Search

We conducted a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of cetirizine to assess the ability of antihistamines to prevent nevirapine-associated rash in patients infected with human immunodeficiency virus type 1. Patients initiating treatment with nevirapine were randomized to receive either cetirizine, 10 mg q.d. (104 patients), or placebo (96 patients) during the first 6 weeks of therapy. Rash occurred in 22 (11%) of 200 patients; 10 (9.6%) were in the cetirizine group and 12 (12.5%) were in the placebo group (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.31-1.81; p = .5). Five of 22 rashes were cases of hypersensitivity syndrome. The rate of nevirapine discontinuation due to rash was similar in the 2 groups (7.7% and 6.25% in the cetirizine and placebo groups, respectively P = .4). Multivariate analysis showed no treatment-group effect but indicated that age >40 years (OR, 3.83; 95% CI, 1.4-10.46; p = .008) was associated with an increased risk of rash. Cetirizine has no preventive effect on nevirapine-associated rash. [ABSTRACT FROM AUTHOR]

Abstract Background Pathogenesis of liver damage in patients with HIV and HCV co-infection is complex and multifactorial. Although global awareness regarding HIV-1/HCV co-infection is increasing little is known about the pathophysiology that mediates the rapid progression to hepatic disease in the co-infected individuals. Results In this study, we investigated the proteome profiles of peripheral blood mononuclear cells from HIV-1 mono-, HCV mono-, and HIV-1/HCV co-infected patients. The results of high-resolution 2D gel electrophoresis and PD quest software quantitative analysis revealed that several proteins were differentially expressed in HIV-1, HCV, and HIV-1/HCV co-infection. Liquid chromatography-mass spectrometry and Mascot database matching (LC-MS/MS analysis) successfully identified 29 unique and differentially expressed proteins. These included cytoskeletal proteins (tropomyosin, gelsolin, DYPLSL3, DYPLSL4 and profilin-1), chaperones and co-chaperones (HSP90-beta and stress-induced phosphoprotein), metabolic and pre-apoptotic proteins (guanosine triphosphate [GTP]-binding nuclear protein Ran, the detoxifying enzyme glutathione S-transferase (GST) and Rho GDP-dissociation inhibitor (Rho-GDI), proteins involved in cell prosurvival mechanism, and those involved in matrix synthesis (collagen binding protein 2 [CBP2]). The six most significant and relevant proteins were further validated in a group of mono- and co-infected patients (n = 20) at the transcriptional levels. Conclusions The specific pro- and anti- apoptotic protein signatures revealed in this study could facilitate the understanding of apoptotic and protective immune-mediated mechanisms underlying HIV-1 and HCV co-infection and their implications on liver disease progression in co-infected patients.

Molecular multiplex assays (MPAs) for simultaneous detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza and respiratory syncytial virus (RSV) in a single RT-PCR reaction reduce time and increase efficiency to identify multiple pathogens with overlapping clinical presentation but different treatments or public health implications. Clinical performance of XpertXpress ® SARS-CoV-2/Flu/RSV (Cepheid, GX), TaqPath™ COVID-19, FluA/B, RSV Combo kit (Thermo Fisher Scientific, TP), and PowerChek™ SARS-CoV-2/Influenza A&B/RSV Multiplex RT-PCR kit II (KogeneBiotech, PC) was compared to individual Standards of Care (SoC). Thirteen isolates of SARS-CoV-2, human seasonal influenza, and avian influenza served to assess limit of detection (LoD). Then, positive and negative residual nasopharyngeal specimens, collected under public health surveillance and pandemic response served for evaluation. Subsequently, comparison of effectiveness was assessed. The three MPAs confidently detect all lineages of SARS-CoV-2 and influenza viruses. MPA-LoDs vary from 1 to 2 Log10 differences from SoC depending on assay and strain. Clinical evaluation resulted in overall agreement between 97 and 100%, demonstrating a high accuracy to detect all targets. Existing differences in costs, testing burden and implementation constraints influence the choice in primary or community settings. TP, PC and GX, reliably detect SARS-CoV-2, influenza and RSV simultaneously, with reduced time-to-results and simplified workflows. MPAs have the potential to enhance diagnostics, surveillance system, and epidemic response to drive policy on prevention and control of viral respiratory infections., Competing Interests: JF, MG, OO, and CU were employed by Thermo Fisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boukli, Flamand, Chea, Heng, Keo, Sour, In, Chhim, Chhor, Kruy, Feenstra, Gandhi, Okafor, Ulekleiv, Auerswald, Horm and Karlsson.)

The first case of coronavirus disease 2019 (COVID-19) in Cambodia was confirmed on 27 January 2020 in a traveller from Wuhan. Cambodia subsequently implemented strict travel restrictions, and although intermittent cases were reported during the first year of the COVID-19 pandemic, no apparent widespread community transmission was detected. Investigating the routes of severe acute respiratory coronavirus 2 (SARS-CoV-2) introduction into the country was critical for evaluating the implementation of public health interventions and assessing the effectiveness of social control measures. Genomic sequencing technologies have enabled rapid detection and monitoring of emerging variants of SARS-CoV-2. Here, we detected 478 confirmed COVID-19 cases in Cambodia between 27 January 2020 and 14 February 2021, 81.3 per cent in imported cases. Among them, fifty-four SARS-CoV-2 genomes were sequenced and analysed along with representative global lineages. Despite the low number of confirmed cases, we found a high diversity of Cambodian viruses that belonged to at least seventeen distinct PANGO lineages. Phylogenetic inference of SARS-CoV-2 revealed that the genetic diversity of Cambodian viruses resulted from multiple independent introductions from diverse regions, predominantly, Eastern Asia, Europe, and Southeast Asia. Most cases were quickly isolated, limiting community spread, although there was an A.23.1 variant cluster in Phnom Penh in November 2020 that resulted in a small-scale local transmission. The overall low incidence of COVID-19 infections suggests that Cambodia's early containment strategies, including travel restrictions, aggressive testing and strict quarantine measures, were effective in preventing large community outbreaks of COVID-19., (© The Author(s) 2023. Published by Oxford University Press.)

We report evaluation of 30 assays' (17 rapid tests (RDTs) and 13 automated/manual ELISA/CLIA assay (IAs)) clinical performances with 2594 sera collected from symptomatic patients with positive SARS-CoV-2 rRT-PCR on a respiratory sample, and 1996 pre-epidemic serum samples expected to be negative. Only 4 RDT and 3 IAs fitted both specificity (> 98%) and sensitivity (> 90%) criteria according to French recommendations. Serology may offer valuable information during COVID-19 pandemic, but inconsistent performances observed among the 30 commercial assays evaluated, which underlines the importance of independent evaluation before clinical implementation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

RT-PCR is the reference method for diagnosis of a Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection. During the setting up of 6 SARS-CoV-2 RT-PCR assays in our laboratory, comparative evaluations were systematically undertaken and allowed to evidence major discrepancies on cycle threshold RT-PCR results between techniques. These tendencies were confirmed in routine application when analyzing sequential samples from the same patients. Our aim was to examine the impact of the technique among factors influencing RT-PCR result, a far surrogate of 'viral load' in the heterogeneous environment of respiratory specimens., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To describe the epidemiological situation of the HIV/AIDS epidemic and to identify the main drivers for vulnerability in Madagascar., Design: Literature review, qualitative research and situational analysis., Data Sources: Search of electronic bibliographic databases, national repositories of documentation from 1998 to 2018. Search keywords included Madagascar, HIV, sexually transmitted infections, men who have sex with men (MSM), sex workers (SWs), transactional sex (TS), injecting drug users (IDUs), vulnerability and sexual behaviour. Qualitative sources were interviews and focus group discussions., Review Methods: Studies focused on HIV and/or vulnerability of HIV in Madagascar in general, and key populations (KPs) and HIV/AIDS response were taken into account. National reports from key HIV response actors were included., Results: Madagascar is characterised by a low HIV/AIDS epidemic profile in the general population (GP) (0.3%) combined with a high prevalence of HIV among KPs (SWs, MSM and IDUs).An increase in HIV prevalence among KP has been observed during recent years. Hospital-based data suggest an increase in HIV prevalence among the GP. The vulnerability traits are inconsistent use of condoms, multipartner relationships and other contextual factors like widespread TS and gender inequality. A high prevalence/incidence of sexually transmitted infections could indicate a high vulnerability to HIV/AIDS. However, there are no reports of HIV prevalence of >1% in antenatal consultation., Conclusion: There is not enough evidence to make a conclusion about the HIV epidemiological situation in Madagascar due to the scarcity of the epidemiological data. However, Madagascar may be closer to a turning point towards a high-prevalence epidemic with severe consequences, particularly when taking into account its socioeconomical fragility and underlying vulnerabilities. More precise epidemiological data and improved HIV/AIDS diagnosis and case management should be a public health priority., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the extent to which drug resistance can be evaluated from proviral HIV-1 DNA genotype compared with RNA genotype at different timepoints., Patients and Methods: In HIV-1-infected patients routinely seen at a university hospital, who needed to change their current ART, antiretroviral drug resistance was determined from DNA genotype and was compared with past RNA genotype (group 1) or same-day RNA genotype (group 2). A 'resistance sum' was defined as the sum of agents to which resistance was present and was calculated across NRTI, NNRTI and PI. We defined 'loss of information' as when a lower resistance sum was observed in DNA than in RNA samples., Results: Of the 74 and 26 patients included in groups 1 and 2, respectively, most had a long median duration of known HIV-1 infection (17.4 and 14.2 years) and ART (15.3 years and 13.5 years). For group 1, the median (range) resistance sums between DNA/RNA were 0 (0-6)/1 (0-6) for NRTIs, 0 (0-4)/0 (0-4) for NNRTIs and 0 (0-7)/0 (0-8) for PIs, which were comparable with group 2. Loss of information in DNA was substantial for group 1 (37.8%) and less so for group 2 (11.1%). In multivariable analysis, only longer ART duration was significantly associated with loss of information. Results were similar in patients harbouring resistance to one or more agents., Conclusions: In a real-life setting, genotyping DNA from PBMC has some degree of concordance compared with RNA. Loss of information in DNA would appear to coincide with longer periods of ART.

Objectives: HIV testing is an important step towards diminishing incident infections. Rapid self-tests whose use is becoming more common in France could help increase access to testing, yet could fail to diagnose HIV during acute HIV infection (AHI). The aim of the present study was to evaluate HIV-detection sensitivity of a commonly used rapid self-test (STAT-VIEW HIV1/2), compared with another point-of-care rapid test (INSTI), among patients presenting with AHI., Methods: Individuals tested at Saint-Antoine Hospital (Paris, France) with negative or indeterminate western blot (WB) results and detectable HIV-RNA were included. Rapid tests were performed retrospectively on stored serum. Patients with and without reactive rapid tests were compared, while probability of having a reactive test was modelled across infection duration using logistic regression., Results: Of the 40 patients with AHI, 23 (57.5%) had a reactive STAT-VIEW rapid test. Patients with non-reactive versus reactive tests had a significantly shorter median time since infection (p=0.01), time since onset of symptoms (p=0.009), higher proportion with Fiebig stage III versus IV (p=0.003), negative WB results (p=0.007), higher HIV-RNA levels (p=0.001) and lower CD4+ and CD8+ cell count (p=0.03, p<0.001, respectively). When examining sensitivity over the course of AHI duration, the probability of HIV detection was 75.5% at 5 weeks from HIV transmission. The INSTI provided similar results with respect to proportion of reactive tests (62.5%), determinants for non-reactive test and probability of HIV detection at 5 weeks of infection (85.0%)., Conclusions: Over half of AHI patients had reactive serology using the STAT-VIEW rapid self-test when performed on serum samples. Considering that detection sensitivity increased substantially over infection time, individuals should not rely on a negative result to accurately exclude HIV infection within at least 5 weeks of potential HIV exposure. Notwithstanding strong recommendations against rapid test use during AHI, some utility in detecting HIV is observed 5-12 weeks after transmission., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Patients infected with human immunodeficiency virus (HIV) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for HIV positive GBM patients is significantly shorter than for those who are uninfected, despite the fact that they receive the same treatments. The nature of the GBM⁻HIV association remains poorly understood. In this study, we analyzed the effect of the HIV envelope glycoprotein gp120 on GBM cell proliferation. Specifically, we performed cell cycle, western blot, protein synthesis and metabolomics analysis as well as ATP production and oxygen consumption assays to evaluate proliferation and metabolic pathways in primary human glioma cell line, U87, A172 cells and in the HIVgp120tg/GL261 mouse model. Glioma cells treated with gp120 (100 ng/mL for 7⁻10 days) showed higher proliferation rates and upregulation in the expression of enolase 2, hexokinase and glyceraldehyde-3-phosphate dehydrogenase when compared to untreated cells. Furthermore, we detected an increase in the activity of pyruvate kinase and a higher glycolytic index in gp120 treated cells. Gp120 treated GBM cells also showed heightened lipid and protein synthesis. Overall, we demonstrate that in glioma cells, the HIV envelope glycoprotein promotes proliferation and activation of glycolysis resulting in increased protein and lipid synthesis.

Puerto Rico has one of the highest rates of HIV/AIDS seen for any US state or territory, and antiretroviral therapy has been a mainstay of efforts to mitigate the HIV/AIDS public health burden on the island. We studied the evolutionary dynamics of HIV-1 mutation and antiretroviral drug resistance in Puerto Rico by monitoring the population frequency of resistance-associated mutations from 2002 to 2011. Whole blood samples from 4,475 patients were analyzed using the TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System in the Immunoretrovirus Research Laboratory at Universidad Central del Caribe. Results show that 64.0% of female and 62.9% of male patients had HIV-1 mutations that confer resistance to at least one antiretroviral medication. L63P and M184V were the dominant mutations observed for the protease (PRO) and reverse transcriptase (RT) encoding genes, respectively. Specific resistance mutations, along with their associated drug resistance profiles, can be seen to form temporal clusters that reveal a steadily changing landscape of resistance trends over time. Both women and men showed resistance mutations for an average of 4.8 drugs over the 10-year period, further underscoring the strong selective pressure exerted by antiretrovirals along with the rapid adaptive response of HIV. Nevertheless, both female and male patients showed a precipitous decrease for overall drug resistance, and for PRO mutations in particular, over the entire course of the study, with the most rapid decrease in frequency seen after 2006. The reduced HIV-1 mutation and drug resistance trends that we observed are consistent with previous reports from multi-year studies conducted around the world. Reduced resistance can be attributed to the use of more efficacious antiretroviral drug therapy, including the introduction of multi-drug combination therapies, which limited the ability of the virus to mount rapid adaptive responses to antiretroviral selection pressure.

Muscadine grape skin extract (MSKE) is derived from muscadine grape (Vitis rotundifolia), a common red grape used to produce red wine. Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) that serves as a survival mechanism to relieve ER stress and restore ER homeostasis. However, when persistent, ER stress can alter the cytoprotective functions of the UPR to promote autophagy and cell death. Although MSKE has been documented to induce apoptosis, it has not been linked to ER stress/UPR/autophagy. We hypothesized that MSKE may induce a severe ER stress response-mediated autophagy leading to apoptosis. As a model, we treated C4-2 prostate cancer cells with MSKE and performed a quantitative Tandem Mass Tag Isobaric Labeling proteomic analysis. ER stress response, autophagy and apoptosis were analyzed by western blot, acridine orange and TUNEL/Annexin V staining, respectively. Quantitative proteomics analysis indicated that ER stress response proteins, such as GRP78 were greatly elevated following treatment with MSKE. The up-regulation of pro-apoptotic markers PARP, caspase-12, cleaved caspase-3, -7, BAX and down-regulation of anti-apoptotic marker BCL2 was confirmed by Western blot analysis and apoptosis was visualized by increased TUNEL/Annexin V staining upon MSKE treatment. Moreover, increased acridine orange, and LC3B staining was detected in MSKE-treated cells, suggesting an ER stress/autophagy response. Finally, MSKE-mediated autophagy and apoptosis was antagonized by co-treatment with chloroquine, an autophagy inhibitor. Our results indicate that MSKE can elicit an UPR that can eventually lead to apoptosis in prostate cancer cells., Competing Interests: The authors have declared that no competing interests exist.

Multiple Sclerosis (MS) is a complex disease where genetic and environmental factors have been implicated. The onset of symptoms occurs in individuals from twenty to fifty years of age, producing a progressive impairment of motor, sensory and cognitive functions. MS is more frequent in females than in males with a ratio of 4:1. The prevalence of the MS varies among ethnics groups such as Europeans, Africans and Caucasians. The estimated prevalence of MS in Puerto Rico is 42 for each 100,000 habitants, which is more than the prevalence reported for Central America and the Caribbean. In spite of this prevalence, the genetic component of MS has not been explored in order to know the alleles' expression of Puerto Rican MS patients and compare it with the allele expression in other ethnic groups. Thirty-five patients and 31 control subjects were genotyped. The allele frequencies expressed in this sample were similar to those expressed for Puerto Ricans in the National Marrow Donor Program Registry (n = 3,149). The most prevalent alleles for MS patients were HLA-DRB1*01 and *03. HLA-DQB1*04 was the most frequent in the control group and HLA-A*30, in MS patients. These findings are in agreement with published data. HLA-DQB1*04 was a marginal protector in this sample and this role has not been described before. The accuracy of the results is limited due to the sample size. After performing a statistical power analysis it showed that by increasing the sample the values would be significant.

The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . A generally held notion is that the Warburg effect is related to energy. Using whole-genome, proteomic MALDI-TOF-MS and metabolite analysis, we investigated the Warburg effect in malignant neuroblastoma N2a cells. The findings show that the Warburg effect serves a functional role in regulating acidic pericellular pH (pHe), which is mediated by metabolic inversion or a fluctuating dominance between glycolytic-rate substrate level phosphorylation (SLP) and mitochondrial (mt) oxidative phosphorylation (OXPHOS) to control lactic acid production. The results also show that an alkaline pHe caused an elevation in SLP/OXPHOS ratio (approximately 98% SLP/OXPHOS); while the ratio was approximately 56% at neutral pHe and approximately 93% in acidic pHe. Acidic pHe paralleled greater expression of mitochondrial biogenesis and OXPHOS genes, such as complex III-V (Uqcr10, Atp5 and Cox7c), mt Fmc1, Romo1, Tmem 173, Tomm6, aldehyde dehydrogenase, mt Sod2 mt biogenesis component PPAR-γ co-activator 1 adjunct to loss of mt fission (Mff). Moreover, acidic pHe corresponded to metabolic efficiency evidenced by a rise in mTOR nutrient sensor GβL, its downstream target (Eif4ebp1), insulin modulators (Trib3 and Fetub) and loss of catabolic (Hadhb, Bdh1 and Pygl)/glycolytic processes (aldolase C, pyruvate kinase, Nampt and aldose-reductase). In contrast, alkaline pHe initiated loss of mitofusin 2, complex II-IV (Sdhaf1, Uqcrq, Cox4i2 and Aldh1l2), aconitase, mitochondrial carrier triple repeat 1 and mt biosynthetic (Coq2, Coq5 and Coq9). In conclusion, the Warburg effect might serve as a negative feedback loop that regulates the pHe toward a broad acidic range by altering lactic acid production through inversion of metabolic systems. These effects were independent of changes in O(2) concentration or glucose supply., (© 2012 Japanese Cancer Association.)

This is a continuation of our efforts to maintain a record of the evolution of HIV-1 infection in Puerto Rico by monitoring the expression levels of antiretroviral drug-resistance-associated mutations. Samples from 2,500 patients from 2006-2010 were analyzed using the TruGene HIV-1 genotyping kit and the OpenGene DNA sequencing system. Results show that 58.8% of males and 65.3% of females had HIV-1 with resistance to at least one medication. The average number of HIV mutations was 6.0 in males and 6.1 in females. Statistically significant differences between men and women were recorded in the levels of HIV-1 expressed mutations and antiretroviral drug resistance. The most prevalent antiretroviral medication resistance shifted from zalcitabine to nevirapine and efavirenz in the five-year period. M184V and L63P were the dominant mutations for the reverse transcriptase and the protease genes, respectively, but an increase in the incidence of minority mutations was observed.

Background: Many plant-derived products exhibit potent chemopreventive activity against animal tumor models as well as rodent and human cancer cell lines. They have low side effects and toxicity and presumably modulate the factors that are critical for cell proliferation, differentiation, senescence and apoptosis. The present study investigates the effects of some medicinal plant extracts from generally recognized as safe plants that may be useful in the prevention and treatment of cancer., Methods: Clonogenic assays using logarithmically-growing cells were performed to test the effect. The cytotoxic effects of Curcuma longa and Zingiber officinale were studied using sulforhodamine B assay, tetrazolium dye assay, colony morphology and microscopic analysis., Results: Out of the 13 lyophilized plant-derived extracts evaluated for growth-inhibitory effects on the PC-3M prostate cancer cell line, two extracts derived from C. longa and Z. officinale showed significant inhibitory effects on colony-forming ability. The individual and augmentative effects of these two extracts were tested for their narrow range effective lower concentration on PC-3M in clonogenic assays. At relatively lower concentrations, C. longa showed significant inhibition of colony formation in clonogenic assays; whereas at same concentrations Z. officinale showed only moderate inhibitory effects. However, when both the agents were tested together at the same concentrations, the combined effects were much more significant than their individual ones. On normal prostate epithelial cells both C. longa and Z. officinale had similar effects but at a lower magnitude. These observations were confirmed by several cytotoxicity assays involving the morphological appearance of the colonies, microscopic observations, per cent inhibition in comparison to control by sulforhodamine B and tetrazolium dye assay., Conclusions: From these observations, it was concluded that the combined effects of C. longa and Z. officinale are much greater than their individual effects, suggesting the role of multiple components and their synergistic mode of actions to elicit stronger beneficial effects.

This is a continuation of our efforts to maintain a record of the evolution of HIV-1 infection in Puerto Rico by monitoring the expression levels of antiretroviral resistance-associated mutations. Samples from 2005 were analyzed (458: 270 males, 137 females, 51 anonymous), using the TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System. Results show that 60.1% of males and 50.2% of females had HIV-1 with resistance to at least one medication. The average number of HIV mutations in males was 6.27, while the average number of HIV mutations in females was 5.49. The highest levels of resistance were to Zalcitabine, Lamivudine, and Stavudine. The reverse transcriptase mutations with the highest frequency of expression were M184V, K103N and D67N. Protease mutations with the highest rate of expression were L63P, M361 and L90M. Significant differences between men and women were recorded in the levels of HIV-1 expressed mutations and resistance.

The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.

Interactions between legumes and rhizobia are controlled by the sequential exchange of symbiotic signals. Two different techniques, 2D-PAGE electrophoresis and differential display were used to study the effects of rhizobial signals on legume development. Application of variously substituted lipo-oligo-saccharidic Nod-factors to roots of Vigna unguiculata resulted in changes in the phosphorylation patterns of microsomal proteins. Reliable amino-acid sequences were obtained for one Nod-factor enhanced protein which was highly homologous to the 57-kDa subunit from Arabidopsis thaliana vacuolar membrane H(+)-ATPase. Immuno-blotting techniques demonstrated that Nod-factors cause rapid and massive increases of this enzyme in treated roots, suggesting that H(+)-ATPases play symbiotic roles. Concomitantly, we used differential display (DD) techniques on mRNA isolated from root-hairs to analyse early root responses to NGR234. Significant matches of several DD clones to known sequences were found. Clone D2.62 was homologous to a multitude of receptor kinases including S receptor-like kinases of A. thaliana and clone D4.1 showed similarities to Lotus japonicus phosphatidylinositol transfer-like protein III and late nodulin 16. Independent confirmatory analyses of these differentially expressed clones indicated expression at very low levels.

Objective: To investigate factors related to early virological response among a cohort of 224 patients who started a protease inhibitor (PI) for the first time. To determine which factors are associated with persistent response among patients with early response., Patients and Methods: Early complete response was defined as an undetectable plasma viral load 2 to 3 months after treatment onset (< 400 copies/ml, Quantiplex HIV 2.0 Chiron diagnostics), incomplete response as at least 1 log reduction of viral load. In patients with an undetectable plasma viral load at 2 or 3 months, we also assessed the persistence of the response on the same regimen. Virology failure was defined by two consecutive viral load levels above the detection limit., Results: In the total cohort, 66% of the patients had an early complete response, 11% a partial response and 23% no response. Complete virological response was significantly more frequent in naive (89%) than in pretreated (59%) patients (p < 0.001). Multivariate analysis of factors predictive of early response in pretreated patients (n = 169) showed that viral load (p = 0.001), the number of nucleoside analogs previously received (p = 0.06) and a full or partial treatment switch (p = 0.10) were associated with complete response. Analysis of later response in the 45 naive patients with prolonged follow-up showed that 22% had treatment failure after 3 to 16 months. None of the baseline variables (viral load, CD4+ cell count or nature of the PI) were associated with duration of response. The only factor associated with persistent response in pretreated patients was a low number of antiretroviral drugs previously received (log-rank test, p = 0.04)., Conclusions: The absence of previous antiretroviral treatment as the main factor associated with an early complete virological response. In patients pretreated with nucleoside analogs who presented early virological success, the number of drugs previously received, often associated with full or partial switch of nucleoside analog, significantly influence the persistence of response to a given triple-drug regimen.

Objective: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART)., Setting: Prospective multicentre cohort in 15 university hospitals in France., Methods: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction)., Results: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l., Conclusion: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.

Objective: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients., Design: An open pilot non-comparative multicentre study., Methods: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase., Results: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]., Conclusion: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.