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Biomedical subjects

C R Brown

Publications and source records attributed to C R Brown.

At least 55 records · Page 3Linked to original sources
PubMed1998

Viral genetic evolution in macaques infected with molecularly cloned simian immunodeficiency virus correlates with the extent of persistent viremia.

Genetic evolution of the simian immunodeficiency virus (SIV) envelope glycoprotein was evaluated in a group of six macaques (Macaca nemestrina) infected with the molecularly cloned, moderately pathogenic SIVsm62d. The extent of envelope evolution was subsequently evaluated within the context of the individual pattern of viremia and disease outcome. Two macaques in this cohort developed AIDS by 1.5 years postinoculation (progressors), whereas the remaining four macaques remained asymptomatic (nonprogressors). Compared with the nonprogressor macaques, the two progressor macaques exhibited higher persistent plasma viremia, higher homologous neutralizing antibody titers, and more extensive mutation and evolution in the V1 region of envelope. Although clearly distinct in each of these parameters from the progressors, the four nonprogressors exhibited more individual variability with respect to the extent of persistent viremia and genetic evolution of the V1 region of envelope. The extent of V1 envelope varied from no apparent V1 evolution in a macaque with good viral containment to extensive evolution in one macaque with persistent viremia. This study underscores the critical role of persistent replication in the genetic evolution of SIV.

Amino Acid Sequence↗
PubMed1998

A look at the facts.

Explore the source record for details and available documents.

Attitude of Health Personnel↗
PubMed1997

Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells.

Activation of CD4(+) T lymphocytes from human immunodeficiency virus-type 1 (HIV-1)-infected donors with immobilized antibodies to CD3 and CD28 induces a virus-resistant state. This effect is specific for macrophage-tropic HIV-1. Transcripts encoding CXCR4/Fusin, the fusion cofactor used by T cell line-tropic isolates, were abundant in CD3/CD28-stimulated cells, but transcripts encoding CCR5, the fusion cofactor used by macrophage-tropic viruses, were not detectable. Thus, CD3/CD28 costimulation induces an HIV-1-resistant phenotype similar to that seen in some highly exposed and HIV-uninfected individuals.

Antibodies, Monoclonal↗
PubMed1997

Correcting temperature-sensitive protein folding defects.

Recently, we found that different low molecular weight compounds, all known to stabilize proteins in their native conformation, are effective in correcting the temperature-sensitive protein folding defect associated with the deltaF508 cystic fibrosis transmembrane regulator (CFTR) protein. Here we examined whether the folding of other proteins which exhibit temperature-sensitive folding defects also could be corrected via a similar strategy. Cell lines expressing temperature-sensitive mutants of the tumor suppressor protein p53, the viral oncogene protein pp60src, or a ubiquitin activating enzyme E1, were incubated at the nonpermissive temperature (39.5 degrees C) in the presence of glycerol, trimethylamine N-oxide or deuterated water. In each case, the cells exhibited phenotypes similar to those observed when the cells were incubated at the permissive temperature (32.5 degrees C), indicative that the particular protein folding defect had been corrected. These observations, coupled with our earlier work and much older studies in yeast and bacteria, indicate that protein stabilizing agents are effective in vivo for correcting protein folding abnormalities. We suggest that this type of approach may prove to be useful for correcting certain protein folding abnormalities associated with human diseases.

Animals↗
PubMed1997

Enhanced follicular dendritic cell function in lymph nodes of simian immunodeficiency virus-infected macaques: consequences for pathogenesis.

HIV and simian immunodeficiency virus (SIV) infections are characterized by several abnormalities in B cell function. Pathogenesis is also associated with marked changes within germinal centers (GC) including hypertrophy and degeneration of follicular dendritic cells (FDC) and accumulation of both viral antigen and activated CD45RO+ CD8+ cells. Since FDC are critical to the generation of antibody-forming cells and specific B cell memory, the simplest assumption is that such B cell defects directly result from virus-induced changes in the GC environment. The present study examined FDC-enriched mesenteric lymph node lymphocyte preparations from early and late stage SIV-infected and uninfected macaques for their ability to support GC reactions in vitro. The results indicate that FDC function as measured by cluster formation, B cell proliferation and SIV-specific antibody production is enhanced in SIV-infected macaques suggesting that, despite FDC atrophy, virus accumulation induces increased FDC-B cell interactions resulting in B cell hyperactivity. The activation and proliferation of CD8+ cells in FDC-enriched cultures further suggest that the infiltrating CD8+ population observed in situ in GC of late-stage SIV/HIV-infected individuals may also benefit from FDC-derived growth signals. Thus, in addition to enhanced B cell proliferation and antibody production, hyperactivity of FDC may potentially promote their own self destruction via the infiltrating CD8+ cells. The increased B cell responsiveness may further exacerbate the disease process due to an overall decrease in the affinity of anti-HIV/SIV antibody, a loss of crucial protective antibodies to other infectious agents and the creation of an environment in which increased trapping of virions facilitates more extensive infection of CD4+ T cells.

Animals↗
PubMed1997

Patterns of genital injury in female sexual assault victims.

OBJECTIVE: New colposcopic protocols allow examiners to better document genital trauma in rape victims. We report our findings on the locations and types of genital injury seen in female assault victims versus women engaging in consensual sex. STUDY DESIGN: Physical examinations were performed on 311 rape victims seen by San Luis Obispo County's Suspected Abuse Response Team between 1985 and 1993 and contemporaneously on 75 women after consensual sexual intercourse. RESULTS: Among 213 (68%) victims with genital trauma, 162 (76%) had 3.1 mean sites of injury. Comparatively, 8 (11%) consenting women had just single-site trauma. Two hundred (94%) victims had trauma at one or more of four locations, as follows: posterior fourchette, labia minora, hymen, fossa navicularis. Trauma types varied by site; tears appeared most often on the posterior fourchette and fossa, abrasions appeared on the labia, and ecchymosis was seen on the hymen. CONCLUSION: A localized pattern of genital trauma can frequently be seen in women reporting nonconsensual sexual intercourse; such findings are useful for the clinical forensic examiner.

Adolescent↗
PubMed1997

Metabolism and thermoregulation in the forest shrew Myosorex varius (Soricidae: Crocidurinae).

The forest shrew (Myosorex varius) is grouped with the subfamily Crocidurinae, but recent allozyme evidence suggests that it is intermediate between the Crocidurinae and the Soricinae. It also exhibits some atypical morphological features. Because the two subfamilies have different habits and levels of metabolism, we measured activity patterns, metabolism and thermoregulation of M. varius to assess whether its physiology was consistent with that of the other crocidurines. Metabolic rate within the thermal neutral zone (29-35 degrees C) averaged 38.9 J g-1hr-1, close to expected levels for a mammal of equivalent size. Body temperatures were quite variable, ranging from 33.2-38.3 degrees C and were defended at temperatures as low as 6 degrees C by increased heat production. These data suggest that M. varius is a typical crocidurine. In contrast to other crocidurines, however, M. varius did not enter torpor. They also exhibit differences in their winter activity patterns and may be territorial, suggesting that at least in some respects M. varius does differ from other crocidurines.

Animals↗
PubMed1997

Strategies for correcting the delta F508 CFTR protein-folding defect.

Many human diseases arise as a result of mutations within genes encoding essential proteins. In many cases, the mutations are not so severe as to render the protein biologically inactive. Rather, the mutations oftentimes result in only subtle protein-folding abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a single amino acid is responsible for the diseased state in the majority of individuals with cystic fibrosis. Here the newly synthesized mutant CFTR protein, missing a phenylalanine residue at position 508 (delta F508 CFTR), is unable to transit from the endoplasmic reticulum to the plasma membrane, where it functions as a regulator of chloride transport. All of the available evidence indicate that the newly synthesized delta F508 CFTR protein adopts a slightly altered conformation and therefore is retained at the level of the endoplasmic reticulum, ostensibly by the actions of the cellular quality control system. Because the mutant protein is capable of functioning as a chloride channel, developing ways to elicit its release out of the ER and to the plasma membrane has important clinical implications. Herein, we discuss our recent studies showing that the protein-folding defect associated with the delta F508 CFTR mutation, as well as a number of other temperature-sensitive mutations, can be overcome by strategies designed to influence protein folding inside the cell. Specifically we show that a number of low-molecular-weight compounds, all of which are known to stabilize proteins in their native conformation, are effective in rescuing the folding and/or processing defects associated with different mutations that oftentimes lead to human disease.

Aminoglycosides↗
PubMed1997

Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1.

The condition of a chimpanzee (C499) infected with three different isolates of human immunodeficiency virus type 1 (HIV-1) for over 10 years progressed to AIDS. Disease development in this animal was characterized by (i) a decline in CD4+ cells over the last 3 years; (ii) an increase in viral loads in plasma; (iii) the presence of a virus, termed HIV-1JC, which is cytopathic for chimpanzee peripheral blood mononuclear cells; and (iv) the presence of an opportunistic infection and blood dyscrasias. Genetic analysis of the V1-V2 region of the envelope gene of HIV-1JC showed that the virus present in C499 was significantly divergent from all inoculating viruses (> or = 16% divergent at the amino acid level) and was suggestive of a large quasispecies. Blood from C499 transfused into an uninfected chimpanzee (C455) induced a rapid and sustained CD4+-cell decline in the latter animal, concomitant with high plasma viral loads. These results show that HIV-1 can induce AIDS in chimpanzees and suggest that long-term passage of HIV-1 in chimpanzees can result in the development of a more pathogenic virus.

Acquired Immunodeficiency Syndrome↗