ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:A live attenuated SIV vaccine strain, termed SIVmac239Δ3 and containing large deletions innef,vprand the negative regulatory element, was previously shown to cause AIDS mostly in monkeys vaccinated as infants. In the present study, we demonstrate that SIVmac239Δ3 is pathogenic in most vaccinated adult monkeys, given enough time.Methods:Eleven rhesus macaques vaccinated as adults with SIVmac239Δ3 were followed for extended periods (up to 6.8 years).Results:We found signs of immune dysregulation in all 11 adult vaccinees. All animals developed persistently inverted CD4 : CD8 T-cell ratios, seven (64%) had persistent recurrent viremia, and six (55%) had decreased CD4 T-cell counts (< 500 × 106cells/l). Further signs included low CD4CD29 lymphocyte subsets, loss of anti-Gag antibodies, anemia, thrombocytopenia, wasting, and opportunistic infections. Two adult vaccinees (18%) subsequently developed AIDS. Development of chronic, recurrent viremia with plasma viral RNA loads ⩾ 103copies/ml and cytoviremia was a poor prognostic sign.Conclusion:Our data demonstrate that with time, a live attenuated, multiply deleted SIV vaccine can cause immune dysregulation in most vaccine recipients, even in initially immune competent, healthy adults. Immune dysfunction can progress to full AIDS. However, pathogenic effects became evident only several years after vaccination. Thus, mass vaccination of humans with similarly constructed live attenuated HIV vaccines, recently suggested for countries with high HIV-1 transmission rates, seems contraindicated.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:We previously produced a line of transgenic mice that carried the HIV-1 genome deficient in thepolgene. Although the HIV-1 genome in the lymphocytes was dormant under normal physiological conditions, it could be reactivatedin vivoby lipopolysaccharide (LPS) administration via induction of interleukin-1α/β and tumour necrosis factor-α. In this report, we analysed further the reactivation mechanism of the latent HIV-1 using this transgenic mouse model.Designand methods: Possible involvement of CpG methylation in HIV-1 latency was examined by treating transgenic lymphocytes with a demethylating agent, 5′-azacytidine. CpG methylation in the HIV-1 long terminal repeat (LTR) was analysed using the bisulfite genomic sequencing method. As previous studies suggested that CpG demethylation depended on the cell cycle progression, we analysed the relation between cell cycle progression and LPS-induced reactivation of HIV-1 by labelling lymphocytes with an intracellular fluorescein, carboxyfluorescein diacetate succinimidyl ester.Results:We found that 5′-azacytidine enhanced HIV-1 expression ninefold compared to treatment with LPS alone. Furthermore, HIV-1 p24 induction by LPS was observed only in cells that had undergone cell division, while induction was prevented in cells in which cell cycle progression was blocked either by mimosine, aphidicolin, or nocodazole. LPS-induced HIV-1 reactivation was associated with demethylation of two CpG sites located in the CREB/ATF binding sites in the HIV-1 LTR in a cell cycle-dependent manner.Conclusions:These observations indicate that cell cycle progression-dependent demethylation of the CREB/ATF sites in the LTR is crucial for the reactivation of latent HIV-1 genome in transgenic mice.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:HIV-1 entry into CD4 cells represents a main target for developing novel antiretroviral agents and microbicides.Design:Sulfated derivatives of theEscherichia coliK5 polysaccharide have a backbone structure resembling the heparin precursor, but are devoid of the anticoagulant activity. The derivatives were chemically sulfated in the N position after N-deacetylation, in the O position, or in both sites.Methods:HIV replication in human T cell blasts, monocyte-derived macrophages and cell lines was studied in the presence of sulfated K5 derivatives.Results:O-sulfated [K5-OS(H)] and N,O-sulfated [K5-N,OS(H)] K5 derivatives with high degree of sulfation inhibited the replication of an HIV strain using CXCR4 as entry co-receptor (X4 virus) in both cell lines and T-cell blasts. K5 derivatives also strongly inhibited the multiplication of CCR5-dependent HIV (R5 virus) in cell lines, T-cell blasts and primary monocyte-derived macrophages. Their 50% inhibitory concentration was between 0.07 and 0.46 μM, without evidence of cytotoxicity even at the maximal concentration tested (9 μM). In addition, both K5-N,OS(H) and K5-OS(H) potently inhibited the replication of several primary HIV-1 isolates in T-cell blasts, with K5-N,OS(H) being more active than K5-OS(H) on dual tropic R5X4 strains. K5 derivatives inhibited the early steps of virion attachment and/or entry.Conclusions:Because K5 derivatives are unlikely to penetrate into cells they may represent potential topical microbicides for the prevention of sexual HIV-1 transmission.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:With the use of highly active antiretroviral therapy, the identification of HIV reservoirs within the body has become an important issue. However, the testis has been largely ignored despite representing a pharmacologic sanctuary which could act as a viral reservoir.Design:Because alterations in testosterone production have frequently been reported in HIV-infected individuals, we investigated whether the testosterone-producing Leydig cells could become directly infected by HIV-1, HIV-2 or SIV.Methods:Purified Leydig cells were infected with a panel of HIV-1, HIV-2 and SIV strains and examined for expression of HIV/SIV receptors. Additionally, the impact of CD4 transduction on Leydig cell infection was determined.Results:Leydig cells were unable to support productive infection of the seven HIV-1 isolates tested. No CD4, CXCR4 or CCR5 expression was evident on the surface of Leydig cells and transduction with a CD4 expressing adenovirus did not induce HIV-1 infection. In contrast, some primary and laboratory adapted CD4-independent HIV-2 and SIV strains were able to enter and replicate productively in Leydig cells.Conclusions:Our results suggest that Leydig cells do not represent a target for HIV-1 infection within the testis. In contrast, Leydig cells support HIV-2 and SIV infectionin vitroand thus represent a potential target for infectionin vivo. Receptor use andin vivosignificance of HIV-2/SIV infection of Leydig cells remain to be determined.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:Hyperlipidaemia associated with antiretroviral treatment has led to concerns for an increased cardiovascular risk in HIV-infected patients.Objective:To assess this cardiovascular risk by comparing the lipoprotein pattern of antiretroviral-treated and untreated HIV-positive patients with patients with familial combined hyperlipidaemia (high cardiovascular risk) or familial hypertriglyceridaemia (low cardiovascular risk).Methods:Fasting serum samples were drawn from consecutive patients with HIV infection or lipoprotein disorders. Total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 and B were determined in serum. Very low density lipoprotein (VLDL) was prepared by ultracentrifugation and analysed for cholesterol, triglycerides and apolipoprotein B.Results:Lipoprotein disorders were found in 114/187 HIV-positive patients (61%). Of these, according to the Fredrickson classification, 10% were type IIa (elevated LDL-cholesterol), 14% type IIb (elevated LDL- and VLDL-cholesterol) and 76% were type IV (elevated VLDL-cholesterol). VLDL composition was analysed in 34 HIV-positive patients with type IV hyperlipidaemia. The ratio of VLDL-triglycerides to VLDL-apolipoprotein B in these patients was 16.2 ± 6.0. This ratio was not different from 14 patients with famlial hypertriglyceridaemia (16.9 ± 6.0;P= 0.61), but differed substantially from 10 patients with familial combined hyperlipidaemia (6.8 ± 1.0;P< 0.0001).Conclusions:In HIV-infected patients with high VLDL, large VLDL particles were found with no increase in number. This pattern resembles familial hypertriglyceridaemia. It is different from familial combined hyperlipidaemia, where an increase in number of small-sized VLDL particles occurs. Further research is needed to assess the contribution of VLDL-associated hypercholesterolaemia in those taking antiretroviral drugs to the cardiovascular risk profile of HIV-positive patients.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To evaluate time to viral rebound in patients undergoing repeated structured treatment interruptions (STI).Method:Fourteen chronically HIV-infected patients enrolled in the Swiss–Spanish Intermittent Treatment Trial (SSITT) underwent frequent blood sampling. Patients underwent four cycles of 2-week STI, followed by 8-week retreatment with the identical antiretroviral treatment (HAART) used before STI. At the fifth cycle, treatment was stopped for a longer period. Before each new STI, plasma viral load (VL) had to reach < 50 copies/ml. VL was measured during day 0 (last day on HAART) and on days 4, 8 and 14 during all five STI.Results:During the first cycle, plasma HIV RNA increased to > 50 copies/ml (range, 67–88) in five patients at day 4, in eight patients (> 100 copies/ml) at day 8 and in 12 patients (> 100 copies/ml) at day 14. Cumulative analysis of the frequency of detectable HIV RNA at days 4, 8 and 14 compared with day 0 for all five cycles revealed nine patients with VL > 50 copies/ml [13 of 54 samples tested (24.1%);P= 0.14] at day 4, 11 patients [33 of 58 samples tested (56.9%);P< 0.0001] at day 8 and 12 patients [53 of 65 samples tested (81.5%);P< 0.0001] at day 14.Conclusions:Significant viral replication can be induced during 1 week STI, and this may increase the risk of the emergence of drug resistance during long-term cycling. Therefore, short-term cycling strategies such as 1-week-on, 1-week-off treatment, although conceptually intriguing, should still be regarded as investigational and should be restricted to rigorously controlled clinical trials ideally involving patients who have never failed treatment before.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:Single nucleotide polymorphisms (SNP) in the genes encoding the human CX3CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX3CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, antiretroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada.Methods:CX3CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL) ⩽ 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL ⩾ 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan–Meier methods.Results:Frequencies of CX3CR1 amino acid haplotypes were 249V 280T (0.75), 249I 280M (0.15), and 249I 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX3CR1 or MDR-1 on time to virological success, nor of CX3CR1 and MDR-1 SNP on time to virological and immunological failure, respectively (P> 0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group (P= 0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX3CR1 249I polymorphism (P= 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence (P⩽ 0.05).Conclusion:Polymorphisms in MDR-1 and CX3CR1 may be associated with accelerated virological and immunological therapy failure, respectively.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID