摘要:

Background:A G-to-A transition in the 3′ untranslated region (UTR) of stromal cell-derived factor (SDF)-1 gene (SDF1-3′A) has recently been described, which in the homozygous state was associated with delayed disease progression.Objective:To analyse the effect of the SDF-1 polymorphism on AIDS-free survival and survival after AIDS diagnosis, also in relation to viral phenotype.Design:Retrospective longitudinal study among 344 homosexual HIV-1-infected men.Results:A more rapid progression to AIDS (Centers for Disease Control and Prevention 1993 definition) was observed inSDF1-3′A/3′A subjects than in wild-type (SDF1-wt/wt) subjects (relative hazard, 1.75;P= 0.07). Using death as an endpoint, accelerated progression was no longer observed (relative hazard, 0.93;P= 0.84), suggesting a late protective effect of theSDF1-3′A/3′A genotype. Indeed, survival after AIDS diagnosis was significantly delayed inSDF1-3′A/3′A subjects (relative hazard, 0.40;P= 0.02). No effect of theSDF1-3′A/wt genotype on disease progression was observed. Interestingly, a higher frequency of Kaposi's sarcoma was observed as the AIDS-defining event amongSDF1-3′A/3′A (40.0%) andSDF1-3′A/wt (30.6%) subjects than inSDF1-wt/wt subjects (17.0%). At the end of the study the total frequency of syncytium-inducing (SI) HIV-1 variants was lower inSDF1-3′A/3′A subjects (22.2%) than inSDF1-3′A/wt (32.5%) andSDF1-wt/wt subjects (40.5%), although not significantly. SDF-1 genotype did not influence the rate of evolution to SI HIV-1. Progression to AIDS after the emergence of SI HIV-1 was accelerated inSDF1-3′A/3′A subjects compared with theSDF1-wt/wt genotypic group (relative hazard, 4.04;P= 0.06).Conclusions:In our study group, homozygosity for a G-to-A transition in the 3′ UTR of SDF-1 is associated with an accelerated progression to AIDS but a subsequent prolonged survival after AIDS diagnosis.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To determine whether disruption of the cleavage site between protease and reverse transcriptase (RT) or the HIV-1 frameshift site could yieldtrans-dominant negative HIV-1 variants that interfere with wild-type viral replication.Design:Residues at the cleavage site between the HIV-1 protease and RT coding regions were mutagenized to produce a protease-RT (PR-RT) fusion protein that was expressed in the context of a full-length provirus. The PR-RT cleavage site mutation was also combined with a read-through mutation at the frameshift site in order to overexpress the mutant Gag-Pol polyproteins.Methods:COS-7 cells were transiently transfected with the mutant constructs to produce viruses harbouring the PR-RT fusion protein. In addition, we performed cotransfection studies in various cell types to analyze the inhibition of wild-type replication by the mutant constructs.Results:Immunoblot analysis revealed that this novel mutation prevented cleavage between the two proteins and that both existed as a PR-RT fusion protein in each of cellular and viral lysates. While both the protease and RT components of this fusion protein remained functionally active, viruses containing the cleavage site mutation were less infectious in tissue culture than wild-type viruses produced by COS-7 cells. This defect was further pronounced when the cleavage site mutation between protease and RT was overexpressed as a consequence of an additional mutation that interfered with frameshifting. Cotransfection of COS-7 cells with the mutant constructs and wild-type HIV-1 interfered with the replication of the latter and reduced the infectiousness of the virus particles produced.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To determine the effect of β-chemokines on HIV-1 infection of primary macrophages, and to search for chemokine derivatives devoid of biological effects but efficient at protecting CD4+ T lymphocytes and macrophages against HIV-1.Design:Use of chemically synthesized molecules devoid of biological contaminants and monocyte-derived macrophages from healthy donors.Methods:Full-length RANTES was chemically synthesized together with three derivatives, truncated of seven, eight and nine amino acids at the amino-terminus ([8–68]RANTES, [9–68]RANTES and [10–68]RANTES), which were tested for their biological activity and antiviral effects.Results:Whereas full-length and truncated RANTES derivatives bound to β-chemokine receptor CCR-5 with the same affinity as recombinant RANTES, the truncated forms were not chemotactic and acted as CCR-5 antagonists in this respect, although a partial agonist effect was noted on cell metabolism. Full-length RANTES and [8–68]RANTES protected T lymphocytes and macrophages from infection by HIV-1, although 10-fold higher concentrations of the truncated analogues were necessary to achieve the same effect as full-length RANTES. With regard to the effect of RANTES on HIV-1 infection of primary macrophages, our results contrast with most previously reported data.Conclusion:These data indicate that through binding to CCR-5, truncated RANTES derivatives that are devoid of detectable biological effects may represent candidates as drugs to protect both lymphocytes and macrophages from HIV-1.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To evaluate the role of the selective forces exerted by the host on the HIV-1 structures involved in viral entry.Design and methods:The V3 region of theenvgene was analysed in cell-free HIV-1 RNA from 17 infected subjects: 11 long-term non-progressors (LTNP) and six symptomless, typical progressor patients. To evaluate the potential biological significance of one of the rare variants detected in the LTNP, it was reproduced by recombinant PCR into a HIV-1 molecular clone.Results:The intrapatient divergence of the V3-loop sequences averaged 8.62% in LTNP and 5.29% in progressors, although LTNP displayed lower divergence from the clade B consensus than progressors (16.65 and 19.76%, respectively). The analysis of non-synonymous and synonymous substitutions indicated that selective pressure was exerted in this region in both LTNP and progressors. Individual peculiarities (unique and rare V3-loop variants) emerged, however, in most sequences from LTNP, and variants bearing mutations in a domain crucial for the V3-loop structure were more prevalent in LTNP (P= 0.0012). The pNL4–3-derived mutant reproducing a V3-loop variant detected in a LTNP was efficiently expressed upon transfection, but the mutant virus was nearly completely unable to infect CD4+ cell lines, activated primary peripheral blood lymphocytes, or monocyte-derived macrophages, suggesting that a defect impaired the entry phase of the replication cycle.Conclusions:The results indicate that host factors impose selective constraints on the evolution of the HIV-1 structures involved in viral entry. In LTNP, these factors are likely to force the virus into attenuated variants.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Haematopoietic progenitor cells (HPC) of HIV-1-infected patients are severely compromised in their replication and clonogenic capacities, and show an enhanced propensity to apoptosis, despite the lack of productive or latent HIV-1 infection.Objective:To investigate telomerase enzyme levels in CD34+ HPC isolated from HIV-1-infected patients, because the absence of telomerase activity has been found to be correlated with a diminished replication potential.Methods:Telomerase levels were measured by a PCR-based telomeric repeat amplification protocol. CD34+ HPC isolated from the peripheral blood of 11 HIV-1-infected patients were compared with CD34+ HPC isolated from peripheral blood (nine subjects) or bone marrow (six subjects) from 15 healthy donors. Telomerase levels were also studied in normal HPC after exposure to either gp120 or transforming growth factor (TGF)-β1.Results:CD34+ HPC isolated from either peripheral blood or bone marrow from healthy donors expressed a high level of telomerase activity. On the contrary, CD34+ HPC isolated from HIV-1-seropositive patients did not express any detectable telomerase activity in nine patients, and a clearly reduced enzymatic activity in two patients. Furthermore, telomerase activity in normal CD34+ HPC exposed to recombinant gp120 was significantly reduced, and to a higher extent than in CD34+ HPC exposed to recombinant TGF-β1.Conclusions:This is the first study to demonstrate severely impaired telomerase activity in uninfected CD34+ HPC isolated from HIV-1-infected patients. The mechanism underlying this impairment probably involves the interaction of HIV-1 envelope glycoprotein gp120 with the cell membrane. These results may add to our understanding of the pathogenesis of the lesion of the HPC compartment.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To assess the impact of specific AIDS-defining conditions on survival in HIV-infected persons, with emphasis on the effect of tuberculosis.Methods:A retrospective cohort analysis of HIV-infected Africans and non-Africans attending 11 specialist HIV/AIDS units in London enrolled for a comparison of the natural history of HIV/AIDS in different ethnic groups.Results:A total of 2048 patients were studied of whom 627 (31%) developed 1306 different AIDS indicator diseases.Pneumocystis cariniipneumonia accounted for 159 (25%) of initial AIDS episodes and tuberculosis for 103 (16%). In patients with HIV disease, tuberculosis had the lowest risk [relative risk (RR), 1.11; 95% confidence interval (CI), 0.75–1.63], and high-grade lymphoma had the highest risk (RR, 20.56; 95% CI, 2.70–156.54) for death. For patients with a prior AIDS-defining illness, the development of subsequent AIDS indicator diseases such asPneumocystis cariniipneumonia (RR, 1.18; 95% CI, 0.77–1.83) and tuberculosis (RR, 1.36; 95% CI, 0.76–2.47) had the best survival, and non-Hodgkin's lymphoma had the worst survival (RR, 9.67; 95% CI, 1.26–74.33). Patients with tuberculosis had a lower incidence of subsequent AIDS-defining conditions than persons with other initial AIDS diagnoses (rate ratio, 0.47; 95% CI, 0.37–0.59).Conclusions:Considerable variation exists in the relative risk of death following different AIDS-defining conditions. The development of any subsequent AIDS-defining condition is associated with an increased risk of death that differs between diseases, and this risk should be considered when evaluating the impact of specific conditions. Like other AIDS-defining conditions, incident tuberculosis was associated with adverse outcome compared with the absence of an AIDS-defining event, but we found no evidence of major acceleration of HIV disease attributable to tuberculosis.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To determine the prevalence of genotypic resistance to nucleoside analogues (NA) in a large group of HIV-infected individuals in Spain, some of whom had no previous treatment with antiretroviral drugs (antiretroviral-naive) and some of whom had such experience (antiretroviral-experienced).Setting:Cross-sectional study in outpatient clinics in three reference hospitals for HIV/AIDS located in Barcelona, Madrid and Seville, Spain.Patients and methods:Primary mutant genotypes were examined in plasma HIV RNA collected from 150 antiretroviral-naive subjects, half in 1993 and the other half in 1997. Furthermore, drug resistance mutations were analysed in plasma collected from another 150 antiretroviral-experienced patients who had received 2 NA for longer than 1 year, either in sequence as monotherapy or as combination therapy. A line probe assay was used for recognizing mutations conferring resistance to zidovudine (ZDV), didanosine (ddI), zalcitabine (ddC), and lamivudine (3TC). A point-mutation nested-PCR assay was used for examining a codon 151 mutation associated with multiple drug resistance.Results:One or more mutations associated with primary resistance to NA were seen in 10 antiretroviral-naive (13.3%) patients in 1993 and in nine (12%) in 1997. In all but two cases, they were associated with ZDV resistance. In contrast, all but six (96%) of the antiretroviral-experienced subjects harboured drug-resistant mutant viruses. The codon 184 mutation (associated with resistance to 3TC) was detected in 92% of patients treated with 3TC, but also in 18% of those treated with only ddI or ddC. The codon 215 mutation was found in 67.3% of patients who had been exposed to ZDV; the codon 69 mutation was found in 15% of patients treated with ddC; and the codon 74 mutation was found in only 7.2% of patients treated with ddI. Finally, the codon 151 multidrug resistant mutation was found in four (2.7%) of 150 patients with a longterm exposure to NA.Conclusions:Overall, the prevalence of drug-resistant HIV-1 genotypes was 12.7% in antiretroviral-naive patients, most of whom had ZDV-resistant mutants. There is no evidence of an increase during the last 5 years. However, multidrug-resistant HIV genotypes are currently circulating in Spain.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Chemokines are involved in the migration of leukocytes and have been implicated in several inflammatory diseases of the central nervous system. Some of their receptors have been proposed to mediate HIV infection.Objective:To determine changes in chemokine and receptor expression in HIV encephalitis, and to determine whether upregulation leads to recruitment of infected monocytes across the blood-brain barrier and participates in HIV neuropathology.Methods:Immunocytochemistry and double-label immunofluorescent laser confocal microscopy was performed with antibodies to chemokines and their receptors on brain tissues from patients who died with or without HIV encephalitis.In vivodistribution was compared within vitrocultures of human neuroglial cells.Results:The β-chemokines monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and RANTES were detected on brain macrophages. Their presence was associated with the histopathological signs of HIV encephalitis. The α-chemokines IP-10 (10 kDa inflammatory protein) and interleukin-8 were expressed by astrocytes in all tissues, including controls. Presence of the CXC-chemokine receptor (CXCR)-4 was seen on brain macrophages/microglia, neurons, and astrocytes. CC-Chemokine receptor (CCR)-5 was detected only on macrophages/microglia. CCR-3 and CCR-1 were expressed by macrophages and endothelial cells.In vitrostudies examining the presence of CCR-3, CCR-5, and CXCR-4 on human brain cell cultures demonstrated abundant neuronal and microglial expression.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1-1, Hp 2-1 and Hp 2-2.Objectives:To investigate the outcome of HIV infection according to haptoglobin type.Design and methods:Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls.Results:The haptoglobin type distribution amongst the patients (17.6% Hp 1-1, 49.9% Hp 2-1, 32.5% Hp 2-2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2-2 group (P= 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25−2.54). Median survival time was 11.0 years (Hp 1-1 and Hp 2-1) versus 7.33 years (Hp 2-2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2-2 patients (P= 0.03 and 0.003, respectively). The Hp 2-2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P< 0.0001).Conclusion:HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To evaluate the efficacy of melaleuca oral solution in AIDS patients with fluconazole-resistant oropharyngeal candida infections.Design:A prospective, single center, open-labeled study.Setting:A university-based inner-city HIV/AIDS clinic.Patients:Thirteen patients with AIDS and oral candidiasis documented to be clinically refractory to fluconazole, as defined by failure to respond to a minimum of 14 days of ≥ 400 mg fluconazole per day. Additionally, patients hadin vitroresistance to fluconazole, defined by minimal inhibitory concentrations of ≥ 20 µg/ml.Interventions:Patients were given 15 ml melaleuca oral solution four times daily to swish and expel for 2–4 weeks.Main outcome measures:Resolution of clinical lesions of oral pseudomembranous candidiasis lesions. Evaluations were performed weekly for 4 weeks and at the end of therapy for clinical signs of oral candidiasis. Quantitative yeast cultures were performed at each evaluation.Results:A total of 13 patients were entered into the study, 12 were evaluable. At the 2-week evaluation, seven out of 12 patients had improved, none were cured, and six were unchanged. At the 4-week evaluation, eight out of 12 patients showed a response (two cured, six improved), four were non-responders, and one had deteriorated. A mycological response was seen in seven out of 12 patients. A followup evaluation 2–4 weeks after therapy was discontinued revealed that there were no clinical relapses in the two patients who were cured.Conclusions:Melaleuca oral solution appears to be effective as an alternative regimen for AIDS patients with oropharyngeal candidiasis refractory to fluconazole.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID