摘要:

Summary:Intravenous injection of SHIV (simian/human immunodeficiency virus, chimeric virus) into rhesus macaques resulted in a viremia in peripheral blood lymphocytes (PBL) and the generation of anti-HIV-1 (human immunodeficiency virus type 1) envelope immune responses. A challenge stock of a SHIV containing HIV-1 HXBc2 envelope glycoproteins was prepared from infected rhesus monkey peripheral blood mononuclear cells (PBMC). The minimum animal infectious dose of the SHIV stock was determined and used in a challenge experiment to test protection. The vaccination of two rhesus monkeys with whole inactivated HIV-1 plus polydicarboxylatophenoxy phosphazene (PCPP) as the adjuvant protected the animals from becoming infected by a SHIV challenge. This experiment demonstrated for the first time that monkeys immunized with HIV-1 antigens can be protected against an HIV-1 envelope-containing virus. As the challenge virus was prepared from monkey PBMC, human antigens were unlikely to be involved in the protection. Protection of rhesus monkeys from SHIV challenge may help define protective immune responses stimulated by HIV-1 vaccine candidates.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:The levels of human immunodeficiency virus type 1 (HIV-1) RNA have been directly quantitated, after an isolation step, in plasma from patients with primary HIV-1 infection by free solution capillary electrophoresis (FSCE) with ultraviolet detection. HIV-1 RNA was detected and quantified at physiological levels by measuring the absorbance by FSCE. All the patients with primary infection showed concentrations in a range of 1.08-1.71 × 108virions/ml of plasma. No signals were observed in seronegative donors. This procedure represents a practical alternative to other methods to quantify HIV-1 RNA and may be useful in assessing the efficiency of antiretroviral agents, especially during the early stage when other conventional viral markers are often negative.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:This study was undertaken to analyze both the GM3 expression on peripheral blood lymphocytes of HIV-infected patients and the relationship between ganglioside content and anti-GM3 reactivity. GM3 expression was determined as a percentage of lipid-bound sialic acid and by cytofluorimetric analysis in 25 AIDS patients, 20 anti-HIV+asymptomatic subjects, 25 patients with different viral disease, and 25 healthy donors. GM3 distribution was analyzed by immunofluorescence and immunoelectron microscopy. A follow-up study to detect anti-lymphocytic GM3 antibodies was performed in progressive and nonprogressive anti-HIV+subjects. Lymphocytes from HIV-infected patients showed a significant increase of plasma membrane GM3 content; no difference was found between CD4+and CD8+cells. Immunofluorescence and immunoelectron microscopic analysis showed that GM3 was distributed in large clusters over the cell plasma membrane. The follow-up study revealed that the occurrence of anti-lymphocytic GM3 antibodies was significantly higher in patients with progressive disease, compared with asymptomatic nonprogressive subjects. These findings revealed that (1) the increased GM3 content in HIV-infected patients is detected at the plasma membrane level, (2) GM3 overexpression is able to induce an increased reactivity with anti-GM3 antibodies, and (3) the appearance of anti-lymphocytic GM3 antibodies in asymptomatic anti-HIV+subjects could have prognostic relevance for the risk of developing AIDS.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Canventol (2-isopropyl-4-isopropyldencyclohex-2-ene-1-ol), a blocker of tumor necrosis factor alpha (TNF-α) release, inhibits human immunodeficiency virus type (HIV-1) production in chronically and acutely infected cells. This effect of Canventol on virus replication could be correlated with its inhibitory influence on necrosis factor (NF)-κB activation and HIV-1 long terminal repeat (LTR)-driven reporter gene expression in Jurkat cells and these could be overcome by the administration of TNF-α. Canventol inhibits activation of the promoter by the viral protein Tat through a TAR-independent mechanism. The HIV-1 promoter is synergistically upregulated when both the TAR-independent and the TAR-dependent modes of Tat action are in operation. Tat-induced downstream events, such as the production of cytokines like TNF-α and NF-κB activation, are central for this upregulation. Inhibitors of the respective modes of action of Tat downregulate HIV-1 LTR activation and virus replication.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Tat regulates human immunodeficiency virus type 1 (HIV-1) gene expression by increasing both the rate of transcription initiation and the efficiency of transcription elongation. The ability of Tat to facilitate HIV-1 transcription preinitiation complex formation suggests that components of the basal transcriptional machinery may be targeted by Tat. Previous studies have demonstrated that Tat interacts directly with the human TATA-binding protein (TBP) and specific TBP-associated factors (TAFs) that comprise the TFIID complex. Here, in vitro glutathione S-transferase protein binding assays containing fully functional or transactivation-defective mutant Tat proteins have been used to investigate the functional significance of the direct interaction between Tat and TBP relative to Tat transactivation. Results demonstrate that full-length Tat, as well as the activation domain of Tat alone, binds human TBP in vitro. Site-directed mutations within the activation domain of Tat (C22G and P181S) that abrogate transactivation by Tat in vivo fail to inhibit Tat-TBP binding. Full-length Tat, the activation domain of Tat alone, and a transactivation-defective mutant of Tat that lacks N-terminal amino acid residues 2-36 bind with equal efficiencies to TBP provided that the H1 α helical domain that maps to amino acids 167-220 within the highly conserved carboxyl terminus of TBP is maintained. These data indicate that an activity mapped within the activation domain of Tat, which is distinct from Tat-TBP binding, is required for transactivation by Tat.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:We studied the distribution and localization of the human papovaviruses JCV and BKV in the central nervous system (CNS) and cerebrospinal fluid (CSF) of HIV-positive patients with and without progressive multifocal leukoencephalopathy (PML) as compared with HIV-seronegative patients. The presence of JCV-DNA and BKV-DNA was evaluated by nested polymerase chain reaction (PCR) and in situ hybridization (ISH) on CNS autopsy tissues of AIDS patients with (group A, n = 13) and without (group B, n = 16) PML and of HIV-negative patients (group C, n = 12). PCR for JCV-DNA and BKV-DNA was also performed on CSF samples collected 7-420 days before death in all the 29 AIDS patients. Tissue PCR for JCV-DNA was positive in all the cases in group A, in 44% of the patients in group B, and in 33% of the patients in group C. ISH was positive in all the cases with PML and in three AIDS cases without PML (12%), but negative in all the HIV-negative cases. BKV-DNA was detected in two cases from group A and in one case from group B. CSF was PCR-positive for JCV-DNA in 8 of 13 (62%) AIDS patients with PML, but in none of the HIV patients without PML, irrespective of the presence of JCV-DNA in CNS tissues. No CSF sample was positive for BKV-DNA. Our data demonstrates that JCV-DNA and, rarely, BKV-DNA can be detected in the CNS of immunocompromised patients with and without PML and also in the CNS of HIV-negative subjects. However, only HIV-positive patients with clinically evident PML and JCV-DNA in the brain have PCR-detectable JCV-DNA in their CSF.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Twenty-six AIDS patients were enrolled in an open label pilot study to evaluate the efficacy and toxicity of topical 1% ophthalmic trifluridine solution for the treatment of chronic mucocutaneous herpes simplex virus disease unresponsive to at least 10 days of acyclovir therapy. Susceptibility testing to acyclovir, trifluridine, and foscarnet was determined by plaque reduction assay. Twenty-four patients were evaluable for efficacy and 25 for toxicity analyses. Seven patients (29%) had complete healing of lesions. The overall estimated median time to complete healing was 7.1 weeks. An additional seven patients had ≥50% reduction in lesion area. The overall estimated median time to 50% healing was 2.4 weeks. Ten (42%) patients discontinued treatment for reasons other than primary treatment failure and seven (29%) for failure to respond to therapy. Baseline patient characteristics associated with greater reduction in lesion area included higher Karnofsky score (p = 0.05), fewer lesions (p = 0.07), smaller lesion area (p = 0.11), and trifluridine susceptibility (p = 0.07). Eight (33%) patients developed new lesions outside of the treatment area while on study, reflecting the local nature of this therapy. No dose-limiting toxicity attributable to trifluridine was reported. Given the limited options for the treatment of acyclovir-resistant herpes simplex disease, topical trifluridine may be a useful alternative in selected patients.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:We assessed the safety and surrogate markers' effect of acemannan as an adjunctive to antiretroviral therapy among patients with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI) in a randomized, double-blind, placebo-controlled trial of acemannan (400 mg orally four times daily). Eligible patients of either sex had CD4 counts of 50-300/μl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. P24 antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients. Sixty-three patients were randomized. All were males (mean age 39 years). The mean baseline CD4 counts were 165 and 147/μl in the placebo and acemannan groups, respectively; 90% of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDS-defining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were - 121 and - 120 cells per year in the placebo and acemannan groups, respectively (p = 0.45); ACD4 from week 16 to 48 was 0 and - 61 cells per year in the acemannan and placebo groups (p =.11), respectively. There was no statistical difference between groups with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11 receiving placebo and 13 receiving acemannan, discontinued study therapy prematurely, none due to serious adverse reactions. Our results demonstrate that acemannan at an oral daily dose of 1600 mg does not prevent the decline in CD4 count characteristic of progressive HIV disease. Acemannan showed no significant effect on p24 antigen and quantitative virology. Acemannan was well tolerated and showed no significant pharmacokinetic interaction with ZDV.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:We assessed the long-term feasibility, safety, and tolerability of two regimens of aerosolized pentamidine (AP) as primary prophylaxis ofPneumocystis cariniipneumonia (PCP) in a large sample of infants and children with symptomatic HIV infection in 21 pediatric departments. One hundred forty children were assigned to receive 60 mg every 2 weeks (n = 60) or 120 mg every 4 weeks (n = 80) of AP, delivered by the ultrasonic nebulizer Fisoneb under the supervision of trained personnel. Children underwent monthly clinical and laboratory controls for toxicity and/or development of PCP for an 18-month period. Baseline characteristics were similar in the two treatment groups. The median age was 5 years. The feasibility of administering AP was excellent in 84 (60%) and good in 38 (27%) children. All children aged <2 years showed excellent or good feasibility. Long-term compliance was good with both regimens. No child had severe adverse reactions requiring discontinuation of the treatment. Cough, sneezing, and bronchospasm were the most frequent side effects occurring, respectively, in 12, 3.7, and 0.7% of the 60-mg treatments and in 19.1, 6.1, and 2.8% of 120-mg treatments (p< 0.05). Their incidence was not different in children younger or older than 5 years. Two episodes of PCP were observed in the group receiving 120 mg monthly, whereas none of the 60 children in the biweekly schedule had PCP (p = 0.20). AP can be safely administered to very young children with few adverse side effects.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:A combination of antiretroviral drugs acting on different cell types (lymphocytes and macrophages) was evaluated in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS). In a first experiment, C57BL/6 mice were infected with a single i.p. administration of LP-BM5 and treated with 0.125 or 0.25 mg/ml AZT in drinking water for 3 months. AZT treatment was found to reduce lymphadenopathy (60 and 65%, respectively), splenomegaly (37 and 50%, respectively), and hypergammaglobulinemia (6 and 50%, respectively). Furthermore, at the highest AZT concentration, BM5d proviral DNA content in lymph nodes and in the spleen showed a reduction of 78 and 70%, respectively, compared to untreated animals. In a second experiment, infected mice were treated with AZT (0.25 mg/ml in drinking water) and with 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) encapsulated into autologous erythrocytes for macrophage protection. Combined treatments resulted in a further reduction of lymphadenopathy (a further 33% with respect to the single treatment of AZT) and splenomegaly (a further 28% respect to the single treatment of AZT) but not of gammaglobulinemia. Proviral DNA in lymph nodes and spleen showed a reduction of 82 and 77%, respectively, compared to infected mice. Stimulation index of T cells was also significantly increased in animals receiving both treatments versus AZT only. In conclusion, the selective administration of antiviral drugs that preferentially protect different cell types seems to provide additional advantages compared to single-agent therapy.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID