ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective and design:To study the role and development of non-cytotoxic CD8+ T-cell-mediated suppression of HIV replication in early perinatal HIV infection in a prospective study of vertically infected infants. CD8 T-cell-mediated HIV suppression was measured several times during the first year of life and correlated with viral load, cytotoxic T-cell (CTL) activity,in vitroantibody production (IVAP) and clinical outcome.Methods:CD8+ T-cell-mediated HIV suppression was measured by comparing the amount of p24 antigen produced by endogenously infected lymphocytes with cultures of the same number of autologous CD4+ T cells from which CD8+ cells were removed immunomagnetically. CD8 viral suppressive activity (VSA) was defined as a ≥50% reduction in p24 antigen in the cultures containing CD8+ cells.Results:CD8+ T-cell-mediated HIV VSA was detected in 11/16 infants in the first year of life, including six/nine infants studied before 6 months and as early as 3 weeks of age. Infants who demonstrated CD8 VSA had a lower early peak and 6-month ‘setpoint’ plasma HIV RNA concentration than infants who lacked CD8 VSA [1.51 versus 4.94 and 0.094 versus 0.639 × 106copies/ml, respectively, and higher CD4 percentage at 1 year of age. Survival of infants lacking CD8 VSA (four/six were rapid progressors) was shorter than for infants who demonstrated CD8 VSA (none out of 10 were rapid progressors). CD8 VSA was present before CTL and before or at the same time as IVAP in two of two and 11 of 14 infants studied, respectively.Conclusions:CD8+ T-cell-mediated VSA can be demonstrated in a large proportion of HIV-infected infants early in the course of infection. This non-cytolytic HIV-suppressive immune response appears to play an important protective role in the early control of perinatal HIV infection at a time when other immune responses are either absent or deficient.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To study alterations of mitochondrial membrane potential (Δψ) and the propensity to undergo apoptosis in peripheral blood lymphocytes (PBL) from subjects with acute HIV syndrome; and to evaluate possible modulations of these phenomena by antioxidants that can be used in therapy, such as N-acetyl-cysteine (NAC), nicotinamide (NAM), or L-acetyl-carnitine (LAC).Methods:Mitochondrial function and the tendency of PBL to undergo spontaneous apoptosis were studied on freshly collected PBL from patients with symptomatic, acute HIV-1 primary infection, which were cultured for different durations in the presence or absence of NAC, NAM or LAC. By a cytofluorimetric method allowing analysis of Δψ in intact cells, we studied the function of these organelles under the different conditions. PBL apoptosis was evaluated by the classic cytofluorimetric method of propidium iodide staining, capable of revealing the typical DNA hypodiploid peak.Results:Significant Δψ alterations and tendency to undergo apoptosis were present in PBL from the subjects we studied. Indeed, when cultured even for a few hours in the absence of any stimulus, a consistent number of cells died. However, the presence of even different levels of NAC, NAM or LAC was able to rescue most of them from apoptosis. Both a fall in Δψ and apoptosis were evident in PBL collected in the earliest phases of the syndrome (before seroconversion), and changed significantly after a few days. A significant correlation was found between spontaneous apoptosis and tumour necrosis factor (TNF)-α or p24 plasma levels, as well as between apoptosis and the percentages of circulating CD4+ or CD8+ T cells.Conclusions:PBL from patients with acute HIV syndrome are characterized by both significant mitochondrial alterations and a dramatic tendency to undergo apoptosis. The use of NAC, NAM or LAC seems to rescue cells through a protective effect on mitochondria, a well-known target for the action of TNF-α and for reactive oxygen species, the production of which is strongly induced by this cytokine. Thus, our data could provide the rationale for the use of such agents in addition to antiviral drugs in primary infection.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To study whether free gp120 can be detected on the plasma membranes of apoptotic CD4+ T lymphocytes in lymph nodes from HIV-positive patients.Methods:Lymph-node cell suspensions prepared from three HIV-positive patients were studied by pre-embedding, double-immunogold-labeling to identify cell type, determine cell morphology, and detect the presence of bound gp120 molecules. Cells were classified by their surface antigens as helper/inducer T lymphocytes (CD4+), cytotoxic/suppressor T lymphocytes (CD8+), B cells (CD20+), and total lymphocytes [CD45+, leukocyte common antigen (LCA)+].Results:gp120 colabeled with both apoptotic and normal CD4+ T lymphocytes and LCA+ cells, but not with either apoptotic or normal CD8+ T lymphocytes or B cells. gp120 was more often identified on apoptotic than on normal CD4+ T lymphocytes. The gp120 and CD45 label were often colocalized. HIV particles were not identified to be associated with or budding from either normal or apoptotic lymphocytes.Conclusions:Free gp120 is found bound to CD4+ T cells in lymph nodes of HIV-infected individuals and potentially mark them for premature death by apoptosis.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objectives:To ascertain the effects of N-acetyl-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) on HIV replication in resting T lymphocytes mixed with chronically infected U1 promonocytic cells; examine the phenotypes of NAC- and OTC-treated cells; and monitor HIV recovery from hu-PBMC SCID mice (SCID mice infected with HIV-1BaLreconstituted with human peripheral blood mononuclear cells) treated with oral OTC.Design and Methods:Unstimulated PBMC from uninfected donors preincubated for 2 days with pH-adjusted NAC or OTC were cultured at a concentration of 1 × 106cells/ml with 100 U1 cells that were chronically infected with HIV-1IIIB. HIV-1 production in the presence or absence of zidovudine was measured by p24 assay at 1–3 weeks, and results were compared with values from the same cell cultures maintained without NAC or OTC exposure. In some experiments U1 cells were separated from PBMC by a 0.4 µm membrane. NAC-treated and -untreated cells were subjected to FACS analysis of multiple-cell-surface adhesion and activation molecules and the results were compared. Hu-PBMC SCID mice were fed OTC for 3 days prior to infection with HIV-1BaLand for the next 3 weeks. Mice were then sacrificed and peritoneal lavage cells were cultured for virus analysis.Results:Unstimulated, non-dividing PBMC supported high levels of HIV replication when in direct contact with U1 cells in the presence of NAC or OTC; CD2 and CD54 (I-CAM1) were down-regulated on NAC-treated PBMC; and OTC-treated mice produced significantly higher yields of HIV-1 from peritoneal cells than did untreated mice.Conclusions:At concentrations ≤5 mM, NAC and OTC potentiate HIV growth in unstimulated PBMC in vitro and in SCID mice. Caution in the use of these agents as antiviral monotherapies is advisable.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To identify the genetic subtypes and characteristics of HIV-1 strains from individuals infected after overseas deployment.Patients and methods:Sixty-one HIV-1-positive individuals detected between 1986 and 1995 in the French army were included in the study. For each patient, the year and country of HIV infection are known. Genetic subtypes of HIV-1 were determined using the heteroduplex mobility assay (HMA) using ED5/ED12 as outer and ES7/ES8 as inner primers. Strains were further characterized by sequencing and phylogenetic analysis of the C2-V3 region. The amino-acid sequences corresponding to the V3 region were aligned on the basis of the subtyping results and were then compared to the consensus V3 sequences of the corresponding subtypes.Results:Among the 61 patients studied, nine became infected in France, and 52 were HIV-negative before overseas deployment but HIV-positive at their return. The majority (n = 43) deployed in Africa and a limited number of patients deployed in Asia (Cambodia, n = 5) or South America (Guyana, n = 4). The nine individuals who were not deployed overseas were all infected with subtype B strains. The majority of the other patients were infected with non-B strains; eight subtype A, 20 subtype B, 16 subtype C, one subtype D, six subtype E and one subtype F. Five of the six subtype E strains were contracted in Cambodia and one in Djibouti, and all subtype C strains were from Djibouti. Phylogenetic analysis revealed a large diversity among the different strains introduced into France. Analysis of the amino-acid sequences of the V3 loop revealed the introduction of uncommon V3-loop patterns.Conclusion:In the group of HIV-1-infected individuals that we studied and who were deployed overseas, 63.4% were infected with non-B strains. In addition, the subtype A, B and C viruses in this population were very heterogeneous. Due to the routine occurrence of international travel and deployment, the predominance of subtype B HIV-1 viruses may change in European countries. However, the possible implications on the dynamics of the HIV-1 epidemic needs further follow-up.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background:HIV-1-infected patients with a CD4+ lymphocyte count ≥500×106/l may be selected for antiretroviral treatment when viral load is above a given cut-off point.Objectives:To assess the stability of viral load measurement at CD4+ T-cell counts above 500×106/l, and the proportion of patients selected for treatment if a cut-off point of 10 000 or 30 000 RNA copies/ml is used.Design and methods:Seventy-eight consecutive asymptomatic antiretroviral-naive HIV-1-infected patients with CD4+ lymphocyte counts ≥500 × 106/l, presenting for previously scheduled medical visits as outpatients, were enrolled. None of the patients had suffered from symptomatic primary infection or seroconverted within 6 months before enrolment. Two blood samples separated by a 1-month interval [day −30 (screening) and day 0 (enrolment)] were collected in an EDTA tube. Plasma was separated and frozen at −70°C within 4 h of collection. HIV-1 RNA was quantified by polymerase chain reaction. CD4+ T cells were measured by flow cytometry.Results:Viral load was fairly stable, and only four (13%) out of 30 pairs had a variation ≥0.5 log10. At day −30 and day 0, log10HIV RNA levels (mean ± SD) were 4.24 ± 0.7 and 4.35 ± 0.87 log10copies/ml plasma (P= 0.23). The difference of the mean was −0.11 (95% confidence interval, −0.28 to 0.07). At day 0 (n = 78) mean ± SD value was 35730 ± 73700 RNA copies/ml (range, <200–438480; median, 9331; 25th and 75th percentiles, 1518 and 37193, respectively). In 13 patients (16%) the viral load was <200 copies RNA/ml. Seven out of 10 patients, who fulfilled the criteria of long-term non-progressors (LTNP), had viral load >10 000 RNA copies/ml, and two patients had >30 000 RNA copies/ml. Only two of the 13 patients with CD4+ T-cell counts >750 × 106/l had viral load >10 000 copies/ml.Conclusions:A single-point viral load assessment is enough in asymptomatic patients with CD4+ lymphocytes counts ≥500 × 106/l since plasma HIV RNA measurements obtained 1 month apart are fairly stable. Approximately 25% of these patients (including some patients with LTNP criteria) will be selected for treatment if 30 000 RNA copies/ml is used as cut-off point, and approximately 50% if the cut-off point is 10 000 RNA copies/ml. Viral load ≥10 000 is very unusual in patients with CD4+ T-cell counts >750 × 106/l.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To evaluate the effects of treatment with alternating and simultaneous regimens of zidovudine and didanosine on neuropsychological function in patients with symptomatic HIV-1 disease, focusing on patients with possible HIV-1-associated central nervous system (CNS) compromise at entry.Design:Randomized non-blinded clinical trial.Setting:Government medical research center.Patients:Thirty-eight patients with symptomatic HIV-1 disease, of whom 21 had evidence of CNS compromise at entry.Results:After 12 weeks of therapy, overall significant improvements in memory (P < 0.01) and focused attention (P < 0.001) were seen on both regimens. These gains, however, were largely limited to those patients with HIV-1-associated CNS compromise at entry (P < 0.05). Improvements were also noted in receptive vocabulary, reading, perceptual discrimination and reasoning, divided attention, motor strength, and in mood and affect. Improvements in those latter functions were generally of limited magnitude and were of comparable size for both compromised and non-compromised patients. There was no overall difference between the two drug regimens in the effects on CNS parameters.Conclusions:Therapy-related improvements were noted particularly for patients with HIV-1-associated CNS compromise. Neuropsychological functions that have been implicated in AIDS dementia — memory and attention — showed the greatest gains. In contrast to the previously described superiority of the simultaneous regimen with regard to immunologic and virologic parameters, there was no difference between the regimens with regard to CNS measures. This supports the contention that the CNS constitutes a relatively independent compartment in terms of HIV disease and treatment.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To evaluate the antiretroviral effect of a combination of zidovudine (ZDV) and didanosine (ddI) on plasma, peripheral blood mononuclear cells (PBMC) and lymph nodes after 24 weeks.Methods:Eight patients naive of antiretroviral therapy were followed by monthly blood samples and two surgical lymph-node biopsies taken at baseline and after 24 weeks. CD4+ T cells were counted monthly by flow cytometry. Plasma HIV-1 RNA was measured monthly by polymerase chain reaction (PCR). Infectious cellular viraemia was measured monthly by a culture technique. Proviral DNA titres in PBMC were measured by endpoint dilution PCR at baseline and 24 weeks. Infectious HIV-1 and proviral DNA titres were measured in the lymph-node mononuclear cells (LNMC). The total HIV-1 RNA content of lymph nodes was measured by PCR. In some cases, phenotypic resistance to ZDV was measured, and codon 215 and 74 mutations in PBMC and LNMC were analysed.Results:A mean increase in CD4 cell count of 122 × 106/l, a mean decrease in HIV-1 RNA of 1.47 log10in plasma and a mean decrease in HIV-1 DNA titre of 0.63 log10were found after 24 weeks of therapy. Nevertheless, there were no statistically significant changes in the mean infectious HIV-1 titre in PBMC and LNMC, in the HIV-1 DNA titre in LNMC or in the total lymph-node HIV-1 RNA burden at week 24. Phenotypic or genotypic markers of drug resistance were rarely found in PBMC at week 24, although they were detected in LNMC from some patients.Conclusion:A discrepancy in the therapeutic effect can be observed between lymphoid organs and blood after 24 weeks of therapy with ZDV and ddI. This difference could be explained by the insufficient antiretroviral potency of this combination facing the significant viral burden present in lymph nodes. Development of drug resistance in this compartment prior to blood can be demonstrated in some cases, although other mechanisms remain to be investigated in future studies to explain this difference.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background:Evidence from ecological studies and from studies of and sexually transmitted disease (STD) patients in sub-Saharan Africa suggests that there is a protective effect of male circumcision against HIV infection. There are, however, few population-based studies that have controlled adequately for potential confounding factors.Methods:Data from five population-based studies in north-western Tanzania were used to investigate the association between male circumcision and the risk of HIV infection and STD. The effects of circumcision on HIV prevalence, syphilis (positive Treponema pallidum haemagglutination; TPHA) and self-reported STD were analysed, controlling for a range of demographic and sociocultural variables, and indicators of sexual behaviour.Results:In north-western Tanzania, circumcision was previously restricted to Muslims and specific ethnic groups, but is now more widespread, particularly in urban areas and among more educated men. Assessment of the reliability and validity of self-reported circumcision status showed that these data could be considered fairly accurate, although there was some tendency for circumcision to be over-reported. On univariate analysis, circumcision status was unrelated to HIV prevalence in most studies. After controlling for confounding variables, however, there was a modest but significant reduction of the HIV prevalence among circumcised men [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.48–0.81]. This effect appeared stronger in urban areas (OR, 0.46; 95% CI, 0.32–0.68) and roadside villages (OR, 0.65; 95% CI, 0.42–1.01) than in rural areas and islands (OR, 1.00 and 1.01 respectively). There was no association between circumcision status and syphilis serology (TPHA), but there was a positive association between circumcision and self-reported STD, although this was not significant after adjustment for confounding variables.Conclusion:Male circumcision has a protective effect against HIV infection in this population, which may be stronger in urban areas and roadside settlements than in the rural areas. Ethnic group and religious denomination are no longer the sole determinants of male circumcision.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID