Biomedical subjects

A-M Vandamme

Publications and source records attributed to A-M Vandamme.

12 recordsLinked to original sources

PubMed2006

Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Bayes Theorem↗

PubMed2006

Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance.

Human Immunodeficiency Virus-1 (HIV-1) antiviral resistance is a major cause of antiviral therapy failure and compromises future treatment options. As a consequence, resistance testing is the standard of care. Because of the high degree of HIV-1 natural variation and complex interactions, the role of resistance mutations is in many cases insufficiently understood. We applied a probabilistic model, Bayesian networks, to analyze direct influences between protein residues and exposure to treatment in clinical HIV-1 protease sequences from diverse subtypes. We can determine the specific role of many resistance mutations against the protease inhibitor nelfinavir, and determine relationships between resistance mutations and polymorphisms. We can show for example that in addition to the well-known major mutations 90M and 30N for nelfinavir resistance, 88S should not be treated as 88D but instead considered as a major mutation and explain the subtype-dependent prevalence of the 30N resistance pathway.

Amino Acid Sequence↗

PubMed2005

Analysis of complex HIV-1 intersubtype recombinants using a Bayesian scanning method.

The increased complexity of HIV-1 genetic heterogeneity raises the issue for reliable classification and analysis of these sequences. Until now, bootscanning analysis has been the main method used for the analysis of potential HIV-1 intersubtype recombinants. We show evidence that in some cases of complex recombinants, where three or more segments with discordant phylogenetic signal may exist in protease (PR) and partial reverse transcriptase (RT) region, Bayesian scanning provides a clearer picture than bootscanning plots about the boundaries of potential recombination. Thus, a recently developed Bayesian scanning tool can facilitate the analysis and classification of HIV-1 mosaic sequences.

Africa, Central↗

PubMed2005

Optimization of a genotypic assay applicable to all human immunodeficiency virus type 1 protease and reverse transcriptase subtypes.

Genotypic assays are used often to guide clinicians in decisions concerning the treatment of patients. An optimized sequence-based genotypic assay was used to determine the whole protease and reverse transcriptase (RT) gene, including the gag cleavage site region and RNase H region. Since non-B subtypes are increasing in countries where subtype B was the most prevalent subtype, and treatment becomes more available in developing countries where the epidemic is characterized by a high prevalence of non-B subtypes, it was important that the genotypic test was evaluated using a panel of different subtypes. Amplification was successful for different subtypes: A, B, C, D, F, G, H, J, CRF01_AE, CRF02_AG, CRF11_cpx, CRF13_cpx and an uncharacterized recombinant sample. The detection limit of the PCR was 1000 copies/ml, except for 1 subtype C sample (PL3) and 1 CRF02_AG sample (PL8). The detection limit for these samples was 5000 copies/ml. A sequence could be obtained in both directions for most of the samples.

DNA Primers↗

PubMed2004

Re-analysis of 34 full-length HIV-1 intersubtype recombinant sequences.

One of the main characteristics of the HIV-1 is its extensive genetic heterogeneity. Intersubtype recombination was first described in 1995 and since then a significant proportion of the HIV-1 isolates was found to comprise mosaic sequences. Re-analysis of 34 full-length HIV-1 intersubtype recombinants, including all "pure" HIV-1 subtypes revealed that 19 of the 34 analyzed mosaics consist of a more complex mosaic pattern than initially described. These findings indicate that the complexity of the HIV-1 recombinants is much greater than previously estimated.

Genetic Variation↗

PubMed2004

HIV-1 genetic variants circulation in the North of Angola.

Few molecular epidemiological data on HIV-1 in Angola are available. In this study, we analysed 37 pol sequences from patients originated from Luanda and Cabinda in Angola. It was our objective to investigate the circulation of different HIV-1 subtypes in this country. We found a high HIV-1 genetic diversity. The predominant subtypes were C and F, while subtypes A, D, G and H were also detected. Three sequences were untypable and may possibly belong to new subtypes or recombinants of unknown subtypes. Moreover, 13 recombinant sequences were found, most of them with very complex patterns including untypable fragments.

Angola↗

PubMed2004

SlidingBayes: exploring recombination using a sliding window approach based on Bayesian phylogenetic inference.

We developed a software tool (SlidingBayes) for recombination analysis based on Bayesian phylogenetic inference. Sliding-Bayes provides a powerful approach for detecting potential recombination, especially between highly divergent sequences and complex HIV-1 recombinants for which simpler methods like neighbor joining (NJ) may be less powerful. SlidingBayes guides Markov Chain Monte Carlo (MCMC) sampling performed by MrBayes in a sliding window across the alignment (Bayesian scanning). The tool can be used for nucleotide and amino acid sequences and combines all the modeling possibilities of MrBayes with the ability to plot the posterior probability support for clustering of various combinations of taxa.

Algorithms↗

PubMed2004

Clinical characteristics of patients in Peru with human T cell lymphotropic virus type 1-associated tropical spastic paraparesis.

BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) is associated with tropical spastic paraparesis (TSP). Peru is an area of endemicity for HTLV-1. METHODS: All patients with suspected cases of TSP referred to our institute (Institute of Tropical Medicine Alexander von Humboldt, Lima, Peru) from 1989 through 2002 were interviewed and tested for HTLV-1. All patients with positive results were evaluated by an expert physician. Disease progression was defined as "rapid" if the time between TSP onset and inability to walk unaided was <2 years. RESULTS: Among 165 patients enrolled, the symptoms and signs most frequently found were spasticity (in 97.5% of patients), hyperreflexia (95.4%), lower limb paresthesia (90.2%), pyramidal signs (82.6%), urinary complaints (82.0%), and lumbar pain (79.0%). Rapid progression was present in 21.5% of patients; mean age at TSP onset was higher among these patients than among slow progressors (P<.001). Severe spasticity, diminished vibratory sensation, and tremor were found more frequently among rapid progressors, compared with slow progressors. CONCLUSIONS: HTLV-1--associated TSP is frequently diagnosed in areas of HTLV-1-endemicity. A subgroup of patients experiences rapid disease progression.

Adolescent↗

PubMed2004

The low evolutionary rate of human T-cell lymphotropic virus type-1 confirmed by analysis of vertical transmission chains.

The evolutionary rate of the human T-cell lymphotropic virus type-1 (HTLV-1) is considered to be very low, in strong contrast to the related human retrovirus HIV. However, current estimates of the HTLV-1 rate rely on the anthropological calibration of phylogenies using assumed dates of human migration events. To obtain an independent rate estimate, we analyzed two variable regions of the HTLV-1 genome (LTR and env) from eight infected families. Remarkable genetic stability was observed, as only two mutations in LTR (756 bp) and three mutations in env (522 bp) occurred within the 16 vertical transmission chains, including one ambiguous position in each region. The evolutionary rate in HTLV-1 was then calculated using a maximum-likelihood approach that used the highest and lowest possible times of HTLV-1 shared ancestry, given the known transmission histories. The rates for the LTR and env regions were 9.58 x 10(-8)-1.25 x 10(-5) and 7.84 x 10(-7) -2.33 x 10(-5)nucleotide substitutions per site per year, respectively. A more precise estimate was obtained for the combined LTR-env data set, which was 7.06 x 10(-7)-1.38 x 10(-5)substitutions per site per year. We also note an interesting correlation between the occurrence of mutations in HTLV-1 and the age of the individual infected.

Adolescent↗

PubMed2003

Analysis of the evolutionary relationships of HIV-1 and SIVcpz sequences using bayesian inference: implications for the origin of HIV-1.

The most plausible origin of HIV-1 group M is an SIV lineage currently represented by SIVcpz isolated from the chimpanzee subspecies Pan troglodytes troglodytes. The origin of HIV-1 group O is less clear. Putative recombination between any of the HIV-1 and SIVcpz sequences was tested using bootscanning and Bayesian-scanning plots, as well as a new method using a Bayesian multiple change-point (BMCP) model to infer parental sequences and crossing-over points. We found that in the case of highly divergent sequences, such as HIV-1/SIVcpz, Bayesian scanning and BMCP methods are more appropriate than bootscanning analysis to investigate spatial phylogenetic variation, including estimating the boundaries of the regions with discordant evolutionary relationships and the levels of support of the phylogenetic clusters under study. According to the Bayesian scanning plots and BMCP method, there was strong evidence for discordant phylogenetic clustering throughout the genome: (1) HIV-1 group O clustered with SIVcpzANT/TAN in middle pol, and partial vif/env; (2) SIVcpzGab1 clustered with SIVcpzANT/TAN in 3'pol/vif, and middle env; (3) HIV-1 group O grouped with SIVcpzCamUS and SIVcpzGab1 in p17/p24; (4) HIV-1 group M was more closely related to SIVcpzCamUS in 3'gag/pol and in middle pol, whereas in partial gp120 group M clustered with group O. Conditionally independent phylogenetic analysis inferred by maximum likelihood (ML) and Bayesian methods further confirmed these findings. The discordant phylogenetic relationships between the HIV-1/SIVcpz sequences may have been caused by ancient recombination events, but they are also due, at least in part, to altered rates of evolution between parental SIVcpz lineages.

Animals↗

PubMed2003

Seroprevalence and risk factors for human T-cell lymphotropic virus (HTLV-I) infection among ethnically and geographically diverse Peruvian women.

OBJECTIVE: To assess the seroprevalence and risk factors for HTLV-I infection in Peruvian women. METHODS: Five hundred and sixty-eight healthy women >20 years of age from three Peruvian regions were randomly selected and screened for HTLV-I. ELISA-reactive sera were confirmed via immunofluorescence assay, recombinant immunoblot assay, Western blot, and PCR. Women from Huanta (n=303), an Andean city inhabited by indigenous Quechuans, El Carmen (n=132), a primarily African-American coastal town, and Lima (n=133), with its Mestizo population, were selected. RESULTS: HTLV-I antibodies were present in 2.5% (14/568) of women (1.3% in Huanta, 3.8% in El Carmen, and 3.8% in Lima); 2.5%, 2.7% and 2.6% of Quechuans, Mestizas and African-Americans, respectively, were infected. History of a blood transfusion (P <0.00002), chronic scabies (P <0.02), having a relative with leukemia (P <0.04), age +/- 38 years (P <0.03), young age at first intercourse (P <0.04), lifetime partners >4 (P <0.04), educational status (P <0.02) and >4 pregnancies (P <0.03) were significantly associated with infection. CONCLUSIONS: HTLV-I is endemic among asymptomatic Peruvian women. Parenteral, vertical and heterosexual transmission are associated with infection.

Adult↗

PubMed2002

Initiation of HAART in drug-naive HIV type 1 patients prevents viral breakthrough for a median period of 35.5 months in 60% of the patients.

The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.

Acquired Immunodeficiency Syndrome↗