Showing papers by "David C. Schwartz published in 2000"
TL;DR: These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease and strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule.
Abstract: A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4(+) T cell counts and <50 copies/ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0. 001]. Antigen-specific CD8(+) T cells were enumerated by flow cytometric detection of intracellular IFN-gamma in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8(+) T cell responses were observed between B*57(+) LTNP and five B*57(+) progressors (P = 0.4). Although similar frequencies of peptide specific CD8(+) T cells were also found, the gag-specific CD8(+) T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57(+) LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.
1,010 citations
TL;DR: It is argued that dissociation of eIF4E from the cap structure is required before decapping, which indicates that these activators of decapping affect a step in mRNA turnover distinct from the competition between Dcp1 and eif4E.
Abstract: A major pathway of eukaryotic mRNA turnover occurs by deadenylation-dependent decapping that exposes the transcript to 5′→3′ exonucleolytic degradation. A critical step in this pathway is decapping, since removal of the cap structure permits 5′→3′ exonucleolytic digestion. Based on alterations in mRNA decay rate from strains deficient in translation initiation, it has been proposed that the decapping rate is modulated by a competition between the cytoplasmic cap binding complex, which promotes translation initiation, and the decapping enzyme, Dcp1p. In order to test this model directly, we examined the functional interaction of Dcp1p and the cap binding protein, eukaryotic translation initiation factor 4E (eIF4E), in vitro. These experiments indicated that eIF4E is an inhibitor of Dcp1p in vitro due to its ability to bind the 5′ cap structure. In addition, we demonstrate that in vivo a temperature-sensitive allele of eIF4E (cdc33-42) suppressed the decapping defect of a partial loss-of-function allele of DCP1. These results argue that dissociation of eIF4E from the cap structure is required before decapping. Interestingly, the temperature-sensitive allele of eIF4E does not suppress the decapping defect seen in strains lacking the decapping activators, Lsm1p and Pat1p. This indicates that these activators of decapping affect a step in mRNA turnover distinct from the competition between Dcp1 and eIF4E.
192 citations
TL;DR: Several immunogens induce HIV-specific neutralization and in vitro lymphoproliferation in adults at low HIV1 risk, but responses in persons at high HIV-1 risk are not known.
Abstract: Several immunogens induce HIV-specific neutralization and in vitro lymphoproliferation in adults at low HIV-1 risk, but responses in persons at high HIV-1 risk are not known. We performed a multicenter, double-blinded, adjuvant-controlled trial with two gp120 vaccines in 296 HIV-1-uninfected volunteers, including 176 reporting higher HIV-1 risk activities. The immunogens were remarkably well tolerated. After three immunizations, 210 of 241 vaccinees (87%) developed neutralizing antibodies, which persisted in 59% after 2 years. The injection drug users receiving SF-2/gp120 had decreased antibody responses relative to the lower risk groups. Envelope-specific lymphoproliferation peaked after two immunizations, and 54% of vaccinees mounted a DTH reaction to gp120 after 4 years. In summary, these immunogens have low adverse reactogenicity and induce durable antibody and T cell responses to the prototype strains. Unexpected differences in antibody responses among diverse HIV-1 risk strata lend support to the conduct of expanded phase II trials in populations other than low-risk volunteers.
62 citations
TL;DR: High-resolution optical mapping employing seven enzymes places 16 BAC clones derived from the DAZ locus of the human Y chromosome long arm into two contigs representing four distinct copies of theDAZ gene and highlights a number of differences between individual copies of DAZ.
Abstract: The accurate mapping of clones derived from genomic regions containing complex arrangements of repeated elements presents special problems for DNA sequencers. Recent advances in the automation of optical mapping have enabled us to map a set of 16 BAC clones derived from the DAZ locus of the human Y chromosome long arm, a locus in which the entire DAZ gene as well as subsections within the gene copies have been duplicated. High-resolution optical mapping employing seven enzymes places these clones into two contigs representing four distinct copies of the DAZ gene and highlights a number of differences between individual copies of DAZ.
22 citations
TL;DR: The numerous and diverse roles for mRNA degradation suggest that the modulation of mRNA stability is a critical step in the regulation of eukaryotic gene expression.
Abstract: BIOLOGICAL SIGNIFICANCE OF mRNA TURNOVER It has become clear that mRNA turnover can play a major role in the control of gene expression. In eukaryotic cells, the decay rates of individual mRNAs vary by more than two orders of magnitude (Singer and Penman 1973; Spradling et al. 1975; Cabrera et al. 1984). There have also been a growing number of examples wherein the regulation of gene expression in response to an environmental cue is attained by altering the rates of degradation for specific mRNAs (for review, see Ross 1995). In addition, a specialized system of mRNA decay, referred to as mRNA surveillance, functions to ensure that mRNA biogenesis has been completed correctly by degrading aberrant transcripts (for reviews, see Chapters 29 and 30). Finally, specific mechanisms of mRNA degradation function in the genespecific silencing induced by double-stranded RNA (for review, see Fire 1999). The numerous and diverse roles for mRNA degradation suggest that the modulation of mRNA stability is a critical step in the regulation of eukaryotic gene expression. PATHWAYS OF mRNA DEGRADATION Four distinct pathways of mRNA turnover have been identified in eukaryotic organisms (Fig. 1). In yeast, degradation begins by shortening of the 3′ poly(A) tail followed by removal of the 5′ cap structure (decapping), thus allowing 5′ to 3′ exonucleolytic digestion of the body of the transcript (Muhlrad and Parker 1992; Decker and Parker 1993; Hsu and Stevens 1993; Muhlrad et al. 1994, 1995). Alternatively, mRNAs can be degraded 3′ to 5′ following deadenylation (Muhlrad et al....
16 citations