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PubMed1977

Stereochemistry of metabolism of amphetamines: use of (-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride for GLC resolution of chiral amines.

Amphetamine and eight related compounds were reacted with the chiral acylating reagent (-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride to obtain, in each case, two diastereomeric amide derivatives. GLC conditions were found for the separation of the diastereomers in seven of the nine cases studied. This procedure may be suitable for the resolution of amino acid enantiomers via the amide derivatives of the methyl esters. Secondary amines were not derivatized under the reaction conditions used. A correlation between absolute configuration and elution order of the diastereomeric amides was observed for five compounds. The chiral acylating reagent was used in the determination of the enantiomeric composition of 2,5-dimethoxy-4-methylamphetamine excreted in rat urine after intraperitoneal drug administration. The chiral acylating reagent is suitable for the determination of the optical composition of compounds extracted from biological fluids.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed2001

Abnormalities of the spatiotemporal characteristics of gait at the onset of freezing in Parkinson's disease.

We investigated the spatiotemporal variables of gait leading up to freezing. Gait analysis was carried out on 14 patients with Parkinson's disease in the off phase of the medication cycle. A computerised, three-dimensional gait analysis system was used to measure the walking pattern. After several trials of normal walking with voluntary stopping, distracting manoeuvres and obstacles on the walkway were used to provoke freezing or festination. The gait variables of normal (off phase), festinating, prestop, and prefreezing strides were analysed using analysis of variance for repeated-measures. Cadence was excessively increased (68%) and stride length decreased (69%) during festination compared with normal off walking; a pattern which remained pronounced when comparing prefreezing strides with normal stopping. Analysing in more detail the three steps before a freeze, we found a progressive decrease of stride length and stable cadence rates and proportions of double support phases. The relationship between cadence and stride length exhibited an exponential increase of cadence with a decreasing stride length during festination and freezing. Results suggest that freezing is caused by a combination of an increasing inability to generate stride length superimposed on a dyscontrol of the cadence of walking.

Aged↗
PubMed1997

Interlimb coordination deficits in patients with Parkinson's disease during the production of two-joint oscillations in the sagittal plane.

Two-limb coordination patterns involving cyclical flexion-extension movements, performed in the same or in different directions, were studied in patients with Parkinson's disease and a group of elderly subjects. The three patterns referred to the homologous (both arms or legs), homolateral (right or left arm and leg), and heterolateral (right arm and left leg or vice versa) limb segment combinations that were performed in the sagittal plane from a seated position. Findings revealed that interlimb coordination deficits were evident in patients with Parkinson's disease. Moreover, mean cycle duration and its variability were increased, particularly during the production of nonhomologous limb movements in different directions. These temporal findings suggest that movement slowness was not a primary consequence of an intrinsic inability to move the limb segments at the required speed but rather reflected an intentional strategy to cope with the complexity of the coordination pattern. Finally, movement amplitude was substantially smaller and more variable in patients with Parkinson's disease, suggestive of hypometria during the production of these cyclical tasks.

Aged↗
PubMed2001

Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV.

Mechanisms of transplacental transmission of human immunodeficiency virus (HIV) are poorly understood. DC-SIGN is a C-type lectin able to bind HIV gp120 with high affinity, mediating HIV adsorption to the surface of dendritic cells for up to several days. Via this mechanism, DC-SIGN significantly enhances the infection of CD4(+) co-receptor (CCR5 or CXCR4)(+) T lymphocytes in trans. In this study, DC-SIGN-specific serum was developed to investigate the cell type responsible for the high level of DC-SIGN RNA expression previously observed in the placenta. DC-SIGN expression was shown on CD68(+) HLA-II(+) CD14(low) S100(+/-) CD83(-) CD86(-) cmrf-44(-) villous cells consistent with Hofbauer cells and also on CD68(+) HLA-II(+) CD14(high) S100(-) CD83(-) CD86(-) cmrf-44(-) decidual macrophages. The DC-SIGN(+) Hofbauer cells co-express CD4 and the chemokine receptors, CCR5 and CXCR4, observations which may account for the ability of these cells to become infected with HIV. These fetal DC-SIGN(+) cells are separated by only a layer of trophoblast from both DC-SIGN(+) maternal cells and maternal blood, potential sources of HIV in infected mothers. Previous studies have suggested that this trophoblast layer is frequently breached during pregnancy. It is therefore proposed that DC-SIGN may facilitate the transplacental transmission of HIV.

Antibody Specificity↗
PubMedDate not supplied

Prospects of HIV-1 entry inhibitors as novel therapeutics.

A great deal of progress has been made in understanding the mechanism of human immunodeficiency virus entry into target cells. Landmark discoveries such as the identification of viral coreceptors and the structure of a portion of the viral envelope protein (Env) bound to its receptor provided important insight into how Env mediates fusion of the viral and cellular membranes. This knowledge has been successfully applied to the development of inhibitors that target discrete steps of the entry process. Some of these compounds efficiently block HIV-1 replication in vitro and are currently being evaluated in clinical trials. In this review, we will introduce the challenges of antiviral therapy and highlight the need for novel therapeutics, such as entry inhibitors, to complement current antiviral regimens. The mechanism by which Env mediates HIV-1 entry and the therapeutic potential of small molecule inhibitors of this dynamic process will be discussed in detail.

Anti-HIV Agents↗
PubMed1998

An intricate Web: chemokine receptors, HIV-1 and hematopoiesis.

Cellular infection by the human immunodeficiency virus type 1 (HIV-1) requires interaction of the viral envelope protein with CD4 and at least one additional cell surface molecule, termed a "cofactor" or "coreceptor." Recent discoveries have determined that macrophage-tropic strains of HIV-1 which are largely responsible for sexual transmission require the beta-chemokine receptor CCR5 in addition to CD4, while the T cell tropic viruses that emerge later after infection use the alpha-chemokine receptor CXCR4. Thus, both CD4 and the appropriate chemokine receptor must be expressed on the cell surface in order for HIV-1 to enter the cell and establish an infection. The in vivo importance of CCR5 for HIV-1 is demonstrated by the finding that individuals homozygous for a 32 bp deletion (delta 32) in the CCR5 gene that renders them effectively CCR5-negative are highly resistant to virus infection. In this review, the structure-function correlates of the chemokine receptors that serve as major coreceptors for HIV-1 and simian immunodeficiency virus entry will be reviewed. Since certain chemokines have been implicated as stem cell inhibitory factors, the biological consequences of chemokine receptor expression as it relates to HIV-1-associated hematodyspoiesis will also be discussed.

Animals↗
PubMed1997

Improvement of clinical staging in cervical cancer with serum squamous cell carcinoma antigen and CA 125 determinations.

Staging of cervical cancer is routinely performed by means of examination under anesthesia in combination with radiographic and/or endoscopic techniques. This "clinical" staging leads to 10-25% misclassification, mostly due to positive lymph nodes or lymph or blood vessel invasion. Determination of pretreatment squamous cell carcinoma antigen (SCC) and CA 125 serum levels may solve part of this staging problem and may improve the selection of the most appropriate individual therapy. Using 2.5 ng/ml (SCC) and 35 U/ml (CA 125) as cutoff levels, we studied 99 patients retrospectively. Elevated levels were found in 27% (SCC) and 23% (CA 125). In clinical stage IB or IIA disease 45/81 patients had positive nodes or lymph or blood vessel invasion at operation. Of these patients 49% had elevated serum levels of SCC or CA 125. Strongest correlation was found with blood vessel invasion (57%). Only 19% of low-stage patients without evidence of vascular spread of disease had positive levels. The positive predictive value of SCC and CA 125 for detection of vascular spread of disease in low-stage cervical cancer was 76%. In most centers surgery is the primary treatment of choice in low-stage cervical cancer. Nevertheless, with respect to patient survival, results of primary surgery and primary radiotherapy are comparable. Radiotherapy given in an adjuvant setting leads to a high incidence of severe complications. In order to overcome part of these complications one should consider radiotherapy as the primary therapy of choice in patients with clinical stage IB or IIA cervical cancer with elevated pretreatment SCC or CA 125 levels.

Adult↗
PubMed1998

Structure-function studies of the HIV-1 coreceptors.

Ten seven-transmembrane-domain G protein-coupled receptors have been identified that are functional HIV-1, HIV-2 and SIV coreceptors. However, the specific structures these receptors have in common that enable them to mediate HIV entry are unknown. Structure-function analyses have revealed that the determinants of coreceptor activity are distinct for each coreceptor, coreceptor activity is dependent on multiple extracellular domains, and various envelope proteins may interact differently with the same coreceptor. G protein coupling and receptor internalization are not required for fusion and infection of established cell lines, or for inhibition of infection by chemokines. The structure-function studies have also helped determine the mechanism by which previously described small molecules inhibit HIV-1 entry. Finally, these studies have led to a hypothesis as to how coreceptor utilization evolves during the course of an infection.

Amino Acid Sequence↗
PubMed1993

Folding and assembly of viral membrane proteins.

It is now clear that folding in the ER is a dynamic, energy-driven process involving a host of cellular folding enzymes and molecular chaperones (see Fig. 1). Within this high-capacity folding environment, nascent molecules fold quickly and efficiently, while misfolded proteins are recognized and retained, being either degraded or rescued. The quality control mechanisms which account for this selective retention are most likely redundant and general in nature--an almost innumerable number of structures, from both endogenous and exogenous proteins, are operated on with equal efficiency. Studies with viral membrane proteins will continue to help illuminate these processes and have contributed greatly to the concepts of conformational maturation and quality control. Furthermore, while the effects of mutations on protein structure and transport cannot always be predicted, useful generalizations can now be made to help develop experimental strategies. Future studies will have to address a variety of unresolved issues. Given the almost limitless sequence and structural variability exhibited by proteins which fold in the ER, no one molecular chaperone is likely to be able to bind to all folding intermediates. Thus, GRP78-BiP is likely to be only one of a number of resident ER molecular chaperones. Identifying these molecules, the structural features to which they bind, and how they interact with other components of the folding machinery are areas in which important advances can be made. A particularly intriguing problem concerns the mechanisms by which the folding machinery is regulated. The synthesis of GRP78-BiP, for example, is strongly induced by elevated levels of misfolded proteins in the ER. How the levels of misfolded molecules are monitored and how this information can be used to regulate GRP78-synthesis is not known. Likewise, the means by which the ER environment, such as its oxidizing potential, is regulated have yet to be elucidated. It is important to note that a direct role for GRP78-BiP (or any other ER molecular chaperone) in folding has yet to be demonstrated in vitro. Reconstituting complex folding reactions in vitro will provide a way to specifically address the roles of folding enzymes and chaperones in protein folding and assembly. The molecular mechanisms which lead to the retention of misfolded proteins in the ER are still poorly understood, as are the mechanisms which lead to their degradation. Finally, whether quality control mechanisms play significant roles in regulating protein transport in other organelles represents an interesting area of research.

Animals↗
PubMed1998

Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope proteins.

Human and simian immunodeficiency viruses (HIV and SIV, respectively) use chemokine receptors as coreceptors along with CD4 to mediate viral entry. Several orphan receptors, including GPR1, GPR15, and STRL33, can also serve as coreceptors for a more limited number of HIV and SIV isolates. We investigated whether these orphan receptors could function as efficient coreceptors for a diverse group of HIV and SIV envelopes (Envs) in comparison with the principal coreceptors CCR5 and CXCR4. We found that a limited number of HIV-1 isolates could mediate inefficient cell-cell fusion with the orphan receptors relative to CCR5 and CXCR4; however, none of the orphan receptors tested could support pseudotype virus infection despite robust infection via CCR5 or CXCR4. All except one of the SIV Envs tested mediated some degree of cell-cell fusion and pseudotype infection, with target cells expressing at least one of these orphan receptors, although CCR5 proved to be the most efficient coreceptor for infection. Only one SIV Env protein, BK28, could mediate infection using GPR1 as a coreceptor, albeit much less efficiently than with CCR5. In addition, use of these coreceptors did not correlate with the published tropism of the SIV clones and was strictly CD4 dependent for both SIV and HIV. We also examined the expression of these molecules in cell lines and primary cells widely used for virus propagation and as targets for infection. All cells examined expressed STRL33, a more limited number expressed GPR15, and GPR1 was much more restricted in its expression pattern. Taken together, our results indicate that GPR15 and STRL33 are rarely used by HIV-1 but are more frequently used by SIV strains, although not in a manner that correlates with SIV tropism.

Animals↗
PubMed1999

HIV and SIV gp120 binding does not predict coreceptor function.

Interaction of HIV and SIV Envelope (Env) proteins with viral coreceptors is a critical step in viral entry. By using a sensitive and specific gp120 binding assay, we have identified a discordance between the ability of a coreceptor to support Env-mediated membrane fusion and high-affinity binding of gp120. Direct binding of gp120 from the dual-tropic HIV-1 strain 89.6 was not detectable for any coreceptor that it uses for fusion, while detectable binding of gp120s from the R5 HIV-1 strains JRFL and CM235 and the SIV strain 239 was not measurable for many CCR5 chimeras and mutants that function efficiently as viral coreceptors. In comparison, binding of chemokines to these same mutants was highly predictive of their ability to signal. Thus, gp120 is more sensitive than chemokines to perturbations of CCR5 structure. We conclude that while chemokine binding to CCR5 is a good predictor of chemokine receptor function, gp120 binding does not always predict coreceptor function.

CD4 Antigens↗
PubMed1999

Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques.

Previously, we described the derivation of a pathogenic strain of simian-human immunodeficiency virus (SHIV(KU-2)) consisting of the tat, rev, vpu, and env genes of HIV-1 (strain HXB2) in a genetic background of SIV(mac)239 that causes AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta) (Raghavan et al., 1997, Brain Pathol. 7, 851-861). We report here on the characterization of a molecular clone of SHIV(KU-2), designated SHIV(KU-2MC4), that caused CD4(+) T cell loss as well as neurological and renal disease in macaques. DNA sequence analysis of selected SIV regions of SHIV(KU-2MC4) revealed 10 nucleotide changes in the LTR, whereas Gag, Vif, Vpr, Vpx, and Nef had 1, 1, 1, 2, and 13 predicted amino acid substitutions, respectively, compared to SIV(mac)239. DNA sequence analysis of HIV-1 derived regions of SHIV(KU-2MC4) revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu, and Env proteins, respectively, when compared to SHIV-4. Unlike the parental SHIV-4, which is not tropic for macrophages, SHIV(KU-2MC4) replicated efficiently in macrophage cultures as determined by p27 assays. However, despite the numerous changes in the Env protein and newly acquired tropism for macrophages, SHIV(KU-2MC4), like the parental SHIV-4, used CXCR4 exclusively as its coreceptor for entry into susceptible cells. Inoculation of SHIV(KU-2MC4) into two rhesus macaques resulted in severe infection in which the numbers of circulating CD4(+) T cells in the blood declined rapidly by 2 weeks postinoculation and virus producing cells in the peripheral blood mononuclear cells were identified throughout the course of infection. At the time of euthanasia (20 and 22 weeks), both macaques had lost a significant amount of weight and had no circulating CD4(+) T cells. In addition, one macaque developed intension tremors and uncoordinated movements. Virological examination of tissues at necropsy revealed active virus replication in both lymphoid and nonlymphoid tissues such as the lung and brain. Histological examination revealed that the induced immunodeficiency was associated with lymphoid depletion of the lymph nodes and spleen, opportunistic infections, lentiviral encephalitis, and severe glomerulosclerosis of the kidney. This molecular clone will serve as the basis for analyzing the molecular determinants through which SHIV(KU-2) causes severe CD4(+) T cell loss, neurological disease, and SHIV nephropathy in rhesus macaques.

AIDS Dementia Complex↗
PubMed2000

Expression and coreceptor function of APJ for primate immunodeficiency viruses.

APJ is a seven transmembrane domain G-protein-coupled receptor that functions as a coreceptor for some primate immunodeficiency virus strains. The in vivo significance of APJ coreceptor function remains to be elucidated, however, due to the lack of an antibody that can be used to assess APJ expression, and because of the absence of an antibody or ligand that can block APJ coreceptor activity. Therefore, we produced a specific monoclonal antibody (MAb 856) to APJ and found that it detected this receptor in FACS, immunofluorescence, and immunohistochemistry studies. MAb 856 also recognized APJ by Western blot, enabling us to determine that APJ is N-glycosylated. Using this antibody, we correlated APJ expression with coreceptor activity and found that APJ had coreceptor function even at low levels of expression. However, we found that APJ could not be detected by FACS analysis on cell lines commonly used to propagate primate lentiviruses, nor was it expressed on human PBMC cultured under a variety of conditions. We also found that some viral envelope proteins could mediate fusion with APJ-positive, CD4-negative cells, provided that CD4 was added in trans. These findings indicate that in some situations APJ use could render primary cell types susceptible to virus infection, although we have not found any evidence that this occurs. Finally, the peptide ligand for APJ, apelin-13, efficiently blocked APJ coreceptor activity.

Adipokines↗