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PubMed2000

Early human immunodeficiency virus (HIV) infection in the HIV Network for Prevention Trials Vaccine Preparedness Cohort: risk behaviors, symptoms, and early plasma and genital tract virus load.

Risk behaviors, symptoms, and virologic characteristics were studied among 103 human immunodeficiency virus (HIV) seroconverters in vaccine preparedness cohorts during 1995-1998. Overall, 83% of subjects were men who had sex with men; most reported multiple risk episodes and symptoms (84%, > or =1 symptom) during seroconversion. Acute HIV was diagnosed in only 8 of 50 who sought medical care. Median initial pretreatment plasma virus load was 25,800 copies/mL (range, undetectable-262,000 copies/mL) a mean of 4 months after seroconversion, and 9.7% had nucleoside-associated mutations; none had multidrug resistance. Semen virus load was more variable, 1.3 log(10) lower and modestly correlated (r=.28; 95% confidence interval, 0.16-0.42) with plasma among untreated men. When the plasma RNA level was <5000 copies/mL, 32% of untreated men, 13% on nucleoside regimens, and 7% on protease inhibitor-containing regimens had detectable seminal RNA. Acute HIV was seldom diagnosed, representing missed opportunities for early treatment and prevention. Most subjects had several relatively stable virus loads before initiation of antiretrovirals, indicating feasibility of assessing HIV vaccines on virus set point in efficacy trials.

Acute Disease↗
PubMed2000

Towards reliable prenatal diagnosis of mtDNA point mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults.

Prenatal diagnosis of mitochondrial DNA (mtDNA) mutations is technically possible, but has only rarely been attempted. This is largely because of uncertainty about the effects of mtDNA heteroplasmy, the mtDNA bottleneck, random segregation or selection of mtDNA species, and difficulty in correlating a particular mtDNA mutant load with clinical outcome. We have investigated the feasibility of prenatal diagnosis for two common mtDNA mutations at nucleotide (nt)8993 by determining mtDNA mutant loads in human oocytes and by reviewing data on 56 pedigrees with these mutations, and by reviewing six studies on mtDNA mutations in human fetuses. Data from heteroplasmic human and mouse oocytes demonstrate that the bottleneck occurs in early oogenesis. Analysis of mutant loads of the nt8993 mutations in fetal and adult tissues confirms that there is no substantial tissue variation, implying that the mutant load in a prenatal sample will represent the mutant load in other fetal tissues. The two nucleotide 8993 mutations each show a strong correlation between mutant load and symptom severity and between maternal blood mutant load and risk of a severe outcome. We generated empirical data for calculating recurrence risk and predicting the clinical outcome of a given mutant load. These predictive data can be used (cautiously) for genetic counselling and prenatal diagnosis of nucleotide 8993 mutations.

Adult↗
PubMed2000

Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group.

Abacavir (1592U89) is a nucleoside inhibitor of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT). Resistance to abacavir was studied with abacavir alone and with abacavir in combination with other nucleoside analogues in cell culture, in virus isolates from zidovudine/lamivudine clinical trials, and in the first dose-escalating 12-week clinical trial (CNA2001) to evaluate abacavir clinical potency. Abacavir alone in vitro selected for mutations at HIV RT codons K65R, L74V, Y115F, and M184V. However, abacavir combined with zidovudine selected against virus with the M184V mutation. Abacavir therapy in vivo resulted in large decreases in HIV load (>1 log), even in 1 subject who had the M184V mutation at baseline. A total of 51% of subjects showed new mutations at any of codons K65R, L74V, and M184V after abacavir monotherapy, compared with 11% who received zidovudine/abacavir. Small changes (2- to 4-fold) in abacavir susceptibility were detected. On stopping therapy, reselection of the pretherapy sequence occurred within 4 weeks.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Practical applications of viral fitness in clinical practice.

PURPOSE OF REVIEW: To review recent clinical data regarding viral fitness and its potential utility in clinical practice. Therapeutic failure of antiretroviral regimens is often due to the development of drug resistance. The viral loads achieved by these drug-resistant variants frequently remain suppressed below pretreatment levels. Furthermore, many patients with virologic failure continue to maintain stable CD4 counts and remain clinically well. One possible explanation for these observations is that the resistant virus that emerges during failure of highly active antiretroviral therapy is less fit than its wild-type counterpart as a result of the requirement to maintain resistance mutations that allow it to replicate in the presence of antiretroviral drugs. Since there are many patients with limited treatment options due to extensive resistance or drug toxicities, or both, there is intense interest in exploring the possibility that viral fitness can be exploited for clinical benefit. This review describes the assays that are used to measure fitness and replication capacity, and investigations of their utility in clinical practice. RECENT FINDINGS: A number of methods have been developed to measure viral fitness. Replication kinetic and competitive culture assays are accurate, but labour and time intensive. The availability of a rapid, single-cycle recombinant assay that measures viral replication capacity presents the possibility that assessments of viral fitness could be incorporated into clinical management. The replication capacity assay appears to correlate with more standard measures of viral fitness, and recently accumulated data in both wild-type and drug resistant viral populations suggest that replication capacity describes an intrinsic characteristic of HIV-1. A number of investigations of the clinical utility of fitness and replication capacity assays have established correlations between these measurements and virologic and immunologic outcomes. SUMMARY: Much progress has been made in the past year in our understanding of viral fitness and replication capacity. Assays that measure these viral characteristics have the potential to expand the range of clinical strategies employed against HIV-1. Further investigations are needed to firmly establish the clinical utility of these assays.

Carbamates↗
PubMed2004

[Determination of hepatitis B virus genotype and detection of lamivudine-resistance mutations].

OBJECTIVES: To determine hepatitis B virus (HBV) genotypes in southern Seville (Spain) and investigate the development of lamivudine-resistance mutations by using a hybridization technique with specific probes and by comparing the results with those of the direct sequencing technique. To evaluate the temporal relationship between variations in the level of HBV-DNA and detection of mutant variants. To analyze the influence of several genotypes on the pattern of mutations developed and on values of viral load and alanine aminotransferase (ALT) after their development. PATIENTS AND METHOD: In 37 patients with chronic HBV infection, HBV genotype was determined using the LiPA technique. In 10 of these patients undergoing lamivudine treatment for a mean of 19.2 months, the development of lamivudine-resistant mutations was investigated. In these 10 patients, the LiPA technique was compared with direct sequencing. During lamivudine treatment, we determined HBV-DNA by polymerase chain reaction (PCR) and ALT every 3-6 months. RESULTS: The most frequent genotypes were D (45.9%) and A (18.9%); 2 patients were genotype B while 18.9% had mixed genotypes. Sequencing showed identical results except in one mixed genotype. Mutations were found in 60% of the cases. The results of sequencing were in agreement, except in the detection of mixed populations composed of mutants and wild-type (WT). Patients with genotype A showed the pattern M204I+WT in the first 12 months and those with genotype D showed the pattern L180M+M204V with or without WT at 18 months. In 5/6 cases, an increase of > 1 log10 in HBV-DNA was observed 3-8 months before the mutation was detected by LiPA. In patients with genotype B, levels of HBV-DNA and ALT after the development of mutations was lower than basal levels and was also lower than those in patients with genotypes A and D. CONCLUSIONS: The LiPA technique for determination of HBV genotype and detection of lamivudine-resistance mutations shows excellent correlation with the most complex sequencing technique. Genotype D predominates in southern Seville. During lamivudine treatment, an increase in the level of HBV-DNA detected by PCR predicts the development of mutations before these are demonstrated by LiPA.

Adult↗
PubMed2005

In vitro resistance to interferon of hepatitis B virus with precore mutation.

AIM: Chronic hepatitis B virus (HBV) infection is predominantly treated with interferon alpha (IFN-alpha), which results in an efficient reduction of the viral load only in 20-40% of treated patients. Mutations at HBV precore prevail in different clinical status of HBV infection. The roles of precore mutation in the progression of chronic hepatitis and interferon sensitivity are still unknown. The aim of this study was to explore if there was any relationship between HBV precore mutation and sensitivity to interferon in vitro. METHODS: HBV replication-competent recombinant constructs with different patterns of precore mutations were developed. Then the recombinants were transiently transfected into hepatoma cell line (Huh7) by calcium phosphate transfection method. With or without IFN, viral products in culture medium were collected and quantified 3 d after transfection. RESULTS: We obtained 4 recombinant constructs by orientation-cloning 1.2-fold-overlength HBV genome into pUC18 vector via the EcoRI and Hind III and PCR mediated site-directed mutagenesis method. All the recombinants contained mutations within precore region. Huh7 cells transfected with recombinants secreted HBsAg and HBV particles into the cell culture medium, indicating that all the recombinants were replication-competent. By comparing the amount of HBV DNA in the medium, we found that HBV DNA in medium reflecting HBV replication efficiency was different in different recombinants. Recombinants containing precore mutation had fewer HBV DNAs in culture medium than wild type. This result showed that recombinants containing precore mutation had lower replication efficiency than wild type. HBV DNA was decreased in pUC18-HBV1.2-WT recombinants after IFN was added while others with precore mutations were not, indicating that HBV harboring precore mutation was less sensitive to IFN in cell culture system. CONCLUSION: These data indicate that HBV harboring precore mutation may be resistant to IFN in vitro.

Antiviral Agents↗
PubMed1997

Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa.

BACKGROUND & AIMS: Mutations in hepatitis C virus (HCV) nonstructural protein 5A (NS5A) may correlate with response to interferon in Japanese patients with chronic hepatitis C. The aim of this study was to examine whether these findings could be expanded to European patients infected with genotypes associated to low (1b) or high (3a) response rates. METHODS: Pretreatment serum samples of 66 patients with chronic HCV infection, 48 infected with genotype 1b and 18 with 3a, were analyzed. RESULTS: Among patients infected with genotype 3a, 1 of 7 long-term responders and none of 11 nonresponders showed NS5A amino acid mutations. Among patients infected with genotype 1b, all 7 long-term responders, but also 27 of 41 nonresponders, showed NS5A mutations. There was no correlation between number of mutations and response to therapy. In 10 patients, sequences obtained before and after treatment were compared and failed to show any change. Serum HCV RNA levels did not differ between patients with and without mutations in NS5A sequence. CONCLUSIONS: No significant correlation was found in patients infected with genotypes 1b or 3a between NS5A sequence and response to interferon alfa. NS5A mutations do not correlate with viral load. Changes in this region were not found during interferon alfa treatment.

Adult↗
PubMed1996

Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype.

Eight zidovudine-experienced subjects received zidovudine and didanosine for 30 weeks followed by 30 weeks of didanosine monotherapy. At study entry, plasma from 4 subjects had human immunodeficiency virus RNA pol T215Y/F mutant and 4 had codon 215 wild type. All 8 subjects had non-syncytium-inducing virus phenotype. Sustained 10-fold decreases in plasma RNA levels were seen only in subjects who initially had 215 wild type RNA, despite the development of a T215Y/F mutation during combination therapy. Virologic and immunologic benefits were maintained in this group with didanosine monotherapy. No subject developed a pol L74V codon mutation. Significant differences in plasma virus load and CD4 cell responses were seen in this zidovudine-didanosine combination pilot study relative to codon 215 genotype.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate.

BACKGROUND: The long-term impact of tenofovir disoproxil fumarate (TDF) on hepatitis B virus (HBV) replication has not yet been studied in HIV-HBV-co-infected patients. METHODS: We conducted a prospective study of HBV-DNA decay kinetics in 28 HIV-HBV-co-infected patients treated by TDF. HBV dynamics were studied using mixed linear models, and baseline factors affecting them were analysed using Cox models. RESULTS: The HBV-DNA load declined by a mean of 4.6 log copies/ml during follow-up (mean 71 weeks), and fell below the detection limit (200 copies/ml) in 21 patients. Inhibition of viral replication by TDF was associated with a decrease in alanine aminotransferase levels (125 versus 68 IU, P < 0.05). HBV-DNA decay was biphasic, with an rapid fall followed by a gradual decline. Baseline factors associated with a steeper first slope in the HBV-DNA decrease were high HBV load, positive hepatitis B e antigen (HBeAg) and YMDD mutations. Baseline factors increasing the time to reach an HBV-DNA level less than 200 copies/ml were high HBV load (150 days when HBV-DNA < 10 log, 316 days when HBV-DNA > 10 log) and positive HBeAg. Previous exposure to lamivudine or TDF-lamivudine did not modify HBV-DNA decrease under therapy in this population with a high prevalence of YMDD mutations. CONCLUSION: The long-term decline in HBV DNA under TDF is biphasic and is primarily influenced by the initial HBV load. However, the clinical significance of such an association remains moderate, and TDF can be efficiently included in the highly active antiretroviral therapy regimen of HIV-HBV-co-infected patients, regardless of HBV strains and their degree of replication.

Adenine↗
PubMed2003

Importance and detection of virus reservoirs and compartments of HIV infection.

Current therapies for treating HIV-1 infection are capable of suppressing virus load in blood to undetectable levels, and result in marked clinical improvement. Despite this suppression, HIV-1 infection persists and virus load quickly rebounds when therapy is interrupted. The origin of the rebounding virus is unknown, but is thought to result from continuing viral replication in anatomic or cellular compartments, and the release of virus from latent infection in reservoirs.

HIV Infections↗
PubMed2002

Degenerate specificity of HTLV-1-specific CD8+ T cells during viral replication in patients with HTLV-1-associated myelopathy (HAM/TSP).

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1 infection, in which HTLV-1-infected CD4(+) T cells and HTLV-1-specific CD8(+) T cells may play a role in the disease pathogenesis. Patients with HAM/TSP have high proviral loads despite vigorous virus-specific CD8(+) T-cell responses; however, it is unknown whether the T cells are efficient in eliminating the virus in vivo. To define the dynamics of HTLV-1-specific CD8(+) T-cell responses, we investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes in an immunodominant viral epitope, frequency of HTLV-1-specific T cells, and degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the frequency and the degeneracy of the HTLV-1-specific CD8(+) T cells correlated well with proviral load in the longitudinal study. The proviral load was much higher in a patient with low degeneracy of HTLV-1-specific T cells compared to that in a patient with comparable frequency but higher degeneracy of the T cells. Furthermore, in a larger number of patients divided into 2 groups by the proviral load, those with high proviral load had lower degeneracy of T-cell recognition than those with low proviral load. Sequencing analysis revealed that epitope mutations were remarkably increased in a patient when the frequency and the degeneracy were at the lowest. These data suggest that HTLV-1-specific CD8(+) T cells with degenerate specificity are increased during viral replication and control the viral infection.

Amino Acid Substitution↗
PubMed1998

Molecular genetic basis of hypertrophic cardiomyopathy: genetic markers for sudden cardiac death.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. The disease is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. A large number of mutations in genes coding for the beta-myosin heavy chain (beta-MyHC), cardiac troponin T (cTnT), cardiac troponin I, alpha-tropomyosin, myosin binding protein C (MyBP-C), and myosin light chain 1 and 2 in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. The Gly256Glu, Val606Met, and Leu908Val mutations in the beta-MyHC are associated with a benign prognosis. In contrast, Arg403Gln, Arg719Trp, and Arg453Cys mutations are associated with a high incidence of sudden cardiac death (SCD). Mutations in cTnT are associated with a mild degree of hypertrophy, but a high incidence of SCD. Mutations in MyBP-C are associated with mild hypertrophy and a benign prognosis. However, it has become evident that factors other than the underlying mutations, such as genetic background and possibly environmental factors, also modulate phenotypic expression of HCM.

Cardiomegaly↗
PubMed2005

Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.

How the replication machinery is loaded at origins of DNA replication is poorly understood. Here, we implicate in this process the Xenopus laevis homolog (xRTS) of the RECQL4 helicase mutated in Rothmund-Thomson syndrome. xRTS, which bears homology to the yeast replication factors Sld2/DRC1, is essential for DNA replication in egg extracts. xRTS can be replaced in extracts by its human homolog, while RECQL4 depletion from mammalian cells induces proliferation failure, suggesting an evolutionarily conserved function. xRTS accumulates on chromatin during replication initiation, after prereplication-complex (pre-RC) proteins, Cut5, Sld5, or Cdc45 but before replicative polymerases. xRTS depletion suppresses the loading of RPA, the ssDNA binding protein that marks unwound origins before polymerase recruitment. However, xRTS is unaffected by xRPA depletion. Thus, xRTS functions after pre-RC formation to promote loading of replication factors at origins, a previously unrecognized activity necessary for initiation. This role connects defective replication initiation to a chromosome-fragility disorder.

Adenosine Triphosphatases↗
PubMed2003

Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations.

Loss of function mutations in the small heterodimer partner (SHP) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies. Two common polymorphisms, G171A and -195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort, G171A and -195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated with higher BMI (P < 0.05) and waist circumference (P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load (P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.

Adipose Tissue↗
PubMed2001

Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations.

Direct sequencing of the pol gene was assessed retrospectively with protease inhibitor susceptibility in a longitudinal study. A total of 134 samples from 26 patients were analysed at regular intervals up to 2 years. Patients were included in virological failure despite indinavir, ritonavir or saquinavir based triple-drug therapy. Both the type and number of certain secondary protease mutations modulated the effect of primary mutations on phenotypic resistance. This was notably applicable to L101/V, and to lesser extents to A711V/T. However, combinations of primary mutations, including 154V could predict resistance to the drug used and nelfinavir in more than 80%. In contrast, in vitro cross-resistance to amprenavir was rarely encountered. In addition, there was a relationship between a higher number of key mutations and poorer virological and clinical outcomes, respectively, from 6 and 3 months on. The key mutations were the protease mutations independently conferring phenotypic resistance and/or the reverse transcriptase mutations predicting treatment outcome. This relationship was independent from drug history, viral load and CD4 cell count measurements. In summary, even on a small sample size, sequence-based genotyping seems to be a good prognostic marker when performed longitudinally. In the context of primary resistance mutations, including additional secondary mutations, it may be useful in the prediction of phenotypic and clinical resistance. This should be assessed to optimize treatment monitoring before emergence of broadly cross-resistant virus.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Evaluation of NucliSens EasyQ HIV-1 assay for quantification of HIV-1 subtypes prevalent in South-east Asia.

BACKGROUND: Monitoring anti-retroviral therapy requires that viral load assays for human immunodeficiency virus type 1 (HIV-1) be applicable to diverse HIV-1 subtypes. OBJECTIVES: To evaluate NucliSens EasyQ HIV-1 assay for quantitation of common HIV-1 subtypes prevalent in South-east Asia. STUDY DESIGN: One hundred and nineteen plasma samples collected in Hong Kong and Cambodia were used to compare the performance of NucliSens EasyQ HIV-1 and COBAS Amplicor HIV-1 Monitor version 1.5 assays. Viral RNA extracted from the NucliSens MiniMAG was also used for HIV-1 subtyping. RESULTS: Performance of NucliSens EasyQ correlated well with COBAS Amplicor (r=0.777, p<0.001) and the small mean difference (0.0462log(10)IU/mL) obtained in the Bland and Altman model indicated good agreement between two assays. The NucliSens EasyQ assay demonstrated a 95% sensitivity at 500IU/mL and 100% specificity. Reproducibility of this assay was within log(10)2-4IU/mL and had a coefficient of variation between 2.3% and 10.4%. Among the 109 specimens included in the analysis, HIV-1 subtyping identified 64 CRF01_AE, 38 subtype B, 3 subtype C, 3 CRF07_BC and 1 subtype G viruses. CONCLUSIONS: Performance of NucliSens EasyQ was comparable to COBAS Amplicor for HIV-1 viral load monitoring. RNA extracts from NucliSens MiniMAG could be used for HIV-1 viral load monitoring, subtyping and drug resistance mutations detection. Our findings highlight the versatility of both NucliSens EasyQ and COBAS Amplicor in monitoring prevalent subtypes and rare circulating recombinant forms (CRFs) in the South-east Asia region.

Cambodia↗
PubMed2003

Mutation accumulation in growing asexual lineages.

The stochastic loss of entire classes of individuals bearing the fewest number of mutations-a process known as Muller's ratchet-is studied in asexual populations growing unconstrained from a single founder. In the neutral regime, where mutations have zero effect on fitness, we derive a recursion equation for the probability distribution of the minimum number of mutations carried by individuals in the least-loaded class, and obtain an explicit condition for the halting of the ratchet. Next, we consider the case of deleterious mutations, and show that weak selection can actually accelerate the ratchet beyond that achieved for the neutral regime. This effect is transitory, however, as our results suggest that even weak purifying selection will eventually lead to the complete cessation of the ratchet. These results may have important implications for problems in biology and the medical sciences.

Models, Genetic↗