis of both PEL and MCD. Other viral genes, in particular a D-type cyclin homologue, the latent nuclear antigen LANA, and one or more of the viral homologues of interferon regulatory factors (vIRFs) may also contribute. Although it is conceivable that viral infection per se could explain much, if not all, of the features of MCD, it is likely that additional genetic alterations play a role in the pathogenesis of PEL.
Antigens, Viral↗
Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays.
A multicentre study was undertaken to define novel assays with increased inter-assay concordance, sensitivity, specificity and predictive value for serological diagnosis of human herpesvirus type 8 (HHV-8) infection. A total of 562 sera from European and Ugandan human immunodeficiency virus (HIV)-infected or uninfected individuals with or without Kaposi's sarcoma (KS) and blood donors were examined under code by 18 different assays in seven European laboratories. Sera from KS patients and all non-KS sera found positive by at least 70%, 80%, or 90% of the assays were considered "true positive." The validity of the assays was then evaluated by univariate logistic regression analysis. Two immunofluorescence assays (IFA) for detection of antibodies against HHV-8 lytic (Rlyt) or latent (LLANA) antigens and two enzyme-linked-immunosorbent assays (ELISA) (M2, EK8.1) for detection of antibodies against HHV-8 structural proteins were found to be highly concordant, specific, and sensitive, with odds ratios that indicated a high predictive value. When used together, the two IFA (Rlyt-LLANA) showed the best combination of sensitivity (89.1%) and specificity (94.9%). The performance of these assays indicate that they may be used for the clinical management of individuals at risk of developing HHV-8 associated tumours such as allograft recipients.
AIDS-Related Opportunistic Infections↗
A chimpanzee rhadinovirus sequence related to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8: increased detection after HIV-1 infection in the absence of disease.
OBJECTIVE: To look for a virus related to Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) in chimpanzees and to investigate phylogenetic and biological similarities to KSHV. METHODS: Peripheral blood mononuclear cell (PBMC) DNA samples from chimpanzees (Pan troglodytes troglodytes) were screened with newly designed consensus oligonucleotide primers for the DNA polymerase gene of KSHV-related gamma2-herpesviruses (rhadinoviruses). Samples from HIV-1-infected and -uninfected chimpanzees were screened with virus-specific primers. Antibodies to KSHV structural and latent antigens were measured by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and Western blot. RESULTS: We identified 972 base pairs (bp) of a new viral DNA polymerase sequence with 81.6% (nucleotides) and 93.2% (protein) identity to that of KSHV/HHV8. It was detected in 15/37 (41%) animals experimentally infected with HIV-1, but only in one out of 30 uninfected animals (P<0.001). Antibodies were found by immunofluorescence to structural, but not latent, KSHV antigens in nearly all HIV-1-infected and uninfected animals. CONCLUSION: Like man and two other Old World primate species, chimpanzees harbour a virus closely related to KSHV/HHV8, termed Pan troglodytes rhadinovirus-1 (PtRV-1). Like KSHV, PtRV-1 is more easily detected by polymerase chain reaction (PCR) in the PBMC of HIV-1-infected than of HIV-1-uninfected individuals, suggesting increased viral load. Despite the close phylogenetic relationship and biological similarities between KSHV and PtRV-1, Kaposi's sarcoma (KS) has not been reported in HIV-1-infected chimpanzees. PtRV-1 may lack some of the pathogenic determinants of KSHV, or humans and chimpanzees may differ in how they control the infection with their respective rhadinoviruses.
AIDS-Related Opportunistic Infections↗
Bone marrow failure associated with human herpesvirus 8 infection after transplantation.
BACKGROUND: Human herpesvirus 8 (HHV-8) infection has been linked to the development of Kaposi's sarcoma and to rare lymphoproliferative disorders. METHODS: We used molecular methods, serologic methods, in situ hybridization, and immunohistochemical analyses to study HHV-8 infection in association with nonmalignant illnesses in three patients after transplantation. RESULTS: Primary HHV-8 infections developed in two patients four months after each received a kidney from the same HHV-8-seropositive cadaveric donor. Seroconversion and viremia occurred coincidentally with disseminated Kaposi's sarcoma in one patient and with an acute syndrome of fever, splenomegaly, cytopenia, and marrow failure with plasmacytosis in the other patient. HHV-8 latent nuclear antigen was present in immature progenitor cells from the aplastic marrow of the latter patient. Identification of the highly variable K1 gene sequence of the HHV-8 genome in both the donor's peripheral-blood cells and the recipients' serum confirmed that transmission had occurred. HHV-8 viremia also occurred after autologous peripheral-blood stem-cell transplantation in an HHV-8-seropositive patient with non-Hodgkin's lymphoma. Reactivation of the infection was associated with the development of fever and marrow aplasia with plasmacytosis; there was no evidence of other infections. HHV-8 transcripts and latent nuclear antigen were expressed in the aplastic marrow but not in two normal marrow samples obtained before transplantation. CONCLUSIONS: Primary HHV-8 infection and reactivation of infection may be associated with nonneoplastic complications in immunosuppressed patients.
Adult↗
Molecular evidence of organ-related transmission of Kaposi sarcoma-associated herpesvirus or human herpesvirus-8 in transplant patients.
In transplant patients, Kaposi sarcoma (KS)-associated herpesvirus or human herpesvirus-8 (HHV-8) infection is associated with the development of KS, primary effusion lymphoma and Castleman disease. Whether HHV-8 is either reactivated in the recipient or transmitted by the donor has been investigated so far only by serologic studies. Thus, we addressed the issue of HHV-8 transmission in the transplantation setting by molecular methods. We exploited the high level variability of the orf-K1 gene and the polymorphism of the orf-73 gene of the HHV-8 genome to assess the genetic relatedness of the HHV-8 strains identified in the posttransplant KS lesions that developed, simultaneously, 20 months after transplantation, in 2 recipients of twin kidneys from the same cadaver donor. The 100% identity of nucleotide sequence of the most variable viral region and the presence of the same, single orf-73 type in both patients provides strong molecular evidence of organ-related transmission of HHV-8 in the setting of transplantation.
Base Sequence↗
Nonmalignant disease associated with human herpesvirus 8 reactivation in patients who have undergone autologous peripheral blood stem cell transplantation.
Fever, cutaneous rash, and hepatitis-for which an infectious cause was suspected-developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8-specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti-HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.
Adult↗
Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73.
We have shown previously that human herpesvirus 8 (HHV8) seroconversion for antibodies to the latency-associated nuclear antigen encoded by ORF73 and/or the lytic capsid antigen (vp19) encoded by ORF65 is associated with orogenital contact and is strongly linked to the development of Kaposi's sarcoma among HIV-infected individuals in the Amsterdam Cohort Studies. Here, we investigate the relationship between seroconversion to these antigens and primary HHV8 infection. Between 1984 and 1997, 215 HHV8 seroconversions to ORF73 (106 cases or 49%) and/or to ORF65 (159 cases or 74%) were recorded in the cohort of homosexual men. The HHV8 seroconversion rate among HIV-infected homosexual men (6.2 per 100 person years) was consistently higher than among HIV-uninfected men (2.6 per 100 person years). In HIV-infected but not in uninfected individuals, seroconversion to ORF73/latency-associated nuclear antigen precedes that to ORF65/vp19. Antibody levels to both ORF65- and ORF73-encoded antigens were higher in HIV-infected than in HIV-uninfected men, and among HIV-seropositives, antibody levels to ORF65/vp19 rise even higher with declining CD4 cell counts and peak with Kaposi's sarcoma development, suggesting continuing and increasing viral replication. In 10.3% of HHV8 seroconversions, transient serum viremia could be demonstrated before or at seroconversion. Together with the previously reported link between unprotected orogenital sex and HHV8 seroconversion, our observations suggest that HHV8 seroconversions result from primary infections.
Antibodies, Viral↗
Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men.
Sexual and nonsexual modes of transmission of human herpesvirus 8 (HHV8) have been suggested, but specific routes remain unclear. Therefore, the objective of this study was to assess risk factors for HHV8 seropositivity and determine specific sexual practices associated with HHV8 seroconversion. Sera from 1,458 homosexual men (Amsterdam Cohort Study, 1984-1996) were tested for antibodies to HHV8 with a modified version of an enzyme immunoassay, using recombinant HHV8 lytic phase capsid (ORF65) and latent phase nuclear (ORF73) proteins. HHV8 seroprevalence at study entry was 20.9% (305/1,458); was highest among those with positive human immunodeficiency virus (HIV) status, no steady partner, and southern European or Latin American nationality; and increased with older age and higher number of sexual partners. During follow-up, 215 men seroconverted for HHV8 (incidence: 3.6/100 person-years). Both prevalence and incidence rates remained more or less stable during the study period. Orogenital insertive sex (odds ratio (OR) = 5.95; 95% confidence interval (CI): 2.88, 12.29) or orogenital receptive sex (OR = 4.29; 95% CI: 2.11, 8.71) with more than five partners in the past 6 months, older age (OR = 2.89; 95% CI: 1.13, 7.34, when older than 45 years), and preceding HIV infection (OR = 2.47; 95% CI: 1.53, 3.99) were independent predictors for HHV8 seroconversion. The authors found strong evidence for orogenital transmission of HHV8 among homosexual men.
Adult↗
Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8): epidemiology and pathogenesis.
Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV-8), is a gamma2 herpesvirus (rhadinovirus) and the most recently discovered human tumour virus. It is involved in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. KSHV is not pathogenic in most otherwise healthy individuals but is highly oncogenic in HIV-1-infected and iatrogenically immunosuppressed individuals. It establishes a latent infection in most KS spindle (endothelial tumour) cells and in the neoplastic B cells of primary effusion lymphomas. The KSHV genome contains several homologues of cellular genes known to regulate cell growth and differentiation. Although some of these have transforming properties in vitro, their precise role in oncogenesis is still under investigation. Other co-factors may be involved in the pathogenesis of KS in HIV-uninfected, immunocompetent individuals, e.g. in African endemic KS, but none have been identified yet. Transmission of KSHV among homosexual men appears to occur through sexual contact, but in endemic countries transmission is frequent in childhood and may occur through close contact within families. Four major variants of KSHV have been defined, on the basis of variability in the K1 gene; they may have co-evolved with certain human populations. In addition, some KSHV strains may have resulted from a recombination event with a related, but not yet identified, gamma2 herpesvirus.
Antiviral Agents↗