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Biomedical subjects

S Rusconi

Publications and source records attributed to S Rusconi.

At least 55 records · Page 3Linked to original sources
PubMed1997

Patterns of in vitro anti-human immunodeficiency virus type 1 antibody production in long-term nonprogressors.

With the aim of evaluating the specific pattern of in vitro antibody production (IVAP) in human immunodeficiency virus type 1 (HIV-1)-infected long-term non-progressors (LTNPs), we tested 20 subjects who had remained asymptomatic for more than 8 years with a CD4+ cell count higher than 500/microliter and 59 patients at different stages of HIV-1 infection as controls. In cell cultures, IVAP was detected in 14 out of 20 LTNPs (70%), in 5 out of 6 recent seroconverters (83%), and in all the other control patients. Anti-p24 antibody production was significantly lower in LTNPs than in asymptomatic patients with a more recent infection. Recent seroconverters and patients with AIDS did not produce anti-p24 antibodies (P = 0.02). Anti-gp160 antibodies were produced by peripheral blood mononuclear cells from LTNPs in 12/20 cases. CD4+ cell count was significantly higher in IVAP-negative than in IVAP-positive LTNPs (P = 0.013), while the viral load was not significantly different. Specific anti-HIV-1 antibody production did not seem to be a correlate of long-term nonprogression.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Adenovirus-mediated gene transfer into monocyte-derived macrophages of patients with X-linked chronic granulomatous disease: ex vivo correction of deficient respiratory burst.

The underlying cause of X-linked chronic granulomatous disease (X-CGD) is mutations in the gp91phox coding gene. Gp91phox is the larger subunit of the cytochrome b558, the membrane-bound terminal redox centre of the respiratory burst oxidase (NADPH oxidase). We have constructed a recombinant adenovirus which contains a functional copy of the human gp91phox cDNA under the control of the cytomegalovirus (CMV) enhancer/promoter region. This vector was used to infect monocyte-derived macrophages of gp91phox-deficient CGD patients. Expression of the gp91phox transgene resulted in ex vivo reconstitution of the respiratory burst activity. Nitroblue-tetrazolium staining indicated that 74% of the patient cells could be phenotypically corrected when compared with a corresponding control culture of normal monocyte-derived macrophages. Adenoviral gene transfer may become a promising tool and gain therapeutical potential by the targeting of autologous monocytes. Genetically corrected autologous monocytes may be used for supportive treatment of X-CGD patients to overcome acute life-threatening infections. Establishment of adenovirus-mediated reconstitution of gp91phox-deficient monocytes therefore represents a first step towards the development of a clinically applicable supportive transient somatic gene therapy in CGD.

Adenoviridae↗
PubMed1997

Loss of antiviral effect owing to zidovudine and lamivudine double resistance in HIV-1-infected patients in an ongoing open-label trial.

In order to compare the resistance pattern to zidovudine plus lamivudine in zidovudine-experienced patients, we studied three HIV-1-infected patients enrolled in NUCB3004, an open-label trial. Over a 24-week follow-up, the patients were studied for drug sensitivity, reverse transcriptase genotype, viral load (HIV-1 RNA level) and viral phenotype (syncytium inducing (SI) or non-syncytium inducing). Virus isolates derived from peripheral blood mononuclear cells (PBMCs) were tested for changes in drug susceptibility. Proviral DNA in the patients' PBMCs and RNA from plasma and culture supernatant were subjected to amplification and sequencing. All three HIV-1 strains showed a decreased susceptibility to either zidovudine or lamivudine after 24 weeks of therapy. The pattern of DNA genotypic resistance to lamivudine in patient A showed a mutation at codon 184 of the reverse transcriptase-encoding gene (methionine to valine). No HIV-1 strains with lamivudine-related mutations in proviral DNA were found among the isolates obtained from patients B and C. In these two patients, the mutation at codon 184 of the reverse transcriptase-encoding gene appeared in RNA, both in plasma and in culture supernatant. Viral phenotyping revealed the maintenance of the SI phenotype at week 24. Two out of the three patients experienced a reduction in HIV-1 RNA levels after 24 weeks of therapy, and in two out of three there was a rebound in viral load at week 28 together with the onset of the codon 184 mutation in RNA. The degree of phenotypic resistance to both zidovudine and lamivudine correlated with the amino acid changes in RNA and the rapid increase in viral load.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Yeast Gpi8p is essential for GPI anchor attachment onto proteins.

Glycosylphosphatidylinositol (GPI) anchors are added onto newly synthesized proteins in the ER. Thereby a putative transamidase removes a C-terminal peptide and attaches the truncated protein to the free amino group of the preformed GPI. The yeast mutant gpi8-1 is deficient in this addition of GPIs to proteins. GPI8 encodes for an essential 47 kDa type I membrane glycoprotein residing on the luminal side of the ER membrane. GPI8 shows significant homology to a novel family of vacuolar plant endopeptidases one of which is supposed to catalyse a transamidation step in the maturation of concanavalin A and acts as a transamidase in vitro. Humans have a gene which is highly homologous to GPI8 and can functionally replace it.

Amino Acid Sequence↗
PubMed1996

Glucocorticoids regulate the expression of the stressprotein alpha B-crystallin.

alpha B-crystallin is a major component of the eye lens but is also found in many extralenticular tissues. In established fibroblasts it is synthesized in response to stress such as hyperthermia. Here we report that the treatment of NIH3T3 fibroblasts with the synthetic glucocorticoid hormone dexamethasone resulted in the accumulation of substantial amounts of alpha B-crystallin, alpha B-crystallin mRNA accumulated slowly and over a period of many days in response to prolonged hormone treatment. alpha B-crystallin promoter-reporter constructs were hormone responsive. A putative glucocorticoid response element (GRE) within the analysed promoter region could bind the glucocorticoid receptor as revealed from in vitro footprint analysis but is not involved in the hormone-mediated gene activation. Deletions of 5' flanking regions to position -465 relative to the transcription start allowed for full hormone responsiveness. A deletion from -465 to -389 abolish hormone-mediated gene induction. No sequence element closely resembling a classical GRE is present within that hormone-responsive region.

3T3 Cells↗
PubMed1996

Human immunodeficiency virus (HIV) phenotype and interleukin-2/ interleukin-10 ratio are associated markers of protection and progression in HIV infection.

Human immunodeficiency virus (HIV) isolability, rate of viral replication, HIV phenotype, type 1 and type 2 cytokine production, and CD4 counts were cross sectionally analyzed in 63 HIV seropositive (HIV+) individuals to establish possible correlations between virologic and immunologic markers of protection and progression. We observed that these markers are tightly correlated. Thus, lack or low prevalence of HIV isolability and the presence of nonsyncitium inducing strains are associated with the strongest type 1 cytokine production, the weakest type 2 cytokine production, and highest CD4 counts. Conversely, the isolation of highly replicating, syncitium-inducing HIV strains is associated with the weakest type 1 cytokine production, the strongest type 2 cytokine production, and lowest CD4 counts. Additionally, it was determined that the interleukin (IL)-10/IL-2 ratio best discriminates among different virologic scenarios. These data suggest that the virologic and immunologic correlates of disease protection and progression might be associated variables that define two different subsets of HIV+ individuals and lend support to a viro-immunologic hypothesis of HIV infection.

Biomarkers↗
PubMed1996

Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG-rich regions.

Cytosine methylation of binding sites for transcription factors is a straightforward mechanism to prevent transcription, while data on an indirect mechanism, by methylation outside of the factor binding sites, are still scarce. We have studied the latter effect using a model promoter construct. For this, a 69 bp G + C rich DNA segment with a cluster of 14 CpG sites was inserted between upstream lexA sites and the TATA box. Transcription was measured in transient transfection assays with lexA-VP16 as an activating factor. When the entire plasmid was methylated at all CpGs before transfection, transcription was blocked (to 3% residual activity), whereas transcription was only mildly inhibited (to 60%) by methylation of a control plasmid that lacked the 69 bp CpG cluster. However, the effect could not simply be attributed to methylation of the CpG cluster: neither a methylated CpG cluster in an otherwise methylation-free reporter gene plasmid, nor the methylated plasmid with an unmethylated CpG cluster, inhibited transcription considerably (69% and 44% remaining activity, respectively). The data presented here suggest that a minimal length of methylated DNA in the promoter is required for repression, and imply that concomitant methylation of CpGs in the promoter region and in remote sequences can cooperatively block transcription, without the need to methylate any binding sites for transcription factors. We also note that the cooperation for a negative effect described here bears an analogy to transcriptional activation, where a promoter often cooperates with a remote enhancer.

Base Sequence↗
PubMed1996

No evidence of a higher risk of progression to AIDS in patients with HIV-1-related severe thrombocytopenia.

The prognostic role of platelet (PLT) counts was evaluated in a cohort of 1,533 HIV-1-infected subjects followed for a median of 21 months. Thrombocytopenia (TCP), defined as a PLT count < or = 100 x 10(9)/L was present at enrollment in 11.2% of cases, with counts < or = 50 x 10(9)/L (severe TCP) in 5.3%. With the subjects with normal PLT counts (PLT >150 x 10(9)/L) as the reference group, the relative risk of developing acquired immunodeficiency syndrome (AIDS) was 0.8 [95% confidence interval (CI) 0.5-1.3, p = 0.4] for subjects with severe TCP, 2.1 (95% CI 1.4-3.1, p = 0.002) for those with PLT counts ranging from 51 to 100 x 10(9)/L (moderate TCP), and 1.6 (95% CI 1.2-2.1, p = 0.0004) for those with borderline PLT values (PLT ranging from 101 to 150 x 10(9)/L). Most of the risk increase associated with moderate TCP and borderline PLT values was explained by a higher prevalence of subjects with an older age and lower CD4+ cell counts. However, at multivariable analysis considering age, sex, risk group, and zidovudine (ZDV) treatment, the risk for subjects with severe TCP remained significantly lower than that for subjects with moderate TCP and borderline values. These results suggest the existence of different types of HIV-1-associated TCP and also suggest that severe TCP (which often arises in the early phases of infection) is not related to disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities.

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.

Animals↗