摘要:

Attachment and entry of HIV-1 into CD4 cells involve a series of events in which different viral envelope proteins interact with specific cell receptors, culminating in fusion of viral and cell membranes. AMD-3100 is a small molecule inhibitor of HIV-1 attachment to the CXCR4 chemokine receptor, and T-20 is a synthetic peptide corresponding to a region of HIV-1 gp41 that blocks fusion to cell membranes. To evaluate the interaction between agents acting at two different steps of the entry process, we conducted in vitro studies of the combination of T-20 and AMD-3100 against an X4 HIV-1 isolate. Single drugs or multiply diluted fixed ratio combinations of drugs were added to peripheral blood mononuclear cells infected with a clinical isolate, 14aPre. Drug interactions were evaluated using the median-effect principle and the combination index technique. The 50% inhibitory concentration (IC50) for T-20 was 0.10 &mgr;g/ml and for AMD-3100 was 0.19 &mgr;g/ml. Synergy was observed between T-20 and AMD-3100 and this increased with higher inhibitory concentrations, with combination indices ranging from 0.62 at IC50to 0.02 at IC95. Whether these synergistic interactions translate into clinical benefit will need to be addressed in the context of clinical trials.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We previously identified a group of 10 long-term nonprogressors (LTNP) with HIV-1 infection. In this study, we have sequenced the envelope gene (C2-V3-C3) from the 10 LTNPs and from a control group of 9 people with rapidly progressing infection (RPI). The 19 individuals' CCR5 genotype and virus phenotype (i.e., syncytium-inducing/non–syncytium-inducing [SI/NSI]) were obtained from a previous study. A phylogenetic tree was constructed containing the 19 envelope sequences together with 42 local control env sequences obtained from other studies. Analysis of the phylogenetic tree did not reveal any relation between the envelope gene (C2-V3-C3) from LTNPs versus RPIs. When data from the CCR5 genotype and the virus phenotype were assembled in the phylogenetic tree, no significant clustering was observed. From alignment of the protein sequences, we found a possible N-glycan in position aa294 in env that was conserved in only 1 of 10 LTNPs; however, it was conserved in 6 of 9 RPIs. Our study could not demonstrate any association between LTNPs and the sequenced envelope gene segment (C2-V3-C3). This lack of association could be due to the relatively small sample size of the data set. Nor did we find any relation between the CCR5 genotype or the SI/NSI phenotype with the sequenced envelope genes from the 19 participants. The possible N-glycan position we have described is an interesting observation that may require further investigation.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

To determine the feasibility of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) studies using cryopreserved cells, we compared lymphocyte proliferation assays (LPA), responder cell frequency (RCF), interleukin-2 (IL-2) and interferon-&ggr; (IFN-&ggr;) production using fresh and cryopreserved peripheral blood mononuclear cells (PBMCs) from 53 HIV-infected patients and 15 uninfected controls. Qualitative CMV LPA results were concordant in ≥84% of the specimens from either HIV-infected patients or controls. Proliferation-based RCF, IL-2, and IFN-&ggr; comparisons showed that cryopreservation reduces the number of CMV-specific responders and decreases cytokine secretion, without changing the rank order of the results (p< .01). In contrast, the number of flow cytometry-enumerated IFN-&ggr;–producing CD4+cells was not significantly changed by cryopreservation. In HIV-infected patients, the differences between fresh and frozen cell assays were not influenced by CD4 cell numbers or HIV viral load. These data indicate that cryopreserved cells are suitable for longitudinal studies of the CMV-specific immune response in HIV-infected patients and uninfected controls.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundHighly active antiretroviral therapy (HAART) became standard for HIV in 1996. Studies at that time showed that most people infected with HIV had initiated HAART, but that members of minority groups and poor people had lower HAART use. It is not known whether high levels of HAART use have been sustained or whether socioeconomic and racial disparities have diminished over time.ObjectivesTo determine the proportion of patients who had received and were receiving HAART by January 1998, and to evaluate predictors of HAART receipt.Design and ParticipantsProspective cohort study of a national probability sample of 2267 adults receiving HIV care who completed baseline, first follow-up, and second follow-up interviews from January 1996 to January 1998.Main outcome variablesProportion currently using HAART at second follow-up (August 1997 to January 1998), contrasted with the cumulative proportions using HAART at any time before January 1998 and before December 1996.AnalysesBivariate and multiple logistic regression analysis of population characteristics predicting current use of HAART at the time of the second follow-up interview.ResultsThe proportion of patients ever having received HAART increased from 37% in December 1996 to 71% by January 1998, but only 53% of people were receiving HAART at the time of the second follow-up interview. Differences between sociodemographic groups in ever using HAART narrowed after 1996. In bivariate analysis, several groups remained significantly less likely to be using HAART at the time of the second follow-up interview: blacks, male and female drug users, female heterosexuals, people with less education, those uninsured and insured by Medicaid, those in the Northeast, and those with CD4 counts of ≥500 cells/&mgr;l (allp< .05). Using multiple logistic regression analysis, low CD4 count (for CD4 <50 cells/&mgr;l: odds ratio [OR], 3.20;p< .001) remained a significant predictor of current HAART use at the time of the second follow-up interview, but lack of insurance (OR, 0.71;p< .05) predicted not receiving HAART.ConclusionsThe proportion of persons under HIV care in the United States who had ever received HAART increased to over 70% of the affected population by January 1998 and the disparities in use between groups narrowed but did not disappear. However, nearly half of those eligible for HAART according to the U.S. Department of Health and Human Services guidelines were not actually receiving it nearly 2 years after these medications were first introduced. Strategies to promote the initiation and continuation of HAART are needed for those without contraindications and those who can tolerate it.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesIncidence of opportunistic protozoal infections causing diarrheal illnesses in patients with HIV has decreased since the introduction of highly active antiretroviral therapy (HAART). The objective of this study was to determine whether the parasites, cryptosporidia, and microsporidia were effectively eradicated or only suppressed following treatment.DesignSix HIV-positive patients with diarrheal symptoms caused by cryptosporidia or microsporidia were prospectively followed up with stool samples and duodenal biopsies. Samples were taken before HAART, between 1 to 3 months, and 6 months post-HAART.MethodsDuodenal samples were analyzed using routine histology and transmission electron microscopy. Stool samples were analyzed by both light microscopy and polymerase chain reaction (PCR) techniques.ResultsPatients who responded successfully to HAART eradicated both cryptosporidial and microsporidial organisms. Symptoms improved within 1 month of therapy but complete eradication of the organisms was only observed after 6 months of treatment.ConclusionsAIDs-related cryptosporidiosis and microsporidiosis can be cured following successful antiretroviral therapy.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ContextFat redistribution (FR) occurring alone or in association with hyperlipidemia has been associated with protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTIs); however, the relationship between FR features, relationship of FR to hyperlipidemia, and pathogenesis of FR is unknown.ObjectiveTo characterize the spectrum of FR, assess relationships among FR features, determine trends in occurrence of FR, and determine relationship of FR to hyperlipidemia.DesignReview of postmarketing indinavir reports of FR in Merck & Co. Inc.'s database.Setting and Participants282 reports of FR among HIV-positive patients taking indinavir submitted through the passive postmarketing system to Merck through February 23, 1998.Results282 FR reports were compared across 3 groups: fat accumulation (FA) only, FA with peripheral wasting (FA with PW), and peripheral wasting only (PWO). Of 282 reports, 56% (159 of 282) had FA only, 22% (63 of 282) had FA with PW, and 21% (60 of 282) had PWO. The proportions of reports of PWO was higher in men, whereas the proportion of reports of FA was higher in women. Blood lipids were provided in 93 of 282 reports; were elevated in 69 of 93, and were normal in 24 of 93 reports. Proportions of hyperlipidemia and hypertriglyceridemia reports were significantly higher in the PWO group versus FA only group (p= .024 and .003, respectively) and versus FA with/without PW groups (p= .038 and .005, respectively). Weight gain was more frequently reported in those with FA (100%) or FA with PW (68%), whereas weight loss was usually reported in those with PWO (83%). In all, 98% of patients reporting FR on indinavir for whom a concomitant drug history was available were also taking lamivudine, stavudine, or both. A higher proportion of patients reporting PWO (34 of 60; 56.7%) versus FA (42 of 159; 26.4%) only took both lamivudine and stavudine.ConclusionsDifferences observed from analysis of cases in clinical features, gender, weight change, concomitant medications, and presence of hyperlipidemia among the three groups of FR cases reported to Merck suggests that PWO may be a distinct entity from other features of FR. The data suggest that certain antiretroviral combinations predispose HIV persons to development of FR.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287(10–103infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Although significant progress has been made in understanding immune reconstitution in peripheral blood following highly active antiretroviral therapy (HAART), less is known about immune changes in lymphoid tissue. Here, the expression of cytokine proteins (interferon gamma [IFN-&ggr;], interleukin [IL]-2, IL-4, IL-10, IL-1&agr;, and IL-1&bgr;) and surface antigens (CD4, CD8, CD1a, CD68) as well as cellular proviral HIV-1 DNA were determined in sequential tonsil biopsies before and at 4, 12, and 48 to 56 weeks posttherapy by quantitative in situ image analysis and fluorescent in situ 5´-nuclease assay (FISNA). Despite plasma virus suppression, a fraction of tonsil cells harbored pro-viral DNA for up to 1 year. A fourfold to eightfold increase in CD8+T cells in tissue compared with seronegative controls and an increased frequency of CD1a+dendritic cells prior to HAART reached control levels at week 56. The frequency of IFN-&ggr; expressing cells was 10-to 15-fold higher than controls before therapy and was comparable with findings in seronegative controls by week 56. Elevated baseline expression of IL-1&agr; and IL-1&bgr; was reduced by week 4 but IL-1&agr; levels remained elevated in 1 of 3 patients at week 56. These findings suggest that with effective viral suppression the immune system in tissue may return to a more resting state.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo assess the prevalence and modes of transmission of HTLV-1 infection in an adult population in Bissau, and to evaluate possible interactions between the pattern of spread of HTLV-1 and HIV-1/HIV-2.Design and MethodsUnivariate and multivariate analyses were used to evaluate gender-and age-specific HTLV-1 prevalences as well as associated risk determinants in an adult population based on a serosurvey comprising 2127 individuals from 304 randomly selected houses in Bissau.ResultsUsing stringent Western blot criteria, the overall seroprevalence of HTLV-1 was 3.6%, 2.2% among men and 4.7% among women, respectively. One individual was seropositive to HTLV-2. The prevalence of HTLV-1, which increased with age in both genders, however more markedly among women, was >4 times higher (9.4%) among older individuals (>44 years of age) than among younger individuals (2.4%). Blood transfusion and HIV-2 seropositivity were independently associated with HTLV-1 seropositivity in men. Among women, both HIV-2 seropositivity and HIV-1 seropositivity were significant risk determinants. Having had sexual partners was associated with a fivefold increased risk among women but did not reach significance.ConclusionThe adult population of Guinea-Bissau has a higher prevalence of HTLV-1 than reported from most other countries in West Africa. The gender-and age-specific pattern of spread of HTLV-1 closely resembles that observed for HIV-2, another retrovirus prevalent to the region. The close correlation between HTLV-1 and HIV-2 most likely reflects the shared risk factors related to sexual behavior. The implication of the high percentage of double infections in this population needs to be determined.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID