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PubMed2001

Definition, classification, and routine diagnosis of urticaria: a consensus report.

Urticaria is a well-known disease entity; however, with an increasing understanding of the molecular mechanisms involved in its pathogenesis, there is also growing evidence for a heterogeneity of urticaria. Currently it is sometimes difficult to compare divergent data reported by different centers researching urticaria due to a lack of precisely described patient populations. A consensus definition and classification of the disease and its subtypes, taking into account new developments, are therefore needed. In addition, this consensus report provides a guideline for diagnostic procedures in different subtypes of urticaria.

Algorithms↗
PubMed2002

Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia.

One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of urgently needed targeted therapies.

Acute Disease↗
PubMed1999

HIV type 1 genetic variability in the northern part of Cameroon.

In 1995, 53 blood samples from Muslim patients with AIDS, or who were thought to have AIDS, were collected in the main hospitals of Adamaoua Province, in the northern part of Cameroon. The variable env C2V3 region of HIV-1 was amplified by nested PCR and phylogenetically analyzed. The results indicated that of 15 amplified samples, 1 belonged to HIV-1 group O, 1 to HIV-1 subtype D, 1 to subtype G, 2 to subtype H, and 10 to subtype A. Furthermore, the northern Cameroonian subtype A could be divided into at least two subclusters as shown by the env tree as well as by two remarkably conserved hexameric amino acid sequences in the apex of V3 (GPGQAF in one subcluster and GPGQTF in the other). This distinction suggests that the HIV-1 subtype A circulating in northern Cameroon evolved from two main sources. More recently, three HIV-1 strains from Nigeria (IBNG) and Djibouti (DJ263 and DJ264), previously reported on the basis of their env C2V3 sequences as subtype A, were found to have a similar A/G mosaic structure alongside their full-length sequence and were tentatively designated as members of a new subtype called "IBNG." Interestingly, within the northern Cameroonian subtype A described, the isolates of the second subcluster clustered distinctly with these A/G mosaic strains, strongly suggesting that they may be members of the IBNG subtype.

Amino Acid Sequence↗
PubMed1994

Evidence of no change in V3 loop antibody recognition pattern in HIV type 1-infected Ethiopians between 1988 and 1993.

To determine the antibody reactivity against a V3 sequence based on local HIV-1 strains in Ethiopia, 635 serum samples derived in 1988 and 1993 were analyzed by peptide enzyme immunoassays. V3 peptides were produced according to the Ethiopian subtype C V3 consensus sequence (RKSIRIGPGQTFYAT), the HIV-1MN and HIV-1IIIB strains (subtype B), and the consensus sequences of subtypes A, D, and E. Initial analyses showed that Ethiopian anti-V3 positive sera cross-reacted between subtype A and subtype C peptides, and displayed much lower reactivities to the other peptides. Using inhibition experiments, it was found that the reactivities in the Ethiopian samples were specific for subtype C. A strong reactivity to the Ethiopian V3 consensus sequence was found in the majority of the Ethiopian samples (59%), independent of geographical origin or year of sampling. In Swedish HIV-1-positive sera, the high reactivities were restricted to the subtype B HIV-1MN peptide. A low prevalence (10%) of strong reactivity to the HIV-1MN V3 peptide was found among the Ethiopian samples. Using substitution peptide analogs it was found that a lack of cross-reactivity between subtype B and C peptides was dependent on the Arg-322 to Gln-322 substitution. The present data show that a similar antibody recognition pattern was present in sera sampled during 1993 as in sera sampled during 1988, suggesting that subtype C of HIV-1 has remained the dominant subtype in Ethiopia.

Amino Acid Sequence↗
PubMed1996

HIV-1 proviral DNA sequences of env gp41 PCR amplificates from Tanzania.

The polymerase chain reaction (PCR) and direct DNA sequencing were used to detect and characterize selected regions of the HIV-1 proviral genome in whole blood samples from Tanzania. Specific PCR amplification products were obtained in gag and/or env (gp41) regions from 15 of the 19 HIV-1 seropositive samples investigated. Env regions from 12 different amplificates were further characterized using the dideoxy sequencing method. Preliminary results indicate that, despite scattered nucleotide mismatches, HIV-1 gp41 amino acid sequences from Tanzania conform to the 1990 Los Alamos African consensus sequence and resemble the HIV-1 subtype A or D consensus sequences in the characterized regions.

Amino Acid Sequence↗
PubMed1997

Five complete genomes of JC virus type 3 from Africans and African Americans.

The central demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the human polyomavirus JC virus (JCV). JCV evolved as geographically based genotypes of which Type 3 is an African variant first characterized in HIV-1 positive patients from Tanzania. This study reports the complete sequence of five JCV Type 3 strains. The entire JCV genome was PCR amplified from urine specimens of three African and two African-American individuals. The African consensus sequence was compared to the Type 1 and Type 2 prototype strains, JCV (Mad-1) and JCV(GS/B), respectively. Type 3 differed in 2.2% of its coding region genome from JCV (Mad-1) and in 1.3% from JCV(GS/B). Within the coding region the sequence variation among the three types was higher in the capsid protein VP1 and in the regulatory protein large T antigen than in the agnoprotein or in VP2/3. Notable Type 3-specific changes were located at sites adjacent to the zinc finger motif and near the major donor and acceptor splice junctions of large T antigen. Four of the five urinary Type 3 strains had an unrearranged, archetypal regulatory region. African strain #309 showed a 10-bp deletion at a location similar to that previously described for #307 from Tanzania. The African-American Type 3 strain #312 was closely related to the African consensus sequence. The complete genome of a urinary JCV strain from another African-American male, previously reported as a possible Type 5, showed a sequence difference of only 0.52% from the Tanzanian consensus and has been reclassified as a subtype of Type 3.

Amino Acid Sequence↗
PubMed1999

Viral Load Monitoring in HIV Infection.

Measurement of HIV-1 viral load is now an accepted part of clinical practice for the determination of clinical prognosis and antiretroviral effectiveness in HIV infection. Consensus guidelines have been published on the appropriate use of this testing. Furthermore, recent advances in molecular technology have improved the sensitivity and reproducibility of viral load assays, and these improved assays have provided new insight into the pathogenesis of HIV disease. This article reviews new issues affecting viral load quantification, including viral subtypes, sex, compartmental differences, and other covariables.

Journal Article↗
PubMed2004

Crystallization of a non-B and a B mutant HIV protease.

HIV polymorphism is responsible for the selection of variant viruses resistant to inhibitors used in AIDS treatment. Knowledge of the mechanism of resistance of those viruses is determinant to the development of new inhibitors able to stop, or at least slow down, the disease's progress caused by new mutations. In this paper, the crystallization and preliminary crystallographic structure solution for two multi-resistant 99 amino acid HIV proteases, both isolated from Brazilian patients failing intensive anti-AIDS therapy are presented, viz. the subtype B mutant, with mutations Q7K, S37N, R41K, K45R, I54V, L63P, A71V, V82A and L90M, and the subtype F (wild type), naturally carrying mutations Q7K, I15V, E35D, M36I, S37N, R41K, R57K, D60E, Q61N, I62V, L63S, I64L and L89M, with respect to the B consensus sequence. Both proteins crystallized as a complex with the inhibitor TL-3 in space group P6(1)22. X-ray diffraction data were collected from these crystals to resolutions of 2.1 and 2.6 A for the subtype B mutant and subtype F wild type, respectively, and the enzyme structures were solved by molecular replacement. The crystals of subtype F HIV protease are, to the best of the authors' knowledge, the first protein crystals obtained for a non-B HIV protease.

Crystallization↗
PubMed1997

Comparative modeling and molecular dynamics studies of the delta, kappa and mu opioid receptors.

Molecular models of the trans-membrane domains of delta, kappa and mu opioid receptors, members of the G-protein coupled receptor (GPCR) superfamily, were developed using techniques of homology modeling and molecular dynamics simulations. Structural elements were predicted from sequence alignments of opioid and related receptors based on (i) the consensus, periodicities and biophysical interpretations of alignment-derived properties, and (ii) tertiary structure homology to rhodopsin. Initial model structures of the three receptors were refined computationally with energy minimization and the result of the first 210 ps of a 2 ns molecular dynamics trajectory at 300K. Average structures from the trajectory obtained for each receptor subtype after release of the initial backbone constraints show small backbone deviations, indicating stability. During the molecular dynamics phase, subtype-differentiated residues of the receptors developed divergent structures within the models, including changes in regions common to the three subtypes and presumed to belong to ligand binding regions. The divergent features developed by the model structures appear to be consistent with the observed ligand binding selectivities of the opioid receptors. The results thus implicate identifiable receptor microenvironments as primary determinants of some of the observed subtype specificities in opiate ligand binding and in functional effects of mutagenesis. Networks of interacting residues observed in the models are common to the opiate receptors and other GPCRs, indicating core interfaces that are potentially responsible for structural integrity and signal transduction. Analysis of extended molecular dynamics trajectories reveals concerted motions of distant parts of ligand-binding regions, suggesting motion-sensitive components of ligand binding. The comparative modeling results from this study help clarify experimental observations of subtype differences and suggest both structural and dynamic rationales for differences in receptor properties.

Amino Acid Sequence↗
PubMed1997

Three-dimensional models of interferon-alpha subtypes IFN-con1, IFN-alpha8, andIFN-alpha1 derived from the crystal structure of IFN-alpha2b.

The crystal structure of human interferon (Hu-IFN)-alpha2b has been determined at 2.9 A resolution. This experimentally derived model provides an accurate structural scaffold on which amino acid changes between the different human IFN-alpha subtypes may be compared. Accurate structural data are essential to identify structurally important residues buried in the hydrophobic core of the molecule from solvent accessible residues that may participate in receptor binding. Furthermore, the location and chemical composition of each amino acid substitution may be used to predict potential conformation changes that may occur in the different subtypes. The possible structural and surface effects of these amino acid changes on receptor binding and biologic activity are analyzed in the context of a proposed IFN-alpha receptor complex model. This model can be improved and corrected as additional biochemical and experimental structural data are obtained. These modeling techniques have been used to assess the structural and functional consequences of amino acid changes between Hu-IFN-alpha2b and consensus IFN (IFN-con1), Hu-IFN-alpha8, and Hu-IFN-alpha1, which each have distinct receptor-binding and biologic properties. Amino acids in IFN-alpha1 and IFN-alpha8 were identified that may explain the lower specific activities of these subtypes versus the activity of IFN-alpha2b. In contrast, a molecular explanation for the reported differences between IFN-alpha2b in receptor binding affinity of either IFN-alpha8 or IFN-con1 was not readily apparent. Notably, 15 of the 19 amino acid differences in IFN-con1 compared with IFN-alpha2b are located on the exterior surface, where they may enhance the antigenicity of this synthetic, nonnaturally occurring IFN. These modeling studies should assist in the design of further experiments to clarify these observations.

Amino Acid Sequence↗
PubMed2005

Role of specific protein kinase C isoforms in modulation of beta1- and beta2-adrenergic receptors.

The function of beta-adrenergic receptor (betaAR) is modulated by the activity status of alpha1-adrenergic receptors (alpha1ARs) via molecular crosstalk, and this becomes evident when measuring cardiac contractile responses to adrenergic stimulation. The molecular mechanism underlying this crosstalk is unknown. We have previously demonstrated that overexpression of alpha1B-adrenergic receptor (alpha1BAR) in transgenic mice leads to a marked desensitization of betaAR-mediated adenylyl cyclase stimulation which is correlated with increased levels of activated protein kinase C (PKC) beta, delta and [J. Mol. Cell. Cardiol. 30 (1998) 1827]. Therefore, we wished to determine which PKC isoforms play a role in heterologous betaAR desensitization and also which isoforms of the betaAR were the molecular target(s) for PKC. In experiments using constitutively activated PKC expression constructs transfected into HEK 293 cells also expressing the beta2AR, constitutively active (CA)-PKC overexpression was first confirmed by immunoblots using specific anti-PKC antibodies. We then demonstrated that the different PKC subtypes lead to a decreased maximal cAMP accumulation following isoproterenol stimulation with a rank order of PKCalpha > or = PKCzeta>PKC>PKCbetaII. However, a much more dramatic desensitization of adenylyl cyclase stimulation was observed in cells co-transfected with different PKC isoforms and beta1AR. Further, the modulation of beta1AR by PKC isoforms had a different rank order than for the beta2AR: PKCbetaII>PKCalpha>PKC>PKCzeta. PKC-mediated desensitization was reduced by mutating consensus cAMP-dependent protein kinase (PKA)/PKC sites in the third intracellular loop and/or the carboxy-terminal tail of either receptor. Our results demonstrate therefore that the beta1AR is the most likely molecular target for PKC-mediated heterologous desensitization in the mammalian heart and that modulation of adrenergic receptor activity in any given cell type will depend on the complement of PKC isoforms present.

Adenylyl Cyclases↗
PubMed1999

Classification, pathogenesis and molecular pathology of primary CNS lymphomas.

Classification, pathogenesis and molecular pathology of primary central nervous system lymphomas (PCNSL) pose major clinico-pathologic problems. Application of histopathologic classification schemes developed for nodal lymphomas, i.e. the Kiel Classification and the Working Formulation, is not reliable and clinically not relevant for PCNSL. The more recent REAL Classification will simplify subtyping of PCNSL, but reliability and clinical significance remain to be determined. There are virtually no experimental data on whether PCNSL develop outside of the brain, or whether they arise from polyclonal lymphoproliferations within the brain. Mutations of oncogenes and tumor suppressor genes have been analyzed in only a few tumors, and their type and frequency is essentially unknown. In conclusion, compared with both neuroectodermal brain tumors and nodal lymphomas, and given the increasing incidence and clinical impact of PCNSL, there is a remarkable lack of histopathologic consensus as well as a surprising shortage of pathogenetic and molecular genetic information.

Brain Neoplasms↗
PubMed2004

Temporal trends in the HIV-1 epidemic in Russia: predominance of subtype A.

During the period 1996-1997, three highly homogeneous variants of HIV-1 were identified, circulating among injecting drug users (IDUs) in the former Soviet Union republics. One of these belonged to HIV-1 genetic subtype A (IDU-A), another belonged to HIV-1 genetic subtype B (IDU-B) and the third was a recombinant between the first two variants (CRF03_AB). However, since 1997, the HIV-1 epidemic has affected an increasing number of geographic regions in Russia. This study was undertaken to survey the prevailing genetic variants and to estimate the current proportions of these three HIV-1 genetic subtypes in Russia. Blood samples were taken in 1999-2003 from 1090 HIV-infected individuals and analysed by gag/env HMA. The IDU-A variant was found to be the majority variant (89.7-100%) in 44 of 45 regions of the Russian Federation studied. The IDU-A variant was also found to spreading rapidly through heterosexual transmission in 1999-2003 (30/34, 88%). CRF03_AB predominates in the Kaliningrad region only (28/29, 96.6%). The IDU-B variant is currently of minor importance in the IDU epidemic but other European subtype B variants predominate among men having sex with men (18/18, 100%). Sequence analysis of the env V3 encoding regions derived from HIV-1 infected individuals in Yekaterinburg (the main centre of the HIV-1 epidemic in Russia in 2002-2003) showed that the IDU-A variant is still highly homogeneous. The mean pairwise nucleotide distance (n = 9) was 2.89 +/- 1.14 (range 1.36-6.14). However, the mean genetic distance between each sequence within the samples collected from the Yekaterinburg IDU-A variant subset and the IDU-A consensus is 2.51 +/- 1.06 (range 1.36-4.66) and considerably higher than in South Russia in 1996 (0.79 +/- 0.51, range 0.38-1.90). The current HIV-1 epidemic in Russia is almost entirely caused by a highly homogeneous A-subtype strain, which will influence vaccine development strategies and must be taken into account in the quality control of molecular tests for the diagnosis of HIV-1.

Adolescent↗
PubMed2000

A distinctive clade B HIV type 1 is heterosexually transmitted in Trinidad and Tobago.

HIV-1 transmission worldwide is predominantly associated with heterosexual activity, and non-clade B viruses account for the most spread. The HIV-1 epidemic in Trinidad/Tobago and the Caribbean shares many features with such heterosexual epidemics, including a prominent role for coincident sexually transmitted diseases. This study evaluates the molecular epidemiology of HIV-1 in Trinidad/Tobago during a period when abrupt transition from homosexual to heterosexual transmission occurred in the absence of injecting drug use, concomitant with a rapid rise in HIV-1 prevalence in the heterosexual population. Of 31 viral isolates studied during 1987-1995, all cluster with subtype B reference strains. In the analysis of full env genes from 22 early seroconverters, the Trinidad isolates constitute a significant subcluster within the B subtype. The Trinidad V3 consensus sequence differs by a single amino acid from the prototype B V3 consensus and demonstrates stability over the decade of this study. In the majority of isolates, the V3 loop of env contains a signature threonine deletion that marks the lineage of the Trinidad HIV-1 clade B epidemic from pre-1984. No phenotypic features, including syncitium induction, neutralization profiles, and chemokine receptor usage, distinguish this virus population from other subtype B viruses. Thus, although the subtype B HIV-1 viruses being transmitted in Trinidad are genetically distinguishable from other subtype B viruses, this is probably the result of a strong founder effect in a geographically circumscribed population rather than genetic selection for heterosexual transmission. These results demonstrate that canonical clade B HIV-1 can generate a typical heterosexual epidemic.

Amino Acid Sequence↗
PubMed1994

Identification of a human delta opioid receptor: cloning and expression.

The delta opioid receptor is an important target for analgesic drug development. This report describes the identification of delta opioid receptor clones from human cDNA libraries and the preparation of a human delta receptor cDNA in the pcDNA3 expression vector for transfection studies. The cDNA encodes a 372 amino acid protein that has 93% amino acid identity to mouse and rat delta receptors. COS-7 cells transfected with this clone express over 1.0 pmol receptor/mg protein when measured by saturation binding with [3H]naltrindole. The delta receptor selective ligands NTB, BNTX, [4'-Cl-Phe4]DPDPE and [D-Ala2,Glu4]deltorphin all have Ki values under 10 nM while the affinities of the mu and kappa opioid receptor ligands CTAP and U-69593, respectively, are over 4.0 microM. Agonists show binding to multiple affinity states of the receptor consistent with the presence of G-protein coupled and uncoupled forms of the expressed receptor. The 8-fold higher affinity of NTB relative to BNTX suggests that the human delta receptor is of the delta 2 subtype.

Amino Acid Sequence↗
PubMed2005

Characteristics of HIV-1 env V3 loop sequences for subtype A1 variant spread in Eastern Europe.

OBJECTIVES: The aim of our investigation was to study the HIV-1 env V3 loop sequences of the subtype A variant of the virus actively circulating in the territory of Eastern Europe (A1-EE). DESIGN: It appears that the characteristics of HIV-1 V3 loop sequences of the thoroughly studied subtype B strains determine the viruses tropism and phenotype. We were interested to find out to what extent these trends are preserved with the subtype A isolates spread in Eastern Europe. METHODS: About 474 HIV-1 strains were isolated by cocultivation with phytohemagglutinin stimulated and interleukin-2 activated PBMC. Isolates were subtyped after distinct regions gag, pol and env were amplified by nested polymerase chain reaction. V3 sequences were studied in detail and compared with the isolates that appeared as SI or NSI in test-cultures MT-2. RESULTS: The subtype A HIV-1 strains spread in Eastern Europe appeared to have V3 loop sequences with a high level of conservatism. The consensus sequences of the SI and NSI isolates proved identical, and correspond to the phenotype markers of subtype B NSI strains. Nevertheless, the subtype A SI isolates induced active syncytium-formation processes in the MT-2 test culture. CONCLUSION: The data obtained evidenced to the following: the HIV-1 subtype A variant spread in Eastern Europe, is capable of using for interaction with receptor structures of sensitive cells the tools and mechanisms, which are significantly different from those described for subtype B.

Amino Acid Motifs↗
PubMed2001

Tamoxifen agonism and estrogen antagonism of c-fos gene promoter activity through non-consensus-responsive elements in MC3T3-E1 osteoblasts.

We find that the activity of a 0.4-kb human c-fos gene promoter (-404/+41), which lacks consensus estrogen-responsive elements (EREs), is regulated by estrogen receptor (ER) ligands in MC3T3-E1 osteoblastic cells through ERs in a manner distinct from ERE-mediated regulation. When ERalpha is coexpressed, both estrogens and antiestrogens upregulate promoter activity. When ERbeta is coexpressed, however, three tested antiestrogens affect c-fos promoter activity, with tamoxifen exerting the greatest effect, while estrogens have no such effect. The tamoxifen agonism through ERbeta is antagonized by 17beta-estradiol, while the 17beta-estradiol agonism through ERalpha is canceled by excess-level coexpression of ERbeta. Deletion analysis revealed that the sequence -206/-110 plays a crucial role in the ERbeta-mediated tamoxifen agonism. Interestingly, there is no ERbeta-mediated tamoxifen agonism when nonosteoblastic cells are tested. Taken together, these results suggest that the transcription of the c-fos gene is regulated by ER ligands possibly through non-ERE elements in ligand structure-, cell type-, and ER subtype-dependent manners.

Animals↗