β-Chemokine MDC and HIV-1 Infection Lee, Benhur; Rucker, Joseph; Doms, Robert W. ...
Science (American Association for the Advancement of Science),
07/1998, Letnik:
281, Številka:
5376
Journal Article
The monoclonal antibody VRC01 targets the CD4 binding site of the human immunodeficiency virus (HIV)-1 envelope. In the clinical study HVTN 104 (NCT02165267), 84 HIV-uninfected adults received ...multiple-dose intravenous (IV) VRC01 (10, 20, 30 or 40 mg/kg) every 4 or 8 weeks or subcutaneous (SC) VRC01 (5 mg/kg) every 2 weeks, and were followed for 32 weeks. We conducted a population pharmacokinetics (popPK) analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first-order elimination; for SC VRC01 a depot compartment with a first-order absorption rate constant was also included. All PK parameters were estimated with acceptable precision. Estimated bioavailability of SC VRC01 was 74%, with peak concentrations occurring 2-3 d after administration. For both IV and SC VRC01, population mean estimates for clearance (CL), central volume of distribution (Vc), inter-compartmental distribution clearance (Q) and peripheral volume of distribution (Vp) were 0.40 L/day, 1.94 L, 0.84 L/day and 4.90 L, respectively; the estimated terminal half-life was 15 d and these were independent of VRC01 dose. Body weight significantly influenced CL (1.2% fold/kg), Vc (1.0% fold/kg), Q (0.69 log(L/day)/kg) and Vp (0.82 log(L)/kg). The developed popPK model, supporting weight-dependent dosing regimens, projected positive trough levels, 5.54 (95% prediction interval: 1.69, 14.5) mcg/mL and 15.9 (5.29, 46.63) mcg/mL, respectively, for the 10 mg/kg and 30 mg/kg 8-weekly regimens being evaluated in ongoing HIV prevention efficacy studies of IV VRC01. These results are critical for future dose-regimen selection and modeling research to identify VRC01 serum concentration levels sufficient for protection against HIV infection.
Human retroviruses, including Human Immunodeficiency Virus (HIV) and Human T-cell Lymphotrophic Virus Types I and II (HTLV-I/II), have been associated with forms of connective tissue autoimmune ...diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These investigations were unable to find evidence for HTLV and/or HIV in a population of 115 autoimmune and control patients based on serology, virological and genomic analysis, including PCR amplification of DNA. These results suggest that there is no increased incidence of prototypic HTLV-I/II infection in this test population of SLE and RA patients. Kaposi's sarcoma (KS) is the most common malignancy associated with acquired immune-deficiency syndrome (AIDS). These investigations compared epidermal and oral-mucosal derived KS cell strains for histological grade associated differences in growth potential and autologous cytokine release. These are the first reports of histological grade associated differences in KS-lesional cell growth potential. This is indicated by the ability of higher histological grade oral-mucosal cells to proliferate in minimally supplemented medium as compared to limited proliferation of low histological grade epidermal lesional strains. Based on ELISA analysis of AIDS-KS cell strains, there were no significant differences in autologous cytokine release based on the histological grade of the lesional cells. In addition, sera analysis of oral and epidermal AIDS-KS and AIDS$\sp+$/KS$\sp-$ patients indicates no significant differences based on site or presence of KS. HTLV and simian T-cell lymphotrophic virus both contain a tax gene which has the ability to transactivate transcription of viral and various cellular genes. These investigations analyzed autologous cytokine and p24 antigen release by a variety of cell lines known to express different concentrations of virus. Included in these studies was a biological clone of MT-1 characterized to contain the viral genome, while only expressing antigen after deoxynucleoside analogue induction. Although not a direct linear relationship, cell lines that expressed higher concentrations of p24 antigen proportionally released higher levels of cytokines. In addition, for correct result interpretation, we established a need to express cytokine levels in both unit/volume and unit/cell density terms.
Using effective temperature and metallicity derived from SDSS spectra for ~60,000 F and G type main sequence stars (0.2<g-r<0.6), we develop polynomial models for estimating these parameters from the ...SDSS u-g and g-r colors. We apply this method to SDSS photometric data for about 2 million F/G stars and measure the unbiased metallicity distribution for a complete volume-limited sample of stars at distances between 500 pc and 8 kpc. The metallicity distribution can be exquisitely modeled using two components with a spatially varying number ratio, that correspond to disk and halo. The two components also possess the kinematics expected for disk and halo stars. The metallicity of the halo component is spatially invariant, while the median disk metallicity smoothly decreases with distance from the Galactic plane from -0.6 at 500 pc to -0.8 beyond several kpc. The absence of a correlation between metallicity and kinematics for disk stars is in a conflict with the traditional decomposition in terms of thin and thick disks. We detect coherent substructures in the kinematics--metallicity space, such as the Monoceros stream, which rotates faster than the LSR, and has a median metallicity of Fe/H=-0.96, with an rms scatter of only ~0.15 dex. We extrapolate our results to the performance expected from the Large Synoptic Survey Telescope (LSST) and estimate that the LSST will obtain metallicity measurements accurate to 0.2 dex or better, with proper motion measurements accurate to ~0.2 mas/yr, for about 200 million F/G dwarf stars within a distance limit of ~100 kpc (g<23.5). abridged
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