摘要:

ObjectiveTo develop an HIV-1 accessory gene immunogen using a DNA vaccine approach.MethodsHIV-1 accessory genesvif,vpuandnefwere modified to express under the control of a single promoter with cellular proteolytic cleavage sites between the coding sequences (VVN-P). Immune responses induced by these constructs were evaluated in mice.ResultsPDNA vaccine construct (pVVN-P) expressing Vif, Vpu and Nef was processed and the fusion protein was cleaved appropriately. Vif, Vpu and Nef as a fusion protein with proteolytic cleavage sites (VVN-P) is able to induce a significant level of cellular immune responses. We also observed that accessory genes Vif, Vpu and Nef (VVN-P) induced an effective T helper 1 proliferative response measured by cytokine production. Furthermore, expression cassette pVVN-P was able to induce cytotoxic T lymphocyte (CTL) responses against diverse HIV-1 viruses in infected target cells.ConclusionWe conclude that cell-mediated immune responses induced by accessory gene constructs from clade B may have a broader recognition of divergent HIV-1 viruses and should be further examined for both prophylactic and therapeutic vaccination schemes against HIV-1.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesTo ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection.Design and settingOpen-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States.Subjects and methodsThirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored.ResultsThe LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens.ConclusionsMost HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo evaluate the decay rate of cellular proviral HIV-DNA and viral replication in patients receiving highly active antiretroviral therapy (HAART) in the very early phase of infection.MethodsThirty-four patients treated with HAART and retrospectively selected for progressive decline of plasma viraemia up to undetectable levels (< 20 copies/ml), were stratified according to CD4+ cell count and plasma viraemia at base line: > 500 × 106cells/l with < 5000 copies/ml (group 1) or with > 5000 copies/ml (group 2), > 5000 copies/ml with 300–500 × 106cells/l (group 3) or with < 300 × 106cells/l (group 4). Plasma HIV-RNA and proviral HIV-DNA were analysed at baseline and after 1, 2, 3, 6, 9 and 12 months of treatment.ResultsAfter 1 year of treatment, a significant decrease of proviral DNA titre was observed in all patients and a decrease > 1 log was achieved in 24 of 29 subjects of the first three groups. The more pronounced decay of HIV-DNA (half-life 28 weeks) up to < 50 HIV-DNA copies/106CD4+ cells was detected in patients of group 1. At the year's endpoint, five patients (four in group 1 and one in group 2) had < 20 HIV-DNA copies. However, HIV strains sensitive to antiretroviral drugs were isolated from peripheral lymphocytes of 16 out of 34 patients.ConclusionIn patients with undetectable plasma viraemia after 1 year of HAART, the highest reduction of proviral DNA up to < 50 copies/106CD4+ cells was obtained only in subjects in the early asymptomatic phase of infection. Nevertheless, a replication-competent virus can be detected in all phases of antiretroviral therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy.MethodsAmino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks.ResultsNumbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 60I + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks.ConclusionsUse of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundFat distribution abnormalities have been reported in patients treated with various antiretroviral drug regimens. The LIPOCO study is an ongoing observational study of unselected HIV-infected patients which aims to better characterize such disorders and their metabolic correlations.MethodsCross-sectional analysis of data collected at baseline in the first 154 male patients included. Investigators divided patients into four predetermined clinical categories of fat distribution: lipoatrophy, obesity, mixed condition and normal. Body composition (tetrapolar bioelectrical impedance analysis and skinfold thickness), fat distribution [computed tomography (CT) scan], plasma glucose and insulin concentrations both fasting and during an oral glucose tolerance test and endocrine and lipid profile were measured and compared between the four groups.ResultsPatients in the lipoatrophy group had significantly decreased abdominal and mid-thigh subcutaneous fat area values and elevated levels of plasma triglycerides. Patients in the obese and mixed groups had significantly increased intra-abdominal fat area values and elevated levels of plasma insulin and C-peptide. The CT scans identified some patients with isolated subcutaneous fat accumulation but no other alterations in fat distribution and no insulin resistance. Visceral adipose tissue measured by CT scan was positively correlated with fasting insulin and the sum of insulin levels (P< 0.0001). Fasting insulin as well as the sum of insulin levels were negatively correlated with the Δ HIV-RNA (log10). In a multivariate logistic regression model, the use of stavudine significantly correlated with fat wasting in both nucleoside reverse transcriptase inhibitor and protease inhibitor groups: odds ratio (OR), 413 [95% confidence interval (CI), 5.2–999;P= 0.0068] and OR, 2.08 (95% CI, 0.92–7.0;P= 0.058) respectively, when compared with the use of zidovudine. Neither lamivudine or didanosine use, nor the use of protease inhibitors were significantly associated with fat distribution abnormalities or fat wasting.ConclusionsThese preliminary results suggest that three major types of fat distribution abnormalities may occur in isolation or in association in HIV-infected patients undergoing active antiretroviral therapy: a fat depletion or `lipoatrophy' syndrome which might be related to the use of stavudine; a mixed or fat redistribution syndrome related to an unusual side-product of effective virus control; and a subcutaneous adiposity syndrome reflecting increase in caloric intake.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundIntensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown.MethodsTwenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities.ResultsThose taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P< 0.01) in those taking ritonavirrcompared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles.ConclusionTreatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen.DesignThe ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection.MethodsHIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected.ResultsSeven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time.ConclusionsThe quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo analyze changes in frequency of systemic AIDS pathology over time and its relationship to central nervous system pathology.Design and methodsA total of 390 AIDS autopsy cases obtained at University of California at San Diego Medical Center from 1982 to 1998 were reviewed retrospectively and linear regression analysis was used to evaluate significance of changes over time.ResultsOverall, the frequency of cytomegalovirus,Pneumocystis cariniipneumonia andMycobacterium aviumcomplex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. The frequency of non-Hogdkin's lymphoma showed an upward trend over time, while the frequency of Kaposi's sarcoma remained unchanged. Following involvement of the lung (84%), the brain continued to be the second most frequently affected organ (63%). Whereas alterations of the brain by opportunistic infections or non-Hogdkin's lymphoma showed a downward trend, HIV encephalitis continued to be detected in at least 25% of the cases. Cases with advanced HIV-related neuropathology and cases with no HIV involvement of the brain showed significant systemic pathology with opportunistic infections and neoplasms. In contrast, cases with early brain pathology (e.g., lymphocytic meningitis) showed minimal systemic pathology. Overall these trends remained unchanged throughout the total period covered by this study.ConclusionsThis study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesBurma produces approximately 60% of the world's heroin, Laos is the third leading producer. Recent outbreaks of injecting drug use and HIV-1 in Burma, India, China, and Vietnam have been associated with Burmese and Laotian overland heroin trafficking routes. We analyzed findings from narcotics investigations, molecular epidemiology studies of HIV-1, and epidemiologic and behavioral studies of injecting drug use, to evaluate the roles that the heroin export routes play in the spread of drug use and HIV-1 in south and south-east Asia.MethodsWe reviewed the medical and narcotics literature, the molecular epidemiology of HIV, and did key informant interviews in India, China, and Burma with injecting drug users, drug traffickers, public health staff, and narcotics control personnel.ResultsFour recent outbreaks of HIV-1 among injecting drug users appear linked to trafficking routes. Route 1: From Burma's eastern border to China's Yunnan Province, with initial spread of HIV-1 subtype B, and later C. Route 2: Eastern Burma to Yunnan, going north and west, to Xinjiang Province, with B, C, and a B/C recombinant subtype. Route 3: Burma and Laos, through northern Vietnam, to China's Guangxi Province, subtype E. Route 4: Western Burma, across the Burma–India border to Manipur, predominant subtype C, and B and E.ConclusionsOverland heroin export routes have been associated with dual epidemics of injecting drug use and HIV infection in three Asian countries and along four routes. Molecular epidemiology is useful for mapping heroin routes. Single country narcotics and HIV programs are unlikely to succeed unless the regional narcotic-based economy is addressed.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

RationaleCOL-1492 is a nonoxynol-9 (N-9)-containing vaginal gel and may be a potential microbicide. As part of an effectiveness trial, an initial toxicity study was conducted.ObjectivesThe main objective of the reported study was the assessment of the toxicity of a 52.5 mg N-9 gel, COL-1492, when used a number of times each day by female sex workers.MethodsThis was a randomized, placebo-controlled triple-blinded trial among female sex workers. The participants were asked to use the product for each vaginal sexual act. At each monthly visit a gynaecological examination with sexually transmitted disease sampling and colposcopy was performed. Venous blood was drawn for syphilis and HIV serology. All women received intensive counselling on condom use. Male condoms and sexually transmitted disease treatment were given free of charge.ResultsOnly blinded results on the colposcopic examinations are reported. The incidence of lesions with or without an epithelial disruption was low: 0.06 and 0.29, respectively, per 100 woman–days in group A; 0.09 and 0.26 respectively per 100 woman–days in group B. There was no significant difference between the two arms.ConclusionThe multiple daily use of COL-1492 by female sex workers did not show an increase of local toxicity over that of a placebo. Colposcopy was discontinued in the autumn of 1997 in accordance with a Data Safety Monitoring Board decision. In the currently ongoing effectiveness trial the assessment of the product's toxicity continues to be monitored by simple visual examination.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID