摘要:

During the course of HIV-1 infection, free virus, infected cells, and free HIV-1 proteins circulate within the host, exposing the host endothelium to these viral factors. We have previously presented evidence showing that soluble HIV-1 gp120 protein interacts with chemokine receptors on primary human endothelium and (through those interactions) induces apoptosis as well as other intracellular effects. The current study examines the effect of exposure of vascular endothelium to gp120 IIIb expressed on the surface of Jurkat cells and in the context of viral particles. Apoptosis was observed in human umbilical vein endothelial cell (HUVEC) cultures exposed to gp160-transfected Jurkat cells as well as to virion particles with gp120 on their surface. Additional experiments show that this apoptotic effect was caused by gp120 protein acting through chemokine receptors on the HUVEC surface, primarily the CXCR4 receptor. At higher concentrations of gp120, this lymphotrophic variant, which has been shown to interact predominantly with CXCR4, seems to interact with and induce apoptosis through the CCR5 receptor. Finally, this apoptotic effect in HUVEC cultures occurs at low levels of the inducing agent, gp120, on cell membranes or on virion particles. These results demonstrate that HIV-1 gp120 is capable of interacting with and killing vascular endothelial cells in multiple in vivo contexts.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Infection of rhesus macaques with chimeric simian–human immunodeficiency viruses (SHIV) is an established method to study AIDS pathogenesis and is increasingly used to assess the efficacy of vaccine and antiviral candidates. For these reasons, a detailed understanding of those molecular determinants, which confer pathogenic potential to SHIV viruses, should assist in both rational experimental design and interpretation of results. In this report, we describe the development and in vivo characterization of a pathogenic molecular clone, SHIVSF33A2, which contains an envelope sequence derived from the CXCR4-dependent isolate, HIV-1SF33. Proviral DNA, amplified from a rhesus macaque infected with the pathogenic isolate SHIVSF33A, was substituted into the corresponding region of the parental, nonpathogenic SHIVSF33genome creating the molecular clone SHIVSF33A2. Coreceptor specificity of SHIVSF33A2was determined to be CXCR4 specific. Naive rhesus macaques were productively infected after a single exposure to cell-free SHIVSF33A2by either the intravenous (IV) or intravaginal (IVAG) routes. Animals infected with SHIVSF33A2suffered a severe loss of peripheral CD4+T cells and high acute plasma viremia with development of simian AIDS 9 months after inoculation. Sequence analysis identified 25 discreet amino acid changes within the V1–V5 regions of the envelope protein when compared with the nonpathogenic parental virus. These data indicate that domains within the HIV-1 envelope protein are sufficient to define pathogenic potential in the context of the SIVmac239 genome.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundSimpler and less toxic antiretroviral strategies are needed to maximize treatment compliance without sacrificing potency, at least for drug-experienced HIV-infected patients currently on regimens containing protease inhibitors (PIs). Small nonrandomized studies have suggested a beneficial role of PI-sparing regimens on lipodystrophy.ObjectivesTo assess the virologic, immunologic, and clinical benefit of switching the PI to nevirapine in patients with HIV-associated lipodystrophy and sustained viral suppression before entry in the study.DesignOpen-labeled, prospective, randomized, multicenter study.SettingSeven reference inpatient centers for HIV/AIDS in Spain.PatientsOne hundred six HIV-infected adults with clinically evident lipodystrophy who sustained HIV-RNA suppression for at least 6 months with PI-containing antiretroviral combinations.InterventionReplacement of the PI with nevirapine during 48 weeks (Group A) versus continuing the prior PI (Group B).MeasurementsSeveral virologic and immunologic analyses, standard and specific biochemical tests, and anthropometric and dual X-ray absorptiometry measurements.ResultsAt week 48, an HIV-1 RNA level <400 copies/ml was maintained in 79% and 77% of patients in Groups A and B, respectively, whereas 74% and 72% of patients had viral load levels <50 copies/ml. Absolute CD4+counts significantly increased in both groups compared with baseline values, and a significant decrease in CD38+CD8+cells was observed in Group A (p< .01) but not in group B. Overall, no significant changes in anthropometric or body shape measurements were found after 48 weeks. Fasting total cholesterol and triglyceride levels decreased in Group A (but not in Group B) compared with baseline values (p< .05), although no significant differences were seen between groups at the end of the study. Subjects in Group A reported a better quality of life (QOL) index than controls (p< .001), with the main reason reported being the greater simplicity of the new drug regimen.ConclusionsProtease inhibitor–sparing regimens, including nevirapine, seem to be an effective alternative for PI-experienced patients. Nevirapine-based triple therapies allow maintained control of HIV-1 RNA levels and improve the immunologic response at 48 weeks of follow-up in patients with prior sustained virologic suppression. The switch to nevirapine significantly improved the lipidic profile in Group A, although there were no differences between groups at the end of the study. Additionally, no significant changes were seen in terms of lipodystrophy-related body shape changes 1 year after the PI substitution. Finally, nevirapine-containing regimens have a simpler dosing schedule, and this facilitates high adherence and improves QOL.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The pathogenesis of some components of the lipodystrophy (LD) syndrome might be linked to the use of nucleosides. Earlier reports did not compare treatment regimens according to the nucleoside backbone. We studied a cohort of individuals who did not switch between stavudine and zidovudine. LD was defined to be present if one of three criteria was met: self-report by the patient, observation by an investigator who had known the patient since commencement of highly active antiretroviral therapy (HAART), or examination by a physician masked to therapy. The mean duration of therapy was 101 weeks (range: 26–234 weeks). Overall prevalence of LD was 48.7%. Lipoatrophy and lipohypertrophy occurred in 33.9% and 28.7% of patients, respectively. Logistic regression showed four parameters to be significantly associated with lipoatrophy: HAART longer than 2 years (p= .002, odds ratio [OR] = 4.4, 95% confidence interval [CI]: 1.608–11.965), baseline viral load >100,000 copies/ml (p= .004, OR = 4.3, CI: 1.726–11.197), age >40 years (p= .016, OR = 3.2, CI: 1.247–8.373), and white ethnicity (p= .041, OR = 5.4, CI: 1.070–28.184). Cholesterol levels of >200 mg/dl at baseline were associated with a risk reduction (p= .047, OR = 0.36, CI: 0.130–0.987). Use of lipohypertrophy as a dependent variable resulted in a significant association with HAART duration (p= 0.028, OR = 2.7, CI: 1.2–6.5) and protease inhibitor use (p= .014, OR = 3.8, CI: 1.3–11.2). LD prevalence is similar with both backbones using stavudine or zidovudine. This is the first time that baseline cholesterol was shown to be significantly associated with lipoatrophy.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV-infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross-sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV-HCV–coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV-HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV-HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV-HCV and HIV groups. HIV-HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37;p= .01 andp= .003, respectively). Lipoatrophy was observed more frequently in HIV-HCV patients in comparison with HIV patients (41% versus 14%;p= .003). In HIV-HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo identify the effects of substance abuse status (active, former, and never) on utilization of highly active antiretroviral therapy (HAART), medication adherence, and virologic and immunologic responses to therapy.DesignProspective cohort study of 764 HIV-1–infected patients who attended an urban HIV clinic and participated in a standardized interview.Main Outcome MeasuresPast utilization of HAART, self-reported nonadherence with antiretroviral therapy, and changes in HIV-1 RNA level and CD4+lymphocyte count relative to prior peak and nadir, respectively.ResultsForty-four percent of active drug users failed to utilize HAART compared with 22% of former drug users and 18% of non–drug users (p< .001 for both comparisons). Among participants who were taking antiretroviral therapy when interviewed, active drug users were more likely to report medication nonadherence (34% vs. 24% of nonusers and 17% of former users), had a smaller median reduction in HIV-1 RNA from baseline (0.8 log10copies/ml vs. 1.7 in nonusers and 1.6 in former users), and had smaller median increases in CD4+lymphocyte count from baseline (65 cells/mm3vs. 116 in nonusers and 122 in former users) (p< .05 for all comparisons with active users).ConclusionsActive drug use was strongly associated with underutilization of HAART, nonadherence, and inferior virologic and immunologic responses to therapy, whereas former drug users and non–drug users were similar in all outcomes. Effective strategies are needed that integrate HIV-1 and substance abuse treatments.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo evaluate the tolerance, pharmacokinetics, and virologic and immunologic outcomes of once-daily indinavir, ritonavir, didanosine, and lamivudine in HIV-seropositive individuals.DesignOpen-label 24-week pilot study.PatientsTen HIV-seropositive subjects who were either antiretroviral-naive or minimally experienced with short-term single-or dual-nucleoside therapy provided informed consent and were enrolled. All subjects received didanosine (400 mg) 30 to 60 minutes before a meal followed by indinavir (1200 mg), ritonavir (400 mg), and lamivudine (300 mg) concurrent with the aforementioned meal.MethodsSafety laboratory tests, including a complete blood cell count and amylase, lipase, liver transaminase, and nonfasting lipid monitoring as well as plasma HIV viral load and CD4+lymphocyte count, were carried out at monthly intervals. Genotyping was performed at baseline. Pharmacokinetic studies for indinavir and ritonavir were performed at week 8.ResultsNine of 10 subjects completed 24 weeks of therapy. No subject demonstrated primary protease inhibitor mutations at baseline. Toxicities experienced by subjects were typically mild and consistent with those commonly reported for each of the medications, including two cases of hematuria. By week 24, median nonfasting cholesterol and triglyceride levels increased by 49% and 108%, respectively. Median baseline plasma HIV viral load and CD4+lymphocyte count were 29,292 (4.47 log10) copies/ml and 224 cells/mm3, respectively. Eight of 10 subjects had a plasma HIV viral load of <50 copies/ml by week 12. The 2 subjects with a detectable HIV viral load reached <50 copies/ml by week 28. Median CD4+lymphocyte counts increased by 193 cells/mm3at week 24. Indinavir and ritonavir plasma concentrations remained above respective inhibitory and effective concentrations (IC95and EC50) (uncorrected for protein binding) throughout the 24-hour dosing interval for 6 of 10 and 8 of 10 subjects, respectively.ConclusionsOur pilot study demonstrates excellent virologic suppression despite low minimum protease inhibitor concentrations during a dosing interval in some patients and is supportive of further study.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Demonstration of long-lived HIV-reservoirs resistant to the effects of combination antiretroviral therapy raises concern over the ability of treatment to maintain long-term beneficial alterations in T-cell subset composition. To address this issue, we have examined the effect of antiretroviral therapy on T-cell subset change during early HIV-infection in a 2-year prospective open-label trial composed of treatment-naive asymptomatic HIV-infected patients with CD4+T-cell counts ≥400 cells/&mgr;l. Therapy consisted of double (zidovudine and lamivudine) or triple (zidovudine, lamivudine, and ritonavir) combination antiretroviral therapy. Retrospective analysis based on magnitude of viral suppression was used to characterize responder and nonresponder groups. Among responders, long-term antiretroviral therapy maintained a significant increase in numbers of total CD4+, naive CD4+/CD45RA+, and memory CD4+/CD45RO+T cells. A concomitant significant decrease in numbers of memory CD8+/CD45RO+and both activated CD8+/HLA-DR+and CD8+/CD38+T cells was also maintained. In contrast, long-term antiretroviral therapy among nonresponders led only to a significant increase in the numbers of CD4+T cells and a significant reduction in numbers of activated CD8+/HLA-DR+T cells. The long-term ability of antiretroviral therapy during early asymptomatic HIV-infection to maintain reversal of disease-induced T-cell activation and maturation abnormalities continues to support the concept that immunologic advantage is gained by commencing early aggressive antiretroviral therapy. Nevertheless, continued management of T-cell subset recovery is significantly more effective in the presence of completely suppressed viral replication.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Individuals infected with HIV are at increased risk of developing aggressive non-Hodgkin's lymphoma with a worse prognosis than those similarly afflicted without HIV infection. The underlying genetic differences in tumor behavior between these two groups are not known. We explored the hypothesis that lymphomas from HIV-positive individuals have distinct somatic genetic changes that may provide clues to the genetic basis of disease progression and outcome. Genome-wide DNA copy number alterations (CNAs) in primary tumors from 14 HIV-positive and 11 HIV-negative patients with diffuse large B-cell lymphoma (DLCL) were quantified using comparative genomic hybridization (CGH). Tumors from HIV-positive patients displayed fewer regional DNA-CNAs than those from patients who did not have HIV. When CNAs were present, they occurred at lower frequency in HIV-positive patients. Gains at chromosomes 8q and Xp were the most frequent changes in the HIV-negative group, and gains on 2p and 12q were common in the combined HIV-positive and HIV-negative groups. No alteration was specific to AIDS-related DLCL. These data suggest that fewer somatic genomic changes are needed for progression to DLCL in HIV-immunocompromised hosts, and that other factors, such as reduced immune surveillance, may contribute to neoplastic progression.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Genetic variation at the human leukocyte antigen (HLA) loci has been shown to be an important risk factor for progression to HIV disease, but its significance in infection is less well understood. We have investigated its role in HIV transmission in a cohort of individuals at risk for heterosexual infection. Analysis of over 80 individuals revealed that that the degree of concordance at HLA A, B, and DR loci differs significantly between transmitting and nontransmitting couples at risk for heterosexual HIV transmission (p< .02), suggesting that allogeneic immune responses may confer a degree of protection against HIV infection. Analysis of the frequencies of specific alleles at the A, B, and DR loci revealed a significantly higher frequency of HLA DR5 among exposed uninfected individuals, relative to population controls.

ISSN:1525-4135    

出版商:OVID    

年代:2001

数据来源: OVID