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PubMed1999

[Human immunodeficiency virus resistance to antiretroviral drugs].

Antiretroviral compounds can select viral strains presenting mutations of the HIV genome. Certain genotypic modifications are expressed by phenotypic resistance. There is no cross resistance between different classes of compounds (nucleosides, non nucleosides, antiproteases), but cross resistance is common within a given therapeutic class. HIV resistance to antiretroviral compounds is one of the principal causes of failure of antiretroviral treatments but cannot explain all escapes. The number of resistance mutations is higher in patients with high viral loads and in patients on multiple drug regimens. Currently resistance testing is limited to clinical research protocols. The usefulness of resistance testing remains to be validated. However the most eminent indications are epidemiological surveillance of primary resistance in primary infections, therapeutic adaptation after accidental exposure to HIV, and management of seropositive pregnant women. Recent retrospective studies have shown that the genotype and the phenotype after a first line treatment failure predict response to certain therapeutic combinations. In the near future, resistance testing could be useful to adapt antiviral strategies after earlier treatment failure.

Anti-HIV Agents↗

PubMed2006

Prevalence and pattern of drug resistance mutations among antiretroviral-treated HIV-1 patients with suboptimal virological response in Malaysia.

To assess the prevalence of major drug resistance mutations in antiretroviral (ARV)-treated patients with detectable viral load (VL) in Kuala Lumpur, Malaysia, genotypic resistance testing was performed among treated human immunodeficiency virus type 1 (HIV-1) patients attending the University Malaya Medical Center between July 2003 and November 2004. The reverse transcriptase (RT) and protease genes from 36 plasma samples with detectable VL were examined for major mutations associated with ARV resistance as reported by the International AIDS Society-USA Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance to nucleoside RT inhibitors (NRTIs), non-NRTIs (NNRTIs) or protease inhibitors (PIs) was 77.8%. In the RT gene, the frequency of mutations associated with NRTIs and NNRTIs resistance was 52.8 and 63.9%, respectively, with M184V and K103N mutations being selected most frequently by these drugs. A patient with Q151M mutation complex was also detected. Twenty-two percent of the patients had mutations associated with PIs. The following pattern of prevalence of ARV-resistant HIV-1 variants was observed: NNRTI-resistant > NRTI-resistant > PI-resistant. The prevalence of major drug resistance mutations among ARV-treated patients with detectable VL is high in Kuala Lumpur. Genotypic drug resistance testing is therefore important for monitoring patients experiencing ARV regimen failure.

Adult↗

PubMed2004

Persistence of multidrug-resistant HIV-1 without antiretroviral treatment 2 years after sexual transmission.

OBJECTIVES: To understand the virological mechanisms of 2-year persistence of multidrug-resistant virus without selective antiretroviral pressure in HIV-1-infected patients. PATIENTS AND METHODS: Two patients were contaminated recently by their HIV-1-infected partners, who had received, before the transmission, all available antiretroviral drugs and who exhibited a severe therapeutic failure. The resistance mutations analysis was performed by clonal sequencing of 1.2 kb of pol gene in plasma of index and sources patients. Sequencing of HIV-1 DNA was performed in PBMCs of index patients. RESULTS: Genotypic testing performed in index patients at time of seroconversion showed resistance mutations to three classes of drugs. All mutations were linked on the same viral genome and all quasispecies carried all mutations. No wild-type virus was detected. The same results were found in source patients and showed that all mutations were transmitted. In the index patients, all mutations persisted over 2 years without antiretroviral treatment. Moreover, the resistance mutations were all archived in the cellular reservoir. Viral load and CD4 count of index patients remained unchanged during 2 years of follow-up. DISCUSSION: Only multidrug-resistant viruses were detected in the source patients and could be transmitted in index patients. In the latter, an expansion of predominant multidrug-resistant quasispecies and the 'archival' of all mutations were observed. These results explain the persistence of mutations and suggest that it is highly difficult to return to a wild-type viral population, sensitive to an antiretroviral treatment. The treatment of index patients is limited and the major risk is the transmission of these multidrug-resistant viruses. This work was presented in part in the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, June 2003; and in the 2nd IAS Conference on HIV Pathogenesis & Treatment, Paris, France, July 2003.

Adult↗

PubMed2006

On the expected relationship between inbreeding, fitness, and extinction.

We assessed the expected relationship between the level and the cost of inbreeding, measured either in terms of fitness, inbreeding depression or probability of extinction. First, we show that the assumption of frequent, slightly deleterious mutations do agree with observations and experiments, on the contrary to the assumption of few, moderately deleterious mutations. For the same inbreeding coefficient, populations can greatly differ in fitness according to the following: (i) population size; larger populations show higher fitness (ii) the history of population size; in a population that recovers after a bottleneck, higher inbreeding can lead to higher fitness and (iii) population demography; population growth rate and carrying capacity determine the relationship between inbreeding and extinction. With regards to the relationship between inbreeding depression and inbreeding coefficient, the population size that minimizes inbreeding depression depends on the level of inbreeding: inbreeding depression can even decrease when population size increases. It is therefore clear that to infer the costs of inbreeding, one must know both the history of inbreeding (e.g. past bottlenecks) and population demography.

Adaptation, Physiological↗

PubMed2003

The Delta 32 mutation of the chemokine-receptor 5 gene neither is correlated with chronic hepatitis C nor does it predict response to therapy with interferon-alpha and ribavirin.

Unlike in HIV, homozygosity for a 32-bp deletion (Delta 32) of the chemokine receptor 5 (CCR5) gene was recently described in increased frequency in patients with chronic hepatitis C (HCV). Thus, it was speculated that this mutation might be relevant for disease susceptibility and influence the response to antiviral therapy. The present study sought to confirm the association between HCV and the Delta 32 mutation of the CCR5 gene and to correlate it with the response to therapy with interferon-alpha-2a and ribavirin. Sixty-two patients with HCV and 119 healthy unrelated controls were genotyped for the Delta 32 mutation. For the correlation between the Delta 32 mutation and response to therapy, only patients (n = 59) who completed 6 months of combination therapy as part of a prospective study were evaluated. The Delta 32 mutation was not observed in increased frequency in HCV. Furthermore, a significant difference of the HCV load or aminotransferase concentrations was not observed in carriers versus noncarriers of the Delta 32 mutation. After stratification for potentially confounding factors such as gender or HCV genotype, a significant difference was also not detected with respect to treatment outcome. These observations argue strongly against a role of CCR5 for susceptibility to HCV infection or response to combination therapy.

Antiviral Agents↗

PubMed2006

Fitness constraints on immune escape from HIV: Implications of envelope as a target for both HIV-specific T cells and antibody.

Sterilising immunity against HIV-1 infection, whilst ideal, appears an unrealistic vaccination goal in the short term. More achievable is slowing the progression to disease and decreasing transmission by mounting strong T cell and neutralising antibody responses to maintain low viral loads. However, in both acute and chronic infection, mutant virus is selected to escape both arms of the adaptive immune system. Each mutation away from wildtype virus likely incurs at least some reduction in replicative capacity ("fitness") of the virus. Rapid reversion to wildtype of some immune escape mutations upon transmission, suggests fitness costs may be significant. HIV-1 Envelope is unique in that it is subject to both neutralising antibody and cell-mediated immune responses. Although Envelope is variable between strains, considerable serial pressure and mutational escape from both neutralising antibody and cytotoxic T lymphocyte attack may result in impaired structure and function. This could ultimately be exploited in HIV vaccine design.

Antibodies, Viral↗

PubMed2001

Evaluation of viral resistance to reverse transcriptase inhibitors (RTI) in HIV-1-infected patients before and after 6 months of single or double antiretroviral therapy.

We evaluated samples of peripheral blood mononuclear (PBMC) cells from 46 AIDS patients, before starting therapy with HIV-1 reverse transcriptase inhibitors (RTI), and after 6 months of drug use. PBMC were stored and tested by a Line Probe Assay (LiPA), in order to assess the frequency of RT mutations in this population. Six patients were taking AZT before initial blood collection (1 to 16 weeks of drug use) and 40 patients had no prior therapy. After baseline evaluation, 19 patients received AZT, 23 AZT plus DDI, 3 started AZT only with DDI added after 3 months, and 3 received a combination of AZT plus 3TC. Detection of at least one mutation was found in 33% (15/46) of patients at baseline, and 83% (38/46) had at least 1 mutation after 6 months of therapy. In the majority of cases, samples presented with the wild type and variants of HIV, simultaneously. Patients receiving monotherapy had a higher frequency of mutations (L41 and F214, Y215) than did patients receiving double-drug therapy (19 vs. 10). No specific mutation associated with DDI was identified in 26 patients so treated. Despite the finding of a mean increase in CD4 count and a mild decrease in viral load, patients tended to have an inverse correlation between the CD4 variation and number of mutations detected after 6 months, suggesting potential loss of drug efficacy in the presence of these genotypic changes.

Acquired Immunodeficiency Syndrome↗

PubMed1983

New thoughts on resistance to chemotherapy.

Kinetic theories of tumor growth do not appear to provide adequate explanations for treatment failure in cancer. It is proposed that drug resistance results from somatic mutations in tumor cell populations and that "front-loaded" first-line treatment strategy with as many effective agents as possible, in the highest dosages possible, represents the clinician's best approach.

Adult↗

PubMed2006

Mutations in Arabidopsis yellow stripe-like1 and yellow stripe-like3 reveal their roles in metal ion homeostasis and loading of metal ions in seeds.

Here, we describe two members of the Arabidopsis (Arabidopsis thaliana) Yellow Stripe-Like (YSL) family, AtYSL1 and AtYSL3. The YSL1 and YSL3 proteins are members of the oligopeptide transporter family and are predicted to be integral membrane proteins. YSL1 and YSL3 are similar to the maize (Zea mays) YS1 phytosiderophore transporter (ZmYS1) and the AtYSL2 iron (Fe)-nicotianamine transporter, and are predicted to transport metal-nicotianamine complexes into cells. YSL1 and YSL3 mRNAs are expressed in both root and shoot tissues, and both are regulated in response to the Fe status of the plant. Beta-glucuronidase reporter expression, driven by YSL1 and YSL3 promoters, reveals expression patterns of the genes in roots, leaves, and flowers. Expression was highest in senescing rosette leaves and cauline leaves. Whereas the single mutants ysl1 and ysl3 had no visible phenotypes, the ysl1ysl3 double mutant exhibited Fe deficiency symptoms, such as interveinal chlorosis. Leaf Fe concentrations are decreased in the double mutant, whereas manganese, zinc, and especially copper concentrations are elevated. In seeds of double-mutant plants, the concentrations of Fe, zinc, and copper are low. Mobilization of metals from leaves during senescence is impaired in the double mutant. In addition, the double mutant has reduced fertility due to defective anther and embryo development. The proposed physiological roles for YSL1 and YSL3 are in delivery of metal micronutrients to and from vascular tissues.

Arabidopsis↗

PubMed2003

Drug resistance is uncommon in pregnant women with low viral loads taking zidovudine monotherapy to prevent perinatal HIV transmission.

Zidovudine monotherapy is used to reduce perinatal HIV transmission in women with low viral loads. There are few data on the risk of drug resistance in this select cohort of women. We determined the prevalence of newly acquired mutations conferring reduced sensitivity to zidovudine after exposure during pregnancy, and found that the development of mutations was uncommon and was restricted to women treated before 1998 who had higher baseline viral loads than those currently recommended monotherapy.

Anti-HIV Agents↗

PubMed2002

Post-methionine-load hyperhomocysteinemia and increased lipoprotein(a) are associated with renal metabolic dysfunction: a hypothesis.

Previous studies have shown that homocysteine influences the structure of lipoprotein(a) [Lp(a)] and its affinity to fibrin, and that there is an increased risk of vascular disease when both homocysteine and Lp(a) are elevated. The aim of this study was to determine whether there is a correlation between increased total homocysteine (tHCY) and high Lp(a) concentrations, and whether increased concentrations of tHCY affect the concentration of unbound serum apolipoprotein(a) [Apo(a)]. Forty-seven male subjects recruited from a primary prevention screening program with normal serum creatinine and Lp(a) concentrations above 30 mg/dL were included and underwent a standardized oral methionine-loading test to increase the plasma tHCY concentration. This increase might lead to a modification of the Apo(a) structure, thus possibly influencing the serum concentration of unbound Apo(a). Fasting blood samples were taken before the tests and after 6 hours. The median values of tHCY increased about 4-fold after the methionine-loading test. Fasting tHCY did not show an association with Apo(a) and a post-methionine load increase of unbound Apo(a) was not observed. Backward multiple linear regression analysis, however, revealed that only post-load tHCY was independently and significantly influenced by Lp(a). Furthermore, Lp(a) correlated significantly with post-load tHCY, but not with fasting tHCY. Subdividing the subjects according to the Lp(a) concentration showed a significantly higher median concentration of tHCY after methionine load in subjects with Lp(a) over 50 mg/dL compared to subjects with Lp(a) under 50 mg/dL (P =.009). A similar cut-off was seen for post-load Apo(a) at 7.3 mg/dL (P =.04). Factors such as age, C677T-methylene-tetrahydrofolate-reductase (MTHFR) mutation, folate, vitamin B(12), and creatinine showed no significant influence on post-load tHCY in the different subgroups. The reasons for our findings remain partially unclear. However, considering our results and the current knowledge on the association of tHCY and Lp(a) concentration with the renal function, we hypothesize that both parameters may be linked by commencing renal metabolic dysfunction. It should be stressed that our hypothesis is speculative and that further studies will be necessary to improve the understanding of the interrelation of tHCY and Lp(a) concentration.

Apolipoproteins A↗

PubMed1997

Failure of ganciclovir treatment associated with selection of a ganciclovir-resistant cytomegalovirus strain in a lung transplant recipient.

We report the case of a lung transplant recipient with progressive cytomegalovirus (CMV) disease due to a resistant CMV strain emerging under ganciclovir (GCV) therapy. A discriminative polymerase chain reaction (PCR) assay, designed to detect the resistance-related V460 mutation within the viral enzyme UL97, revealed the presence of a mutated strain in a heterogeneous isolate 51 days after transplantation. The conventional antiviral susceptibility assay had failed to demonstrate resistance to GCV. Under prolonged GCV therapy, the mutated strain dominated the wild-type strain, as shown by the PCR assay. This domination led to laboratory resistance, associated with recurrent fever and progressively severe retinitis. As this discriminative PCR assay was shown to be effective in detecting mutated strains that constitute a minority in the virus load, it should allow better management of patients with CMV disease.

Adult↗

PubMed2000

Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, inherited cause of early stroke and dementia, with a poor prognosis. This study was performed to clarify lesion appearance and pattern of lesion distribution in CADASIL. 20 members of a single family were tested for the CADASIL gene mutation and studied with cranial MRI. Scans were evaluated for lesion load and pattern of lesion distribution. 19 patients had cranial MRI, of whom 11 had normal MRI scans, were clinically unaffected and tested negative for the CADASIL gene mutation. The remaining eight patients had abnormal cranial MRI scans: seven patients were positive for the CADASIL gene mutation and one (untested) patient was severely clinically affected. Three of the patients who tested positive for the CADASIL gene mutation were clinically unaffected at the time of imaging. All eight patients with abnormal cranial MRI had subcortical white matter abnormalities, mostly in frontal and temporal lobes. Lesions involving the corpus callosum were present on sagittal T2 weighted images in four of five clinically affected and one of three clinically unaffected patients. Lesions involving the deep grey nuclei and the brain stem were common. On T1 weighted images, lesions were either poorly defined (confluent white matter hypointensity) or well defined (cystic infarcts or enlarged perivascular spaces). Atrophy was infrequent. Familiarity with the range of cranial MRI appearances may aid diagnosis of CADASIL. Recognition of cranial imaging features in asymptomatic CADASIL patients could prompt earlier diagnosis.

Adult↗

PubMed1998

Short-term evolution of HIV-1 viraemia and CD4+ cell counts in patients who have a primary mutation to zidovudine.

OBJECTIVE: To investigate the different responses to antiretroviral treatment including zidovudine, of patients harbouring HIV with primary resistance to zidovudine, serum viral load, and CD4+ cell counts, for 24 weeks in a group of antiretroviral-naive patients with the codon 215 mutation of the HIV pol gene and in a control group at the start of treatment. DESIGN: A case-control retrospective study (1989-1996). METHOD: Nineteen out of 210 patients previously studied harboured the codon 215 mutation, had a self-reported compliance with treatment, a minimum follow-up of 24 weeks, and were treated with zidovudine alone or in combination with other nucleoside analogues. These patients were matched with 19 patients with wild-type strains at entry by initial CD4+ cell counts, clinical status, and antiretroviral treatment. RESULTS: During the first 12 weeks, CD4+ cell counts increased (76+/-26 and 64+/-26 x 10(6)/l in wild-type and mutant virus-infected groups, respectively), decreasing slightly until week 24, although no significant differences were found between the two groups studied. Serum viral load decreased in both groups (change in serum viral load of 0.80+/-0.11 log10 and 0.87+/-0.26 log10 copies/ml, wild-type and mutant virus-infected, respectively), although no significant differences were found between groups. CONCLUSION: No significant differences were found between patients with the primary mutation to zidovudine and control patients harbouring wild-type virus in terms of short-term response measured by serum viral load and CD4+ cell counts.

Adult↗

PubMed2001

Decay of HIV type 1 DNA and development of drug-resistant mutants in patients with primary HIV type 1 infection receiving highly active antiretroviral therapy.

The present study was aimed at describing the effect of highly active antiretroviral therapy (HAART) in 10 patients with primary HIV infection (PHI). Clearance rates of HIV RNA and HIV DNA in peripheral blood as well as the preexistence and the emergence of drug-resistant strains of HIV were determined over 52 weeks of treatment. The data indicate that HAART is able to induce a suppression of plasma viral load together with a significant decrease, but not a suppression, of peripheral blood mononuclear cell-associated proviral DNA in PHI subjects. Analysis of drug-resistant strains revealed that three PHI patients, showing a complete virologic response, developed mutations in the pol gene, thus suggesting that a persistent residual virus replication exists despite a sustained suppression of plasma viremia.

Adolescent↗

PubMed2005

Loss of gametophytic self-incompatibility with evolution of inbreeding depression.

Gametophytic self-incompatibility (SI) in plants is a widespread mechanism preventing self-fertilization and the ensuing inbreeding depression, but it often evolves to self-compatibility. We analyze genetic mechanisms for the breakdown of gametophytic SI, incorporating a dynamic model for the evolution of inbreeding depression allowing for partial purging of nearly recessive lethal mutations by selfing, and accounting for pollen limitation and sheltered load linked to the S-locus. We consider two mechanisms for the breakdown of gametophytic SI: a nonfunctional S-allele and an unlinked modifier locus that inactivates the S-locus. We show that, under a wide range of conditions, self-compatible alleles can invade a self-incompatible population. Conditions for invasion are always less stringent for a nonfunctional S-allele than for a modifier locus. The spread of self-compatible genotypes is favored by extremely high or low selfing rates, a small number of S-alleles, and pollen limitation. Observed parameter values suggest that the maintenance of gametophytic SI is caused by a combination of high inbreeding depression in self-incompatible populations coupled with intermediate selfing rates of the self-compatible genotypes and sheltered load linked to the S-locus.

Alleles↗

PubMed2003

Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. AIM: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. PATIENTS AND METHODS: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non- tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. RESULTS: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. CONCLUSION: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis.

Carcinoma, Hepatocellular↗

PubMed2001

Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys.

Mutations in human immunodeficiency virus type 1 reverse-transcriptase codons 89 and 184 confer inhibitor resistance and alter the mutation spectrum of the enzyme. Six macaques were inoculated with wild-type or mutated derivatives (E89G or E89G and M184V) of simian immunodeficiency virus macaque (SIVmac) 239. Five of the infected monkeys maintained high virus loads; the sixth, which was infected with the E89G mutant strain, maintained viremia at a level below the limit of detection. Sequence analysis demonstrated substantial reversion of the E89G mutation in the animals with progressive infection and preservation of this mutation in the animal with controlled infection. A P272S mutation occurred at high frequency in the viruses containing M184V, which did not revert. These results demonstrate that the E89G mutation has a significant negative impact on SIVmac fitness, whereas SIVmac bearing M184V achieved high, sustained virus loads, perhaps with a compensatory effect of the P272S mutation.

Animals↗