SEARCH · PubMed Health

Results for “mutation load”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources

PubMed1999

Development and significance of the HIV-1 reverse transcriptase M184V mutation during combination therapy with lamivudine, zidovudine, and protease inhibitors.

To analyze the emergence and role of the lamivudine (3TC)-selected HIV-1 reverse transcriptase (RT) M184V mutation under triple therapy, we performed a retrospective study of 40 nucleoside RT inhibitor-pretreated and 16 drug-naive patients who were switched to combined treatment with zidovudine (ZDV) plus 3TC plus a protease inhibitor (PI). Plasma viral load and pol genotype were analyzed at baseline and after 24 and 48 weeks of combination therapy. Emergence of the M184V RT mutation at week 48 was detected in 3 of 16 (18.7%) initially drug-naive subjects as opposed to 21 of 40 (52.5%) ZDV-pretreated patients. Multivariate logistic analysis detected HIV-1 RNA load at week 24 as the best predictor of subsequent selection of the M184V mutant (p = .0121). Among ZDV-resistant study subjects at week 24 (n = 17), those with mutant RT M184V codon had a more favorable HIV-1 RNA slope than those with wild-type RT 184M codon (p = .0551). This trend was observed, although in a less evident manner, even in pretreated ZDV-sensitive patients. These findings suggest that development of the 3TC-resistance M184V mutation under triple therapy with 3TC, ZDV, and a PI may have unexpected beneficial effects in vivo in addition to those associated with resensitization of ZDV-resistant virus to ZDV.

Anti-HIV Agents↗

PubMed2000

A retrograde signal is involved in activity-dependent remodeling at a C. elegans neuromuscular junction.

We have characterized how perturbations of normal synaptic activity influence the morphology of cholinergic SAB motor neurons that innervate head muscle in C. elegans. Mutations disrupting components of the presynaptic release apparatus, acetylcholine (ACh) synthesis or ACh loading into synaptic vesicles each induced sprouting of SAB axonal processes. These sprouts usually arose in the middle of the normal innervation zone and terminated with a single presynaptic varicosity. Sprouting SAB neurons with a similar morphology were also observed upon reducing activity in muscle, either by using mutants lacking a functional nicotinic ACh receptor subunit or through muscle-specific expression of a gain-of-function potassium channel. Analysis of temperature-sensitive mutants in the choline acetyltransferase gene revealed that the sprouting response to inactivity was developmentally regulated; reduction of synaptic activity in early larval stages, but not in late larval stages, induced both sprouting and addition of varicosities. Our results indicate that activity levels regulate the structure of certain synaptic connections between nerve and muscle in C. elegans. One component of this regulatory machinery is a retrograde signal from the postsynaptic cell that mediates the formation of synaptic connections.

Acetylcholine↗

PubMed2003

Drug-resistant HIV-1 in the semen of men receiving antiretroviral therapy with acute sexually transmitted infections.

Sexually transmitted infections may enhance the sexual transmission of HIV-1. It is possible that loss of virological control in patients with such infections receiving antiretroviral therapy (ART) may even facilitate the transmission of drug-resistant HIV. We have recently demonstrated that in those on maximally suppressive ART this effect is reduced. We have examined the virus obtained from the blood plasma and seminal plasma of six HIV-1-infected men receiving poorly suppressive ART with acute urethritis for the presence of drug resistance-associated mutations. In four men with gonorrhoea the blood and seminal plasma HIV-1 had mutations conferring reduced susceptibility to one or more available drugs. In one of these men the viral load of drug-resistant virus in seminal plasma was 20-fold higher during gonorrhoea than following antibiotic treatment, with no change in blood plasma viral load. We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1.

Acute Disease↗

PubMed2004

Functional analysis of acidic amino acids in the cytosolic tail of the Na+/H+ exchanger.

The mammalian Na(+)/H(+) exchanger is a membrane protein with a C-terminal regulatory cytosolic domain and an N-terminal membrane domain. Na(+)/H(+) exchanger isoform 1 (NHE1) possesses a conserved amino acid sequence of seven consecutive acidic residues in the distal region of the cytosolic tail. We examined the structural and functional role of this acidic sequence. In human NHE1, varying mutations of the sequence (753)EEDEDDD(759) resulted in defective NHE1 activity. Mutation of the core acid sequence, (755)DED(757), or of the entire sequence caused a decrease in the activity of NHE1 in response to acute acid load. This was not due to changes in Na(+) affinity but rather due to decreased maximum velocity of the protein and delayed activation. Mutation of the target sequence did not affect the ability of the cytoplasmic domain to bind carbonic anhydrase II or tescalcin but did affect calmodulin binding. Mutation of the acidic domain also caused altered sensitivity to trypsin and changes in size of the protein in gel-filtration chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our results demonstrate that the acidic sequence is critical in maintaining proper conformation of the cytosolic domain, calmodulin binding, and in maintenance of Na(+)/H(+) exchanger activity.

Amino Acid Sequence↗

PubMed1990

Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.

Bayes Theorem↗

PubMed2000

Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Risk factors for recurrence after resection of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) require more precise definition. METHODS: Forty patients who underwent liver resection for HBV-related HCC were studied. Their clinical findings, laboratory data (including viral status), pathologic findings, and operative methods were evaluated for recurrence risk in univariate and multivariate analyses. RESULTS: The HB envelope (HBe) antigen, wild-type HBV, intrahepatic metastases, elevated serum activities of aspartate aminotransferase and alanine aminotransferase, and moderately or severely active hepatitis were more likely to be found in patients with a high viral load than in patients with a low viral load. Precore mutant-type HBV was more likely to be found in patients with a low viral load than in patients with a high viral load. The platelet count was significantly lower in the patients with a high viral load. A high viral load, the presence of wild-type HBV, the absence of anti-HBe, the absence of precore mutant-type HBV, Child score B, a low platelet count, and a positive surgical margin were risk factors for recurrence in univariate analysis. A nonanatomic resection tended to be a risk factor. A high viral load and positive surgical margin were independent risk factors for recurrence. CONCLUSIONS: The measurement of viral load and detection of anti-HBe, wild-type HBV, and precore mutant-type HBV are useful for estimating a patient's prognosis after resection of HBV-related HCC.

Adult↗

PubMed2004

Emergence and compartmentalization of fatal multi-drug-resistant cytomegalovirus infection in a patient with autosomal-recessive severe combined immune deficiency.

The authors describe a patient with autosomal-recessive severe combined immunodeficiency (SCID) with severe, multiorgan cytomegalovirus (CMV) disease. In the face of appropriate therapy, the patient developed a 100-fold gradient in viral load across the blood-brain barrier. Disseminated disease, including pneumonitis, contributed to a fatal outcome. Serial genotypic analyses revealed multiple UL97 and UL54 (DNA polymerase) mutations that conferred phenotypic resistance to all currently licensed systemic CMV antivirals.

Adult↗

PubMed2003

Potential role of tetrahydrobiopterin in the treatment of maternal phenylketonuria.

OBJECTIVE: To evaluate the clinical relevance of tetrahydrobiopterin (BH4) supplementation for pregnant women with phenylketonuria (PKU)/hyperphenylalaninemia (HPA) and the possibility of treating these patients with BH4 instead of a phenylalanine (Phe)-restricted diet. METHODS: Genotyping was performed on 41 patients with PKU/HPA identified by newborn screening. Evaluating the genotype according to their BH4 responsiveness is published. Follow-up of 3 patients with mild PKU treated with BH4 is evaluated. Discussion of the transfer of these experiences to the possibility of treating mothers at risk for maternal PKU is presented. RESULTS: In 41 patients with PKU/HPA, we found 17 (41%) bearing at least 1 allele with a mutation described as being responsive to BH4. In 8 of the patients, BH4 loading had been performed in the newborn period, in 6 of whom the test showed a clear decrease of blood Phe 4 and 8 hours after loading. One of the nonresponders was reinvestigated at 3 years of age, showing a clear response (genotype Y414C/R408W): BH4 supplementation resulted in a much higher Phe tolerance (500 instead of 250 mg/day) with blood Phe levels <200 micromol/L. Two children (genotype E390G/IVS10-11g>a and L48S/L48S, respectively) were treated with BH4 only (15-20 mg/kg body weight/day), one from birth, the other from 2 years of age. Blood Phe decreased from >800 micromol/L to a mean of 321.4 and 331.7 micromol/L, respectively (range: 141-718 micromol/L) under a normal diet (total observation time: 4 years). Development was normal with no adverse reactions. CONCLUSIONS: BH4 supplementation seems to be a promising alternative treatment in some patients with mild PKU. Because blood Phe levels in maternal PKU should be maintained at 120 to 360 micromol/L, clinical relevance may be even greater than for treatment of children with PKU/HPA. BH4 supplementation may also be combined with a Phe-restricted diet, allowing higher Phe intake and protecting mothers from high Phe blood peaks. However, additional studies are necessary to prove the safety and economy of such an alternative treatment in patients with PKU/HPA, especially during pregnancy.

Biopterins↗

PubMed2000

A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria.

AIMS/HYPOTHESIS: Patients with glucokinase mutations are characterised by mild, persistent fasting hyperglycaemia, a small increment in glucose in response to an oral load and a dominant family history. These patients frequently present with gestational diabetes and often require insulin treatment during pregnancy. We assessed whether the selection of gestational diabetic subjects by clinical criteria would result in a high detection rate of glucokinase mutations. METHODS: Caucasian gestational diabetic subjects from the United Kingdom who had fasting hyperglycaemia in pregnancy but did not meet the diagnostic criteria for maturity-onset diabetes of the young (MODY) were selected for direct sequencing of the glucokinase gene if they fulfilled the following four criteria; (1) persisting fasting hyperglycaemia outside pregnancy (5.5-8 mmol/l) (2) a small increment (< 4.6 mmol/l) during a 2-h oral glucose tolerance test (3) insulin treatment during at least one pregnancy but subsequently controlled on diet and (4) a history of Type II (non-insulin-dependent) diabetes mellitus, gestational diabetes or fasting hyperglycaemia (> 5.5 mmol/l) in a first-degree relative. RESULTS: Of the 15 subjects 12 (80%) with all these clinical criteria had glucokinase gene mutations. These included four previously unreported mutations (N180K, R191W, Y215X and L288-1G --> A). CONCLUSION/INTERPRETATION: Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5% (range 0-6%). Our study in gestational diabetes to successfully used clinical criteria to assist in the definition of a genetic subgroup.

Amino Acid Substitution↗

PubMed2002

Presence of Intact vpu and nef genes in nonpathogenic SHIV is essential for acquisition of pathogenicity of this virus by serial passage in macaques.

Use of the macaque model of human immunodeficiency virus (HIV) pathogenesis has shown that the accessory genes nef and vpu are important in the pathogenicity of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). We examined the ability of two nonpathogenic SHIVs, SHIV(PPC) and DeltavpuDeltanefSHIV(PPC), to gain pathogenicity by rapid serial passage in macaques. In this study, each virus was passaged by blood intravenously four times at 4-week intervals in macaques. Animals were monitored for 40 weeks for levels of CD4 T cells and quantitative measures of virus infection. DeltavpuDeltanefSHIV(PPC) maintained a limited phase of productive replication in the four animals, with no loss of CD4(+) T cells, whereas SHIV(PPC) became more pathogenic in later passages, judging by plasma viral load and viral mRNA in lymph nodes, infectious peripheral blood mononuclear cells and CD4(+) T cell loss. The nef, LTR, and env of the SHIV(PPC) viruses underwent numerous mutations, compared to DeltavpuDeltanefSHIV(PPC). This study confirms the seminal role that nef, LTR, and vpu could play in regulation of pathogenesis of HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed2006

A sensitive genotyping assay for detection of drug resistance mutations in reverse transcriptase of HIV-1 subtypes B and C in samples stored as dried blood spots or frozen RNA extracts.

Exposure to antiretroviral drugs in resource-constrained settings is likely to result in the emergence of drug-resistant HIV-1 variants, limiting treatment options. Genotypic drug resistance testing assists clinical management and outcomes assessment, but a sensitive and reproducible genotypic assay feasible for resource-constrained settings is needed. A sensitive, reproducible genotyping assay to detect HIV-1 drug resistance mutations in reverse transcriptase and protease was developed and validated using blood stored as dried blood spots or as frozen RNA extracts from Zambian children infected with subtype C. HIV-1 genotypes derived from samples stored as dried blood spots were compared to those derived from paired liquid plasma samples in American young adults infected with HIV-1 subtype B. The method reproducibly amplified patient-specific sequences and detected drug resistance mutations from all of the dried blood spots or excess frozen RNA extracts with detectable viremia over a broad range of viral loads (193-3 million HIV-1 RNA copies/mL) in both HIV-1 subtypes B and C infection. This method captured the genetic variation typical of HIV-1 infection, including mutations at usual sites of drug resistance, polymorphisms, and mixtures. This sensitive and reproducible genotypic assay is feasible for detection of antiretroviral resistance in resource-constrained settings.

Adolescent↗

PubMed2005

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Alleles↗

PubMed2005

Relationship between drug resistance mutations, plasma viremia, and CD4+ T-cell counts in patients with chronic HIV infection.

Transmission of drug-resistant viruses has been shown to be associated with lower virus replication capacity and higher CD4+ cell counts in recent human immunodeficiency virus (HIV) seroconvertors. The impact of drug resistance mutations on CD4 cell counts in chronically HIV-infected patients has not been examined. A total of 825 patients whose plasma specimens were submitted to a reference laboratory for genotypic testing from 1999 to 2002 were analyzed. There was no significant difference in the median CD4+ cell count when comparing 63 drug-naive and 762 treatment-experienced patients [399 (IQR, 141-525) vs. 319 (IQR, 174-521); P = 0.8]. In contrast, the median viral load was significantly higher in drug-naive than in pre-treated patients [4.6 (IQR, 4.1-5.25) vs. 4.1 (IQR, 3.4-4.7) logs; P < 0.0001]. Overall, drug resistance mutations appeared in 81% of patients, with a median number of 9 (IQR, 5-14). The rate of drug resistance genotypes was 9.5% for drug-naive patients and 86.7% for pre-treated individuals. In the univariate analysis, a lower viral load (P < 0.0001), the presence of drug-resistant viruses (P = 0.038), and specific mutations in the reverse transcriptase (RT) gene [presence of M184V (P = 0.016) or K70R (P < 0.0001), and lack of L74V (P < 0.003)] were all associated with higher CD4+ counts. However, in the multivariate analyses, only a lower viral load and the presence of K70R were significantly associated with higher CD4+ cell counts. In summary, drug-resistant viruses are associated with lower viral loads, but after adjusting for plasma viremia, subjects carrying drug-resistant viruses do not show significantly higher CD4 cell counts. Thus, keeping on treatment HIV-infected individuals failing virologically and harboring drug-resistant viruses may ameliorate their immunological deterioration until new drugs became available.

Anti-HIV Agents↗

PubMed1994

Rapid and practical detection of beta-globin mutations causing beta-thalassemia by fluorescence-based PCR-single-stranded conformation polymorphism analysis.

We report a useful method for daily clinical examination for the diagnosis of thalassemia. We applied a fluorescence-based image analyser to a non-radioisotopic PCR-single-stranded conformation polymorphism (SSCP) analysis to detect mutations in the beta-globin gene. PCR primers were labelled with rhodamine X and the amplified fragments from the beta-globin gene were resolved by non-denaturing polyacrylamide gel electrophoresis. After loading, the glass plate was set in the image analyser and scanned with a green laser. We detected four common mutations in exon I and two major mutations in intron 1 of the beta-globin gene isolated from patients with beta-thalassemia. Moreover, to discriminate mutations and natural polymorphisms, we used primers including one base mismatch at the polymorphic site, which can substitute the polymorphic site by a constant base in the PCR amplified fragment. This fluorescence-based system was simple to operate and results were obtained rapidly as clear image data. Therefore, once the optimal conditions of the electrophoresis are determined, this system will be suitable for daily clinical use, especially for screening of molecular defects and for the prenatal diagnosis of genetic disorders.

Base Sequence↗

PubMed2005

Null mutation of myeloperoxidase in mice prevents mechanical activation of neutrophil lysis of muscle cell membranes in vitro and in vivo.

Membrane lysis is a common and early defect in muscles experiencing acute injuries or inflammation. Although increased mechanical loading of muscles can induce inflammation and membrane lysis, whether mechanical loads applied to muscle can promote the activation and cytolytic capacity of inflammatory cells and thereby increase muscle damage is unknown. We tested whether mechanical loads applied to mouse muscle cells in vitro can increase membrane lysis, and whether neutrophil-mediated lysis of muscle cells is promoted by mechanical loads applied in vitro and in vivo. Cyclic loads applied to muscle cells for 24 h in vitro produced little muscle cell lysis. Similarly, the addition of neutrophils to muscle cell cultures in the presence of superoxide dismutase (SOD) produced little muscle cell lysis. However, when cyclic mechanical loads were applied to neutrophil-muscle co-cultures in the presence of SOD, there was a synergistic effect on muscle cell lysis, suggesting that mechanical loading activates neutrophil cytotoxicity. However, application of mechanical loads to co-cultures of muscle cells and neutrophils that are null mutants for myeloperoxidase (MPO) showed no mechanical activation of neutrophil cytotoxicity. This indicates that loading promotes neutrophil cytotoxicity via MPO. Activity assays confirmed that mechanical loading of neutrophil-muscle co-cultures significantly increased MPO activity. We further tested whether muscle membrane lysis in vivo was mediated by neutrophils when muscle was subjected to modified loading by using a mouse model of muscle reloading following a period of unloading. We observed that MPO-/-soleus muscles showed a significant 52% reduction in membrane lysis compared to wild-type mice, although the mutation did not decrease inflammatory cell extravasation. Together, these in vitro and in vivo findings show that mechanical loading activates neutrophil-mediated lysis of muscle cells through an MPO-dependent pathway.

Animals↗

PubMed2006

An additive/subtractive genotypic score as a determinant of the virological response to didanosine in HIV-1 infected patients.

OBJECTIVE: To assess the genotypic determinants of the virological response (VR) to didanosine (ddI) in nucleoside reverse transcriptase inhibitors (NRTI)-experienced patients. METHODS: Human immunodeficiency virus type 1 (HIV-1) genotype was determined at baseline in 74 ddI-naive-patients with baseline viral load >500 copies/ml and receiving ddI as part of a new regimen. VR was defined as a plasma HIV-1 RNA <50 copies/ml after three months on ddI. NRTI resistance mutations associated with higher or lower frequencies of VR with a p-value<0.25 were retained in different sets of mutations, where the mutations associated with a worse VR were added, whereas the mutations associated with a better VR were subtracted. The most significant mutation scores were then studied in a multivariate analysis. RESULTS: Changes at three codons (M41L, L210W, T215Y/F/D/C/E) were associated with a worse VR and three mutations (K70R, M184V, K219Q) with a better VR. The strongest association with the VR was obtained with the score M41L+L210W+T215Y/F/D/C/E-K70R-K219Q. The score was independently associated with the VR in the multivariate analysis. CONCLUSION: Taking into account the mutations associated with a better VR may improve genotypic resistance algorithms. Our results are of interest for the management of antiretroviral therapy in NRTI-experienced patients.

Algorithms↗

PubMed1994

[Genetic effects of cosmic radiation in Drosophila melanogaster].

To examine possible effects of space radiation on living organism, we have analyzedtwo types of mutations, sex-linked recessive lethal mutations and somatic mutations, in fruit fly of the species Drosophila melanogaster. Drosophila strains used were wild type strains and a radiation-sensitive strain mei-41. Two different developmental stages of samples were sent into space; young adult males to analyze sex-linked recessive lethal mutations and about 30hr-old larvae to detect somatic mutations in wing epidermal cells. For wild type and mei-41 strains each, about 200 adult male flies and about 6,000 larvae were loaded on space shuttle Endeavour. The male flies returned from space were mated to virgin female flies of a tester strain, and the presence of the lethal mutations was analyzed at F2 generation. The frequencies of sex-linked recessive lethal mutations in flight groups were 2 and 3 times higher for wild type Canton-S and mei-4 1, respectively, than those in ground control groups. Most larvae sent to space emerged as adult flies within about 10 days after the landing. The presence of wing-hair somatic mutations, which give morphological change in hairs growing on the surface of wing epidermal cells, was analyzed under microscope. In wild type strain Muller-5, the frequency of wing hair mutant spots in flight group was about 1.5-fold higher than that in ground control, and in Canton-S-derived wild type strain the frequencies were similar between the two groups. By contrast, for mei-41 strain the mutation frequency was lower in flight group than in control group. The observed higher frequency of lethal mutations in the flight group might be due to a possibility that radiation effects on reproductive cells could be greatly enhanced under micro gravity. However, if this would be the case, we do not have appropriate explanation for the apparent absence of such synergistic effects on somatic wing-hair mutation system.

Abnormalities, Radiation-Induced↗

PubMed1999

Quantitative changes in cytomegalovirus DNAemia and genetic analysis of the UL97 and UL54 genes in AIDS patients receiving cidofovir following ganciclovir therapy.

Five AIDS patients with cytomegalovirus (CMV) retinitis who had received ganciclovir (GCV) therapy were followed with serial blood sampling to detectchanges both in CMV load and in the genetic composition of genes UL97 and UL54 whilst receiving cidofovir (CDV) therapy. CDV neither reduced CMV load in blood nor prevented its quantitative resurgence during therapy. These effects were not explained by the initial presence or development of CDV-associated drug resistance mutations in UL54. In two patients, UL97 genotypic resistance to GCV involving either a L595S mutation or a deletion of amino acids 590-603 were present at the initiation of CDV and, in both patients, repopulation of CMV strains with wild-type UL97 sequences occurred during CDV therapy. These data are consistent with GCV-resistant strains containing UL97 mutations being less fit than their wild-type counterparts and so being able to persist only with the selective pressure of GCV.

Acquired Immunodeficiency Syndrome↗