ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo investigate the phylogenetic relationship of HIV-1 proviral long terminal repeat (LTR) variants present in postmortem samples of lymph node, spleen, lung, dorsal root ganglion and spinal cord as well as in the peripheral blood of an HIV-1-infected patient dying with AIDS.Design and methodsPostmortem tissues were studied by a combination of histology, cell culture and molecular analyses. The patient had a stable CD4 count of 10×106/l during the 12 months preceding death. A 540 base-pair fragment of the LTR including U3/R/U5 was amplified using polymerase chain reaction on proviral DNA from the five postmortem tissues and peripheral blood mononuclear cells obtained 2 months prior to death. The population of viral variants was determined by sequencing at least five plasmid clones of the amplicons. The relationship between the variants present in different body sites was investigated using molecular phylogeny methods.ResultsHIV-1 was present in all organs analysed and correlated with the presence of abnormal histology. Genetic variation leading to divergence from the consensus sequence was more frequently present in characterized transcription factor binding sites within the LTR (P<0.0001) although the HIV-1 LTR quasispecies in the different body sites showed similar, relatively low levels of divergence (intra-organ median heterogeneity ranging from 0.0094 to 0.017). Phylogenetic analysis showed that the spinal cord and dorsal root ganglion harboured an LTR population genetically distinct from that present in other organs and more closely related to a previously characterized neurotropic strain of HIV (strain JRcsf).ConclusionThe independent clustering of HIV-1 LTR variants present in spinal cord and dorsal root ganglion shows that HIV-1 LTR evolution can occur in a compartmentalized fashion. The data show that the LTR is an important region to analyse in sequence variation studies of HIV since it may play a role in nervous tissue adaptation of HIV-1 and neuropathogenicity. Outgrowth of HIV-1 LTR variants that are most fit for the utilization of tissue-specific transcription factors can occur in the nervous tissue.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo determine the extent of HIV-1 genetic variation in Indian patients. Design: To avoid any bias in selecting viral variants, HIV-1 DNA was amplified directly from the peripheral blood mononuclear cells of patients and sequenced. Genetic similarity between Indian sequences and other geographic isolates was analysed by phylogenetic analysis algorithms.MethodsA fragment encompassing the C2/V3-V5 regions of HIV-1 gp120 was amplified from the lymphocyte DNA of 12 Indian patients. Multiple clones from each patient were sequenced. Nucleotide sequences encompassing about 650 base pairs were aligned for the Indian and other geographically distinct isolates. Inter-isolate relationships were analysed by means of distance, parsimony and neighbour-joining algorithms.ResultsNucleotide sequence comparisons showed low interpatient variation. Amino-acid comparisons revealed a high degree of homology between Indian sequences in this study and those studied earlier. On distance and parsimony trees, most of the Indian sequences clustered together as subtype C. However, sequences from three patients also showed significant homologies and phylogenetic clustering outside of subtype C.ConclusionsThe predominant strain of HIV-1 in India belongs to subtype C and little interpatient nucleotide sequence divergence in the majority of cases suggests recent spread of HIV-1 in this region. This study also presents the first evidence for non-C subtypes in the Indian population with two epidemiologically linked samples remaining unclassified for any existing env subtype. The presence of variant subtypes in Indian patients sheds light on the transmission routes of HIV-1 to India and emphasizes the need to include these sequences in vaccine development strategies.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo study type 1 and type 2 cytokine patterns in HIV-negative high-risk intravenous drug users (IVDU).DesignWe investigated interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-6 and IL-10 production by phytohaemagglutinin (PHA)-stimulated and unstimulated peripheral blood mononuclear cell (PBMC) cultures from HIV-negative high-risk IVDU, HIV-negative controls and HIV-positive subjects.MethodsCytokine production was measured in supernatants using enzyme-linked immunosorbent assay (ELISA) in 10 HIV-negative high-risk IVDU, 25 HIV-negative controls, and 12 HIV-positive IVDU. We also determined spontaneousin vitroimmunoglobulin (Ig) G and IgM production.ResultsHIV-negative high-risk IVDU showed increased IFN-γ and decreased IL-4, IL-10 and IL-2, although the latter was not significant compared with HIV-negative controls. Further, HIV-negative high-risk IVDU had reduced IgG production and impaired IgM-IgG switch.ConclusionsThe reduced IL-2 and IL-4 production suggest an impaired CD4+ T-cell function in HIV-negative high-risk IVDU. The increased IFN-γ production along with the decreased type 2 cytokine profile is consistent with the hypothesis that protective immunity against HIV may reside in type 1 responses and cell-mediated immunity.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo examine possible changes in mucosal B-cell activation status.DesignTo examine the frequency and isotype distribution of total and HIV-specific antibody-secreting cells (ASC) in the intestinal mucosa of HIV-infected individuals.MethodsMucosal lymphocytes were obtained by enzymatic treatment of duodenal pinch biopsies and the numbers of ASC were assayed with the enzyme-linked immunospot technique.ResultsHigh numbers of HIV-specific ASC were found in the intestine of all HIV-infected individuals despite low levels of HIV-specific blood ASC. All HIV-infected individuals had large numbers of intestinal immunoglobulin (Ig) A-ASC against the HIV envelope glycoprotein gp160. Eight out of nine patients also had HIV gp160-specific intestinal IgG-ASC. These HIV-specific ASC were detected irrespective of disease stage, route of infection, or levels of circulating CD4+ T cells. HIV-specific ASC were found in peripheral blood from patients with CD4+ T cells ≥100×106/l blood, but in none of three patients with low CD4+ T-cell counts. The frequencies of virus-specific ASC in the blood were on average 100-fold lower than that observed within the intestinal mucosa. Mucosal polyclonal B-cell activation was evident in HIV-infected individuals, as documented by significantly elevated numbers of Ig-secreting cells (ISC) in all three major Ig classes; on average, seven-, five- and 20-fold numbers of IgA, IgG and IgM-ISC compared with healthy controls. Furthermore, substantial numbers of ASC reacting with unrelated antigens such as dog albumin and keyhole limpet haemocyanin were detected in HIV-infected patients. Interestingly, patients with CD4+T cells < 100×106/l blood displayed large numbers of HIV-specific intestinal ASC even though total numbers of ISC, including ASC reactive to unrelated antigens, were decreased.ConclusionsThe large numbers of virus-specific ASC found in the intestine of HIV-infected individuals may be a consequence of local replication of HIV-1 resulting in a continuous antigen stimulation. The persistence of strong intestinal anti-HIV responses even at late stages of disease suggest that the mucosal B-cell responses are functionally intact throughout the disease. Furthermore, these results suggest that there is no correlation between HIV-specific ASC numbers and polyclonal B-cell activation. These observations indicate that intestinal B-cell activation is profoundly disregulated in HIV-infected individuals.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo improve the pharmacokinetics and lymphoid tissues targeting of 2',3'-dideoxyinosine (ddl) by encapsulation in liposomes.MethodsThe pharmacokinetics and tissue distribution of free and liposome-encapsulated ddl were determined in C57BL/6 mice following intravenous and subcutaneous administration of a single bolus dose (3 mg ddl/kg).ResultsIntravenous administration of liposome-encapsulated ddl greatly reduced the systemic clearance of the anti-HIV agent. The elimination plasma half-life of ddl incorporated in 112 and 83 nm liposomes was 46 and 14 times higher than that of the free drug, respectively. The tissue distribution profile of liposomal lipids clearly showed that the use of liposomes allows efficient targeting of lymph nodes and macrophage-rich tissues (spleen and liver) for at least 24 h following intravenous injection. In contrast, the accumulation of liposomes in these tissues was much lower following subcutaneous administration.ConclusionIncorporation of ddl in liposomes greatly improved the pharmacokinetics of the anti-HIV agent after intravenous injection. The use of liposomes could represent a convenient approach to targeting lymphoid tissues. Strategies aimed at improving drug retention within liposomes should further enhance and prolong drug delivery to lymphoid organs.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo report the occurrence of a syndrome of recurrent neurological deficits in advanced HIV disease and to discuss its management and prognosis.DesignRetrospective case study.SettingA regional treatment centre for HIV-infected individuals in northwest England.Main outcome measuresTransient neurological deficit was defined as a focal neurological deficit of rapid onset which resolved completely within 24 h. Frequency, character and duration of episodes were recorded. Prior illnesses, CD4 count, changes in drug therapy and brain imaging investigations were also documented.ResultsSeven cases with recurrent transient neurological deficits were identified among 748 patients over a 10-year period. Six had a CD4 cell count <50×106/l. The episodes lasted between 1 and 12 h and resolved completely without lasting sequelae. Dysphasia and hemiparesis were the most common presentations. Recurrent episodes for each patient tended to follow a similar pattern. None had computed tomographic evidence of cerebral infarction or clinical evidence of completed stroke. Prognosis was varied and not evidently altered by the episodes of neurological deficit. Three patients may have benefited from treatment with migraine prophylactics.ConclusionA syndrome of recurrent transient neurological deficits may occur in advanced HIV disease. We believe that in some cases this may be due to local cerebral vasospasm, comparable to a classic migraine aura.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo study the relationships between stage of HIV disease, reflected by CD4+ lymphocyte percentages and p24 antigen levels, and HIV-associated central nervous system (CNS) abnormalities, measured by computed tomography (CT) brain-scan ratings and neurobehavioral tests.DesignConsecutive case series.SettingGovernment medical research center.PatientsEighty-six previously untreated children with symptomatic HIV-1 disease.ResultsCD4% measures correlated significantly with overall CT brain-scan severity ratings (r = −0.45;P<0.001) as well as with its component parts (cortical atrophy, white matter abnormalities, and intracerebral calcifications); they were of comparable magnitude for vertically and transfusion-infected children. CD4% measures were also associated with the general level of cognitive function (r = 0.32;P<0.005). Furthermore, patients with detectable serum p24 antigen levels (n = 39) had CT brain scans that were more abnormal than patients with undetectable p24 levels (n = 20; CT abnormality ratings of 21.3 versus 35.9;P<0.02); similar differences were found for the cortical atrophy and calcification ratings. p24 levels also correlated with the overall CT brain-scan severity rating (r = 0.34;P<0.01).ConclusionsDegree of CT brain-scan abnormality and level of cognitive dysfunction were significantly associated with the stage of HIV-1 disease, as reflected by either CD4 leukocyte measures or elevations of p24 antigen. The relation between the CT brain-scan lesions and markers of HIV disease (both CD4 and p24) suggest that these CNS abnormalities are most likely associated with HIV-1 infection, and further support the hypothesis that the interaction between systemic disease progression and CNS manifestations is continuous rather than discrete.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo examine the relationship between maternal HIV infection, placental malaria infection, and infant mortality as a first step in investigating the possibility of increased vertical transmission of HIV due to placental malaria infection.DesignRetrospective analysis of data from a cohort study of mothers and infants in rural Malawi conducted from 1987 to 1990.MethodsPregnant women in Malawi were enrolled in a study examining chemoprophylaxis during pregnancy. At delivery, placental malaria infection status was determined. Infants born into this study were visited every 2 months for the first 2–3 years of life. Deaths were investigated using a standardized Verbal autopsy' interview. Maternal serum collected during pregnancy was tested for antibodies to HIV-1 by enzyme-linked immunosorbent assay with Western blot confirmation.ResultsOverall, 138 (5.3%) of 2608 women in the study were HIV-1-seropositive. Infant mortality rates were 144 and 235 per 1000 live births for children born to HIV-seronegative and HIV-seropositive women, respectively (P<0.001). In a multivariate model, the odds of dying during the post-neonatal period for an infant born to a mother with both placental malaria and HIV infection was 4.5 times greater than an infant born to a mother with only placental malaria, and between 2.7 and 7.7 times greater (depending on birthweight) than an infant born to a mother with only HIV infection.ConclusionsThis study strongly suggests that exposure to both placental malaria infection and maternal HIV infection increases post-neonatal mortality beyond the independent risk associated with exposure to either maternal HIV or placental malaria infection., If confirmed, malaria chemoprophylaxis during pregnancy could decrease the impact of transmission of HIV from mother to infant.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo determine if serologic marker responses to zidovudine treatment during the first year of antiretroviral therapy could predict subsequent HIV disease progression independently of absolute CD4 lymphocyte responses.MethodsWe conducted a case-control study in patients with asymptomatic HIV disease, who were initiating zidovudine therapy in a randomized, prospective trial. A total of 102 patients who progressed to AIDS or advanced AIDS-related complex and 177 randomly selected controls matched by baseline CD4 cell count and duration of follow-up had serum samples (from prior to and at 8, 16, 32 and 48 weeks of zidovudine treatment) assayed for acid-disassociated HIV p24 antigen, β2-microglobulin (β2M), neopterin, soluble interleukin (IL)-2 receptor, soluble CD4 protein and soluble CD8 protein.ResultsMedian time to event for cases was 20.2 months; median follow-up on study was 35.4 months for controls. After controlling for absolute CD4 count at baseline, increased baseline serum concentrations of HIV p24 antigen, β2M, neopterin, and soluble IL-2 receptor were highly predictive of increased risk of HIV disease progression. In a multiple logistic regression model, controlling for baseline marker values, change in β2M consistently added independent value to change in CD4 count in predicting subsequent risk of disease progression.ConclusionsMonitoring serum immunologic markers, in particular β2M, in addition to absolute CD4 lymphocyte counts prior to and within the first 4 months after initiating dideoxynucleoside therapy can increase the accuracy of estimations of subsequent long-term risk of clinical HIV disease progression. This information may be useful to clinicians and patients who are making decisions about initiating or changing antiretroviral therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID