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Results for “Copy number variants”

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PubMed1989

Heterochromatic regions in different Drosophila melanogaster stocks contain similar arrangements of moderate repeats with inserted copia-like elements (MDG1).

Seven out of twenty 30-50 kb genome fragments with an MDG1 copia-like element cloned in cosmids were found to carry homologous sequences which belong to a new family of non-mobile heterochromatic moderate repeats (the HMR family). These repeats along with the MDG1 copies inserted in them are under-replicated in polytene chromosomes. Such repeats may also be located in the intercalary heterochromatin site 12E of the X chromosome. Chromosomal heterochromatic regions are enriched with one of the two main genomic variants of MDG1, MDG1het, identifiable by EcoRI restriction. From Southern DNA blot analysis the number of MDG1het copies and their sites within the heterochromatin are invariant in all the stocks examined, while there is not a single MDG1 site along the polytene chromosomes shared by all the stocks in question.

Animals↗

PubMed2026

Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUND: Porokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined. OBJECTIVE: To elucidate the molecular basis of solitary PM. METHODS: We analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis. RESULTS: Solitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years. CONCLUSION: Solitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

General dermatology↗

PubMed2003

Real-time PCR assay of individual human immunodeficiency virus type 1 variants in coinfected human lymphoid tissues.

In the course of infection, human immunodeficiency virus type 1 (HIV-1) mutates, diverging into a "swarm" of viral quasispecies, and the predominance of CCR5- or CXCR4-utilizing quasispecies is strongly associated with the pattern of disease progression. Quantification of CCR5- and CXCR4-utilizing viruses in viral swarms is important in the investigation of the mechanisms of this phenomenon. Here, we report on a new real-time PCR-based methodology for the evaluation of replication of individual CCR5- and CXCR4-utilizing variants. The assay is highly reproducible, with a coefficient of variation of <3%, and it accurately estimates the numbers of virus-specific RNA copies even when their difference in the mixture is 2 orders of magnitude. We demonstrate that replications of CCR5- and CXCR4-utilizing variants can be evaluated and distinguished in experimentally coinfected human lymphoid tissue. The assay we developed may facilitate study of the mechanisms of the R5-to-X4 switch in viral swarms in human tissues infected with HIV-1.

Base Sequence↗

PubMedDate not supplied

Protection of CCRF-CEM human lymphoid cells from antifolates by retroviral gene transfer of variants of murine dihydrofolate reductase.

Expression of certain variants of dihydrofolate reductase (DHFR) in mammalian cells protects them from methotrexate. Retroviral transfer of the gene for such a variant DHFR into hematopoietic cells might permit selection of modified cells in vivo by antifolate administration or alleviate antifolate-induced myelosuppression in patients receiving antifolate therapy. We examined protection of cells of the human lymphoblastoid line, CCRF-CEM, transduced with variants of mouse DHFR. In transduced cells selected with G418 but not with antifolate, the variant that had arginine substituted for leucine 22 did not protect against either methotrexate or trimetrexate; however, four other variants did offer protection, with the best having leucine 22 changed to tyrosine. Polyclonal cultures transduced with the different variants express DHFR at about the same level, but clones within each polyclonal population differ in DHFR expression levels and in resistance. These differences in expression were shown to reflect different integration sites for proviral DNA. Exposure to trimetrexate selects highly resistant clones, with high expression due to both high copy number and integration sites that are favorable for expression. Differences in the resistance of cultures expressing different variants at the same level are due to differences in the catalytic activity of the expressed DHFR, its affinity for antifolates, and its stability.

Animals↗

PubMed2006

Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands.

Susceptibility to HIV infection and AIDS progression is variable among individuals and populations, and in part genetically determined. Genetic variants of genes encoding HIV co-receptors and their chemokine ligands have been described, and some of these variants were associated with resistance to HIV infection and/or disease progression. We review here the reported data regarding the variants of the CCR5, CCR2, CX3CR1, MIP-1alpha/CCL3, MIP-1beta/CCL4, RANTES/CCL5 and SDF-1/CXCL12 genes. The Delta32 deletion mutant of CCR5, resulting in a non-functional receptor not reaching the cell surface, is unambiguously associated with strong, although incomplete, resistance to HIV infection for homozygotes, and retarded progression for heterozygotes. Specific haplotypes encompassing the CCR5 and CCR2 loci, and the copy number of the CCL3L1 gene, have also been convincingly correlated with delayed progression. For other gene variants, involving CXCL12/SDF-1 and CX3CR1, conclusive evidence for their relevance in the frame of HIV susceptibility is still lacking.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Organization and dynamics of satellite and telomere DNAs in Ascaris: implications for formation and programmed breakdown of compound chromosomes.

In the nematode genus Ascaris the germline genome contains considerable amounts of extra DNA, which is discarded from the somatic founder blastomeres during early cleavage. In Parascaris univalens the haploid germline genome is contained in one large compound chromosome, which consists of a euchromatic region containing the somatic genome flanked by large blocks of heterochromatin. Fluorescence in situ hybridization of fractions of the germline-limited satellite DNA revealed two highly repeated sequence families establishing the entire heterochromatin (HET blocks). The repeats, a pentanucleotide, TTGCA, and a decanucleotide, TTTGTGCGTG, constitute separate segments of the HET blocks. The blocks are polymorphic in length and, hence, in copy number of the repeats, and the arrangement of the segments. The numerous sequence variants of both repeats display a disperse distribution. The type and rate of base substitutions within both repeat units depend on position. Prior to the elimination process in presomatic cells, termed chromatin diminution, the chromosomes undergo differential mitotic condensation. Interstitial 'chromatin linkers' flanking the prospective numerous somatic chromosomes remain entirely decondensed. The somatic chromosomes are released from the plurivalent chromosomes via excision of the linkers at onset of anaphase, followed by exclusion of the akinetic linker chromatin and HET blocks from the daughter nuclei. In Ascaris suum, the germline-limited satellite, which consists of one 123 bp repeat, is scattered throughout the numerous chromosomes in small heterochromatic knobs of variable sizes, residing at chromosomal ends and/or intercalary positions. The programmed breakage, which appears to proceed in a similar manner to that in P. univalens, results in the loss of all heterochromatic knobs, accompanied by an increase in chromosome number. In both species, all germline chromosomes are capped by tracts of TTAGGC repeats. In P. univalens, such telomeric tracts also occur at the termini of the euchromatic intercalary regions. Upon diminution all telomeric tracts are discarded. De novo telomere addition occurs in all somatic cell lineages of both species. The presented data shed light on the evolutionary history of chromosome aggregation and satellite DNA formation, and putative mechanisms involved in the process of site-directed breakage to reestablish stable somatic chromosomes.

Animals↗

PubMed1997

Comparative genomic hybridization analysis of chromosomal changes occurring during development of acquired resistance to cisplatin in human ovarian carcinoma cells.

The genetic changes underlying the development of resistance to the platinum-containing drugs are poorly defined. We analyzed six resistant cell lines using comparative genomic hybridization (CGH) in order to screen and identify possible genetic changes in common. We compared parental 2008 and A2780 human ovarian cancer cells to sublines selected for resistance to cisplatin (DDP) (2008/C8, 2008/C13*5.25, 2008/A, A2780/CP); we also compared 2008 cells to sublines selected for resistance to antimonite (2008/H) and arsenite (2008/I) which demonstrated cross-resistance to DDP. DNA samples from the resistant cell lines were hybridized against DNA from the parental cells rather than from normal human cells to permit detection of only those changes associated with the development of resistance. The DNA sequence copy number changes were surprisingly numerous in the DDP, antimony, and arsenite-resistant variants of the 2008 cell line and most of the chromosomes were affected. On the other hand, in the A2780/CP subline only a few changes were found and these were limited to just four chromosomes. The most common findings among the DDP-resistant cell lines were gains of material from chromosomes or chromosome arms 2q (5 out of 6 lines), 4 (4/6), 6q (5/6), and 8q (4/6). Deletions were observed on chromosomes or chromosome arms 2p (4/6), X (4/6), 7p (5/6), 11p (4/6), and 13 (4/6). The most frequently involved chromosomal regions, affected in the majority of cell lines, were: gain of 2q14.1-q33, 4p15.2-p13, 4q22-q25, 4q31.1-q34, 6q13-q16, 8q12-q21.2, and loss of Xp22.2-q21, 7p21-p14, 11cen-p14 in sublines of 2008, and loss of 2pter-p22 and 13q21 in sublines of 2008 and A2780. The results suggest that the acquired resistance and cross-resistance to DDP in these cell lines was associated with substantial genomic instability, quite unlike the changes observed in association with the development of resistance to drugs participating in the multidrug resistance phenotype.

Chromosome Aberrations↗

PubMed1996

A single gene copy merozoite surface antigen and immune evasion?

During the course of chronic malaria infection antigenic variants of a parasite antigen are expressed and exposed on the surface of infected erythrocyte membranes. There also exists a number of apparently invariant single gene copy blood-stage antigens, exposed or non-exposed, which have been shown to afford immunity under experimental conditions. To determine why the host, presented with invariant 'protective' antigens, is unable to control infections effectively, immunity to a representative single gene copy antigen, the merozoite surface protein 1 (MSP1) was investigated in Plasmodium chabaudi chabaudi AS, a murine model of chronic malaria. Immunization with monoclonal antibody affinity purified native MSP1 resulted in enhanced control of parasitaemia on challenge, irrespective of the parasite inoculum size; challenge with a single parasite, however, suggested that expansion of resistant parasite subpopulations was not occurring. Challenge of mice immunized with recombinant fusion proteins encoding N- or C-terminal regions of the P.c. chabaudi AS MSP1 produced inconsistent effects, often parasitaemias were indistinguishable from controls despite significant anti-MSP1 antibody responses. The not unlikely contamination of MSP1 native preparations with erythrocyte (E) components was considered. Immunization with a mixture of the MSP1 C-terminus recombinant polypeptide and a Triton X-100 solubilized lysate of normal E resulted in enhanced control of parasitaemia, however, no effect was seen after administration of either component on its own. Co-immunization of E with the N-terminus polypeptide reversed the inhibition seen, on this occasion with this construct alone.

Animals↗

PubMed2006

Novel deletion variants of 9q13-q21.12 and classical euchromatic variants of 9q12/qh involve deletion, duplication and triplication of large tracts of segmentally duplicated pericentromeric euchromatin.

Large-scale copy number variation that is cytogenetically visible in normal individuals has been described as euchromatic variation but needs to be distinguished from pathogenic euchromatic deletion or duplication. Here, we report eight patients (three families and two individuals) with interstitial deletions of 9q13-q21.12. Fluorescence in situ hybridisation with a large panel of BACs showed that all the deleted clones were from extensive tracts of segmentally duplicated euchromatin, copies of which map to both the long and short arms of chromosome 9. The variety of reasons for which these patients were ascertained, and the phenotypically normal parents, indicates that this is a novel euchromatic variant with no phenotypic effect. Further, four patients with classical euchromatic variants of 9q12/qh or 9p12 were also shown to have duplications or triplications of this segmentally duplicated material common to both 9p and 9q. The cytogenetic boundaries between the segmentally duplicated regions and flanking unique sequences were mapped to 9p13.1 in the short arm (BAC RP11-402N8 at 38.7 Mb) and to 9q21.12 in the long arm (BAC RP11-88I18 at 70.3 Mb). The BACs identified in this study should in future make it possible to differentiate between clinically significant deletions or duplications and euchromatic variants with no established phenotypic consequences.

Adolescent↗

PubMed2026

Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.

Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in the tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. We searched our pathology files in 2004-2024 for available cases and performed targeted next-generation sequencing along with whole-genome single-nucleotide polymorphism arrays and 3-dimensional genomics/Hi-C sequencing in selected cases. Our cohort included 3 classic adamantinomas (2 females and 1 male; age, 14-56 years), 5 OFDs (3 females and 2 males; age, 9-25 years), and 2 OFD-like adamantinomas (1 female and 1 male; age, 30-41 years). Of the 10 tumors, 9 arose from the tibiae; 1 classic adamantinoma originated from the radius. The 3 classic adamantinomas harbored multiple copy number gains involving chromosome 7, 8, 10, 12, and/or 19. Focal deletion of chromosome 17, intergenic rearrangement involving FGFR1, and NRAS p.G12D were each present in 1 classic adamantinoma. Of the 5 OFDs, KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in 1 case; no additional copy number/single-nucleotide variants were identified. Of the 2 OFD-like adamantinomas, one case with tumor clusters visible only on cytokeratin immunostain harbored no variants, whereas another case with tumor clusters visible on light microscopy and cytokeratin/p40 immunostains showed gains of chromosome 7, 8, 19, and 20. By Hi-C, 1 classic adamantinoma harbored an approximately 9 Mb tandem duplication on chromosome 12q, 1 OFD harbored a rearrangement with breakpoints near MECOM and HOOK3, and the OFD-like adamantinoma with tumor clusters visible only on cytokeratin immunostain harbored no structural variant. In conclusion, classic adamantinomas and OFD might be genetically distinct. Classic adamantinomas harbored multiple alterations, including chromosome/arm-level copy number gains, the detection of which could aid their distinction from OFDs. Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.

Humans↗

PubMed1995

Transformed mouse cell lines that consist predominantly of cells maintaining bovine papilloma virus at high copy number.

Rare cells that contain large amounts of bovine papilloma virus (BPV) DNA have been observed in populations of BPV-transformed mouse ID13 cells. The viral DNA molecules in these "jackpot cells" have been thought to have switched from the controlled replication typical of latent BPV infection to the uncontrolled "runaway" prelytic replication characteristic of terminal stage infection of bovine epidermal cells. By sequential subcloning of high-BPV derivatives of ID13, we isolated stable cell lines enriched more than 1000-fold for cells showing large amounts of BPV by fluorescence in situ hybridization analysis. High-BPV subclones contained a variant plasmid as well as wild-type BPV DNA; analysis of the BPV variants in two independently isolated subclones that showed the high-BPV phenotype in 50 to 80% of cells in the population indicated that both variants had undergone tandem duplication of the BPV long control region, which contains the viral origin of replication and transcription enhancer sequences. Transfer of the high-copy-number phenotype by transfection of DNA from high-BPV cells was accompanied by transfer of the variant plasmid. Density gradient analysis of BPV plasmid replication in high-BPV subclones showed the random-choice mode of replication observed in the parental ID13 population, rather than the rapid BPV replication found in epidermal cells destined for lysis and death. Our results indicate that high-BPV cells in actively dividing ID13 populations are not produced by uncontrolled replication of viral DNA and suggest that they may result instead from abnormal plasmid partitioning.

Animals↗

PubMed2026

The genetic control of rapid genome content divergence in Arabidopsis thaliana.

Genome evolution in eukaryotes is predominantly driven by the dynamics of repetitive sequences, which vary widely in both copy number and sequence composition. Rates of repeat evolution differ between and within species and are likely modulated by both genetics and environment. To uncover factors shaping the rate of genome content evolution, we analyzed 1043 resequenced Arabidopsis thaliana genomes using a novel K-mer-based approach to characterize genome content variation and identify hypervariable regions underlying differences in repeat abundance. We next treated repeat abundance as a quantitative trait and performed genome-wide association analyses across more than 400 repeat families to identify the genetic basis of copy number variation. Integrating these results through a meta-GWAS approach revealed both cis-acting variants and more than 50 candidate trans-acting loci associated with repeat abundance genome-wide. Cis-acting variation was predominantly localized to pericentromeric and centromeric regions, whereas trans-acting loci were enriched for candidate genes involved in DNA replication, DNA repair, and DNA methylation regulation. The results are consistent with purifying selection acting against mutations that accelerate genome content divergence, favoring alleles that constrain repeat expansion. Together, these findings provide new insights into the genetic architecture and evolutionary forces shaping genome evolution in A. thaliana and establish a framework for investigating these processes in other plant species.

Arabidopsis↗

PubMed2006

Profiling of length heteroplasmies in the human mitochondrial DNA control regions from blood cells in the Korean population.

The length heteroplasmies in the hypervariable (HV) regions of mitochondrial DNA (mtDNA) from blood cells were examined in 57 healthy Korean donors. Interestingly, all the healthy Korean subjects displayed length heteroplasmies in both the HV1 and HV2 regions. Closer examination of the HV2 length heteroplasmies indicated that most of these donors (84%) exhibited a minimal 303-315 homopolymeric C (poly-C) tract frameshift of 1 bp (mixture of one major and minor mtDNA type). Sixteen percent of the donors however had poly-C tract frameshifts of 2 bp or more. The donor group with major length variants (two or more frameshifts) had about a two-fold decrease in mtDNA copy number compared with the group exhibiting only a 1 bp frameshift. This result supports the possibility that a severe frameshift in the 303-315 poly-C tract may also cause the impairment of mtDNA replication in hematopoietic tissue.

Adolescent↗

PubMed1983

The Balbiani ring 2 gene in Chironomus tentans is built from two types of tandemly arranged major repeat units with a common evolutionary origin.

The internal structure of the 37 kb long Balbiani ring 2 (BR 2) gene in Chironomus tentans has been studied by analysis of a collection of cloned cDNA sequences and in genomic Southern blot analysis with the cDNA sequences used as probes. The BR 2 gene contains two types of tandemly arranged major repeat units 200 bp long, represented in our study by the pCt 7 and the pCt 63 cDNA inserts. The pCt 7 major repeat units are arranged in one or possibly a few blocks and cover 10 kb of the gene; the pCt 63 units form one uninterrupted block, 22 kb in length. Genomic Southern blot hybridizations revealed a number of sequence variants of the pCt 7 major repeat unit. In contrast, the 100 copies of the pCt 63 major repeat unit seem to be almost identical. The pCt 7 major repeat unit, 180 bp in length, is organized in the same way as the previously described 215 bp long pCt 63 major repeat, i.e., it contains a repetitive and a non-repetitive part. Moreover, the two major repeat units show a high degree of sequence homology, indicating that the pCt 7 and pCt 63 sequence blocks within the Br 2 gene have evolved through stepwise amplification from a common ancestral sequence.

Journal Article↗

PubMed2004

Lack of mutations in DJ-1 in a cohort of Taiwanese ethnic Chinese with early-onset parkinsonism.

Recently, mutations in DJ-1 (PARK7) were described as a novel cause of early-onset parkinsonism. We analysed the DJ-1 gene in a cohort of patients originating from Taiwan with early-onset Parkinson's disease; 41 subjects were clinically and genetically examined. These patients were evaluated previously for the presence of parkin mutations (PARK2) and were found to be negative. The entire DJ-1 open-reading frame was amplified from cDNA, analysed for size alterations indicative of mutations affecting splice motifs, and sequenced to identify coding variants. In addition, we developed quantitative polymerase chain reaction assays to examine the genomic copy number of DJ-1 exons. No potential splice site mutations, coding sequence alterations, or exon deletion/duplications were detected. Our results and previous studies suggest that alterations to DJ-1 are not a common cause of early-onset Parkinson's disease and other causes, genetic and/or environmental, remain to be identified.

Adult↗

PubMed2006

Comparison of quantitative competitive polymerase chain reaction-enzyme-linked immunosorbent assay with LightCycler-based polymerase chain reaction for measuring cytomegalovirus DNA in patients after hematopoietic stem cell transplantation.

Development of highly sensitive quantitative assays for cytomegalovirus (CMV) DNA detection is crucial for identification of immunodeficient patients at high risk of CMV disease. We designed 2 internally controlled competitive quantitative assays, enzyme-linked immunosorbent assay (ELISA)-based and real-time polymerase chain reaction (PCR) tests, using amplification of the same segment of the CMV genome. The aim of this study was to compare sensitivity, specificity, and laboratory performance characteristics of these assays. In both assays, a 159-bp segment of UL83 gene was amplified. External and internal controls were constructed by cloning the amplification product and heterogenous DNA segment flanked by target sequences for CMV-derived primers into bacterial plasmids, respectively. Real-time PCR was performed on LightCycler (Roche Diagnostics, Mannheim, Germany), and amplicons were detected using fluorescence resonance energy transfer probes. Alternatively, PCR products were labeled by digoxigenin, hybridized to immobilized probes, and detected by ELISA. The assays were tested on genomic DNA isolated from laboratory strains of CMV, QCMD control panel, and CMV DNA-positive peripheral blood DNA samples from hematopoietic stem cell transplant recipients, previously characterized by pp65 antigenemia and qualitative nested PCR. Real-time and ELISA-based PCR assays showed a linear course of 1-10(8) and 10-10(5) copies of CMV DNA per reaction, respectively. When compared with ELISA-based PCR, real-time PCR showed superiority in inter- and intra-assay reproducibility. Both assays were highly specific in detecting CMV DNA. No difference in amplification efficiency of internal or external standards and wild-type CMV DNA was found. The assays exhibited 83% concordance in CMV DNA detection from clinical samples, all discrepant samples having low CMV DNA copy numbers. There was a good correlation between viral DNA loads measured by the 2 assays. Statistically significant correlation was observed between the numbers of CMV DNA copies and pp65-positive leukocytes in the samples tested. Both variants of competitive PCR are adequately sensitive to be used for CMV DNA quantitation in clinical samples. LightCycler PCR, having superior performance characteristics and being less time-consuming, seems to be more suitable for routine diagnosis.

Cytomegalovirus↗

PubMed1999

Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum.

Many pathogens evade the host immune response or adapt to their environment by expressing surface proteins that undergo rapid switching. In the case of Plasmodium falciparum, products of a multigene family known as var are expressed on the surface of infected red cells, where they undergo clonal antigenic variation and contribute to malaria pathogenesis by mediating adhesion to a variety of host endothelial receptors and to uninfected red blood cells by forming rosettes. Herein we show that a second gene family, rif, which is associated with var at subtelomeric sites in the genome, encodes clonally variant proteins (rifins) that are expressed on the infected red cell surface. Their high copy number, sequence variability, and red cell surface location indicate an important role for rifins in malaria host-parasite interaction.

Animals↗

PubMed1999

Antiviral activity of the human immunodeficiency virus type 1-specific nonnucleoside reverse transcriptase inhibitor HBY 097 alone and in combination with zidovudine in a phase II study. HBY 097/2001 Study Group.

The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

Adult↗