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Results for “mutation load”

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PubMed2000

TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice.

The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

Activating Transcription Factor 6↗

PubMedDate not supplied

[Defect in lytic granule exocytosis: several causes, a same effect].

An in vivo disturbance of lymphocyte homeostasis occurs during the course of the hemophagocytic syndrome (HS). HS is a severe and often fatal syndrome resulting from potent and uncontrolled activation and proliferation of T-lymphocytes, mainly polyclonal CD8 lymphocytes, leading to excessive macrophage activation, high level of proinflammatory cytokine production and multiple deleterious effects. The onset of HS characterizes several inherited disorders in humans. In most of these conditions, the molecular defect impairs the granule-dependent cytotoxic activity of lymphocytes, thus highlighting the determinant role of this function in driving back the immune system to a state of equilibrium following infection. Several lines of evidence suggest that an increase in the expansion phase rather than a decrease in the contraction phase of the CD8+ T cells population characterizes the HS. Failure to kill antigen presenting cells through a transaction mechanism of cytotoxic cells should favor a sustained response, although the mechanism may be more complex than simple decrease of antigen load. Defect in the granule dependent cytotoxic function of lymphocytes result from perforin mutation in familial hemophagocytic lymphohistiocytosis type 2, from Munc13-4 (UNC13D) mutation in familial hemophagocytic lymphohistiocytosis type 3, from Rab27a mutation in Griscelli syndrome type 2, and from CHS/LYST mutation in Chediak-Higashi syndrome. The characterization of the molecular causes leading to these conditions identified Rab27a and Munc13-4 as two critical effectors of the exocytic machinery, required for the terminal transport/docking or priming of the cytotoxic granules, respectively. Different members of the Rab and Munc13 family of proteins are also used in neurotransmitter release at the neurological synapse, highlighting the similarity of the mechanisms regulating both secretory pathways. Future investigations regarding HS will continue to elucidate this exocytic pathway machinery and improve our understanding of how it finely regulates the immune response, an area that is likely to be useful for therapeutic intervention.

Cytoplasmic Granules↗

PubMed2006

The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment.

The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass. Loss-of-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. Lrp5-null (Lrp5-/-) mice exhibited significantly lower bone mineral density and decreased strength. The osteogenic response to mechanical loading of the ulna was reduced by 88 to 99% in Lrp5-/- mice, yet osteoblast recruitment and/or activation at mechanically strained surfaces was normal. Subsequent experiments demonstrated an inability of Lrp5-/- osteoblasts to synthesize the bone matrix protein osteopontin after a mechanical stimulus. We then tested whether Lrp5-/- mice increased bone formation in response to intermittent parathyroid hormone (PTH), a known anabolic treatment. A 4-week course of intermittent PTH (40 microg/kg/day; 5 days/week) enhanced skeletal mass equally in Lrp5-/- and Lrp5+/+ mice, suggesting that the anabolic effects of PTH do not require Lrp5 signaling. We conclude that Lrp5 is critical for mechanotransduction in osteoblasts. Lrp5 is a mediator of mature osteoblast function following loading. Our data suggest an important component of the skeletal fragility phenotype in individuals affected with osteoporosis-pseudoglioma is inadequate processing of signals derived from mechanical stimulation and that PTH might be an effective treatment for improving bone mass in these patients.

Anabolic Agents↗

PubMed1996

Human T cell leukemia virus type I (HTLV-I) molecular genotypes and disease outcome.

The approach taken in our laboratory to determine viral markers associated with human T cell leukemia virus type I (HTLV-I) disease induction was to compare viral genomes and host immune responses from HTLV-I-infected patients from two geographical areas with significant differences in the incidence rate of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM), Tumaco, Colombia, and Kyushu Island, Japan. These studies showed that TSP/HAM patients have higher antibody levels against viral antigens and a higher proviral load compared to asymptomatic carriers and adult T cell leukemia (ATL) patients. A mutation in the tax gene was found to be associated with TSP/HAM, which in turn correlates with a higher transactivation activity of Tax. In addition, we found that HTLV-I-infected individuals contain infected cells that are clonally expanded. The genomic structure of these expanded clones shows that defective proviruses are present in asymptomatic carriers. A predilection in the defectiveness, however, was found to correlate with the presence (Cosmopolitan molecular genotype) or absence of the tax mutation (Japanese molecular genotype). Our results suggest that defective proviruses retaining structural genes might be a risk factor for TSP/HAM development. Contrary, defective proviruses retaining regulatory genes in the pX region could be a risk factor for ATL development. The molecular mechanism by which these defective proviruses is generated and expressed should give new insight into HTLV-I pathogenesis.

Clone Cells↗

PubMed2006

Broad cellular immunity with robust memory responses to simian immunodeficiency virus following serial vaccination with adenovirus 5- and 35-based vectors.

Adenovirus serotype 35 (Ad35) is a promising vaccine platform for human immunodeficiency virus (HIV) infection and emerging infectious diseases as it is uncommon in humans worldwide and is distinct from Ad5, the major vaccine serotype for which many individuals have pre-existing immunity. The immunogenicity of a first-generation, replication-competent Ad35-based vaccine was tested in the simian immunodeficiency virus (SIV) rhesus macaque model by evaluating its capacity to boost immunity generated by Ad5-based vectors. A series of four immunizations with replication-defective Ad5 vectors expressing SIVmac239 gag induced high-frequency responses mediated by both CD8(+) and CD4(+) T cells directed against several epitopes. Ad5-specific neutralizing antibody responses that did not neutralize Ad35 were rapidly induced but waned over time. Subsequent immunization with Ad5-based vectors was minimally effective, whereas immunization with Ad35-based vectors generated a strong increase in the frequency of Gag-specific T cells with specificities that were unchanged. While this boosting response was relatively transient, challenge with the distinct pathogenic isolate SIV/DeltaB670 generated robust and selective recall responses to Gag with similar specificities as induced by vaccination that were elevated for 25 weeks relative to controls. Vaccination had measurable albeit minor effects on virus load. Unexpectedly, regional hypervariability within the Gag sequence of SIV/DeltaB670 was associated with mutation of the conserved CD8(+) T-cell epitope CM9 without concurrent flanking mutations and in the absence of immune pressure. These findings support the further development of Ad35 as a vaccine vector, and promote vaccine regimens that utilize serial administration of heterologous adenoviruses.

Adenoviruses, Human↗

PubMed2002

Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out.

Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P <.001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P <.001).

Animals↗

PubMed2005

Effects on immunological and virological outcome of patients using one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor in a triple antiretroviral therapy: normal clinical practice versus clinical trial findings.

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Adult↗

PubMed2000

Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study. CAESAR co-ordinating committee.

OBJECTIVES: Lamivudine has potent activity against HIV-1 and hepatitis B virus (HBV). Co-infection with these two viruses is common, and this may therefore influence the choice of antiretroviral therapies. A cohort of co-infected patients treated with lamivudine were studied in order to evaluate the differential effects of lamivudine on the two viral populations within the same individual after 44-52 weeks of therapy. DESIGN AND METHODS: Retrospective virological analysis of an HIV-1/HBV co-infected lamivudine cohort derived from a randomized, placebo-controlled study of lamivudine in HIV infection, the CAESAR study. RESULTS: Five of thirteen patients with HBV viral load > 10,000 copies/ml after 44-52 weeks of lamivudine therapy had genotypic drug resistance. Four of these five had a rebound of viral replication over the period of study and in one case this was associated with an alanine transaminase serum elevation. Ten of the thirteen patients had a 44-52 week HIV viral load > 1000 copies/ml, all of whom also had HIV reverse transcriptase M184V or M184I mutations. CONCLUSIONS: Extrapolating these results to the population yields an estimated 1-year incidence of drug-resistant HBV of at least 14% in lamivudine-treated HIV-1/HBV co-infected patients. The clinical and virological benefit of HBV lamivudine monotherapy in co-infected patients should be balanced against the potential for emergence of drug resistance. Further, these data suggest that the determinants of HIV and HBV drug resistance are different and that parallel evolution, rather than co-evolution of HBV and HIV-1 in co-infected individuals occurs.

CD4 Lymphocyte Count↗

PubMed1975

Population genetic studies in bees (APIDAE, Hymenoptera). I. Genetic load.

Three populations of Apis mellifera each predominantly of a different subspecies (mellifera, ligustica and adansonii) and 7 species of stingless bees (Meliponinae, Apidae) were manipulated for applying the MORTON, CROW & MULLER's methodology in order to estimate the lethal equivalents (B) of each population. A total of 249 queens were used, 27 being meliponids and 222 Apis mellifera. The populations of Apis have a B that does not differ significantly when they are compared to each other (1.29, 1.36, 1.32) and the balanced average equals 1.33. When the x-alleles are not considered, this balanced value is 0.262. The figures for B in the seven species of stingless bees ranged between 0.104 and 0.159 with balanced average of 0.132. The main reason for this smaller load in meliponids may rest in their effective population numbers, which are smaller than those of Apis. The average mortality for diploid females (0.141) and for haploid males (0.163) allows the estimation of the total elimination (sigma E = 0.073). Since for haplo-diploid systems the total mutation rate is sigma mu = 2 sigma E divided by 3 the figure 0.048 is obtained. Since about 15% of the genes in Apis mellifera are sex limited, this value of sigma mu should be added of 0.0072 (that is 0.15 X 0.048) and then, the total mutation rate becomes 0.055. Using a quite different method, the one by MORTON, CROW & MULLER, the figure 0.076 was obtained. If a mutation rate of 10(-5) is assumed, the number of genes in Apis mellifera that can make a contribution to the genetic load would vary between 5,500 and 7,600.

Animals↗

PubMed2002

The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.

Nicastrin regulates gamma-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid beta secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD (n=116) and LOAD (n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE epsilon4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2-13.3; P=.01). These results are compatible with an important role of gamma-secretase dysfunction in the etiology of familial EOAD.

Age of Onset↗

PubMed2002

Mechanical properties of skeletal bone in gene-mutated stöpsel(dtl28d) and wild-type zebrafish (Danio rerio) measured by atomic force microscopy-based nanoindentation.

An atomic force microscopy (AFM)-based nanoindenter was used to evaluate the mechanical properties of skeletal bones in wild-type and gene-mutated zebrafish (Danio rerio), stöpsel(dtl28d). Both skeletons were isolated from adult zebrafish and tested under a load of 5 mN. It was found that stp/stp bone has a similar nanohardness but significantly greater elastic modulus compared with that of wild-type bone. The residual indenter impressions using AFM and the fracture surfaces of both bones using scanning electron microscopy were examined and showed that the bone of zebrafish becomes more brittle after the stp mutation. This first observation of the alteration of bone mechanical behavior by gene mutation in zebrafish system is of scientific and clinical relevance to many areas of study, such as bone fracture and fragility mechanisms in human heritable disorders and bone-materials fabrication via gene engineering.

Animals↗

PubMed2006

Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa.

OBJECTIVES: To evaluate virologic response up to 48 weeks, and emergence of HIV-1 resistance mutations at 24 weeks, in therapy-naive adults initiating zidovudine/lamivudine/tenofovir DF. DESIGN: : A cohort within the DART trial. METHODS: Plasma HIV-1 RNA was assayed in 300 adults with baseline CD4 cell count < 200 cells/mul from sites in Uganda and Zimbabwe using the Roche Amplicor assay v1.5. Samples with HIV-1 RNA > 1000 copies/ml at 24 weeks were sequenced in the pol region. RESULTS: Median baseline CD4 cell count was 101 cells/mul and HIV-1 RNA 279,910 copies/ml (mean, 5.4 log10). At 48 weeks, 61% (165/272) had HIV-1 RNA < 50 and 72% (196/272) < 400 copies/ml, compared with 59% (167/281) and 79% (221/281) at 24 weeks. At 24 and 48 weeks, 15 and 24% respectively had HIV-1 RNA > 1000 copies/ml (6 and 17% > 10 000 copies/ml), and mean CD4 cell count increases were 103 and 127 cells/mul, respectively. Higher baseline CD4 cell count was the most important predictor of virological suppression at 48 weeks, with little effect of baseline viral load. Eighteen of 20 genotypes from week 24 samples with HIV-1 RNA > 1000 copies/ml showed key resistance mutations in reverse transcriptase. Fourteen had M184V [10 with one to four additional nucleoside analogue mutations (NAMs)]; one had three NAMs only; and the remaining three had K65R. One participant with M184V had major non-nucleoside reverse transcriptase inhibitor-associated mutations, despite no disclosed treatment with this class. CONCLUSION: Zidovudine/lamivudine/tenofovir has good virological efficacy in advanced HIV disease. In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often.

Adenine↗

PubMed2003

Similar Ca(2+)-signaling properties in keratinocytes and in COS-1 cells overexpressing the secretory-pathway Ca(2+)-ATPase SPCA1.

Mutations in the ubiquitously expressed secretory-pathway Ca(2+)-ATPase (SPCA1) Ca(2+) pump result in Hailey-Hailey disease, which almost exclusively affects the epidermal part of the skin. We have studied Ca(2+) signaling in human keratinocytes by measuring the free Ca(2+) concentration in the cytoplasm and in the lumen of both the Golgi apparatus and the endoplasmic reticulum. These signals were compared with those recorded in SPCA1-overexpressing and control COS-1 cells. Both the sarco(endo)plasmic-reticulum Ca(2+)-ATPase (SERCA) and SPCA1 can mediate Ca(2+) uptake into the Golgi stacks. Our results indicate that keratinocytes mainly used the SPCA1 Ca(2+) pump to load the Golgi complex with Ca(2+) whereas the SERCA Ca(2+) pump was mainly used in control COS-1 cells. Cytosolic Ca(2+) signals in keratinocytes induced by extracellular ATP or capacitative Ca(2+) entry were characterized by an unusually long latency reflecting extra Ca(2+) buffering by an SPCA1-containing Ca(2+) store, similarly as in SPCA1-overexpressing COS-1 cells. Removal of extracellular Ca(2+) elicited spontaneous cytosolic Ca(2+) transients in keratinocytes, similarly as in SPCA1-overexpressing COS-1 cells. With respect to Ca(2+) signaling keratinocytes and SPCA1-overexpressing COS-1 cells therefore behaved similarly but differed from control COS-1 cells. The relatively large contribution of the SPCA1 pumps for loading the Golgi stores with Ca(2+) in keratinocytes may, at least partially, explain why mutations in the SPCA1 gene preferentially affect the skin in Hailey-Hailey patients.

Animals↗

PubMed2004

Thrombotic microangiopathy associated with unusual viral sequences in HIV-1-positive patients.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare disorder caused by endothelial cell damage. TMA has been associated with the human immunodeficiency virus 1 (HIV-1) infection, yet only a minority of all HIV-1 patients develops TMA. Since HIV-1 has been shown to interact with endothelial cells, we investigated whether certain mutations in the HIV-1 envelope protein are associated with the development of TMA in HIV-1-infected patients. METHODS: Plasma was obtained from nine HIV-1-positive patients with TMA. Viral loads were determined from the samples and compared with the clinical data. Viral envelope protein sequences from the regions known to be responsible for viral tropism were isolated, sequenced and compared with known HIV-1 isolates. The isolates were expressed as synthetic fusion proteins; binding of these fusion proteins to CD4+ cells as well as to endothelial cell lines was investigated. RESULTS: The viral loads in patients with HIV/TMA were highly variable with no correlation to the clinical status. Most patients carried macrophage-tropic viral envelope protein sequences and an unusual insertion was found in the V2 variable region. The isolates showed increased CD4 binding, but a direct binding to endothelial cells was not observed. CONCLUSIONS: Although TMA is generally diagnosed in patients with advanced HIV-1 infection, viral loads per se were not predictive of TMA in this study. While a direct interaction with endothelial cells was not detectable, specific viral envelope mutations were found in a region known to influence viral tropism. Hence, viral-specific factors might contribute to the pathogenesis of HIV-associated TMA.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Influence of a monocyte chemoattractant protein 1 mutated allele on the response to protease inhibitor-based antiretroviral therapy.

BACKGROUND: Antiretroviral drug efficacy has been widely studied in relation to viral factors. Mutations in the HIV co-receptors and their natural chemokines, however, may be critical in HIV infection and treatment response. We compared the efficacy of protease inhibitor (PI) treatment among PI-naïve patients grouped according to whether they carried the chemokine CC motif receptor 2 (CCR-2) 64I and monocyte chemoattractant protein 1 (MCP-1)-2518G alleles. METHODS AND RESULTS: HIV-infected patients who were PI-naive were selected for the study (n=164) but there was no restriction on lymphocyte CD4 count or plasma HIV viral load. Follow-up was for the first 24 months of treatment. Clinical and laboratory data were obtained every 3 months. All the participants were genotyped for the MCP-1-2518G, CCR-2 64I, CCR-5Delta32 and stromal derived factor 1 (SDF1) 3'A mutated alleles. The results indicated that patients carrying the mutated allele of MCP-1 had a higher mean CD4 cell count throughout the follow-up period than those with the common allele (P=0.01). Also, patients with the MCP-1 and CCR-2 mutated alleles were more likely to continue to have an undetectable viral load following treatment (P=0.05). CONCLUSION: A better response to PI treatment appears to be conferred by mutations in the host MCP-1 and CCR-2 genes, and may be related to the cellular axis-of-entry used by the retrovirus.

Adult↗

PubMed2000

Mutagenicity of diesel exhaust particles from two fossil and two plant oil fuels.

Particulate matter of diesel engine exhaust from four different fuels was studied for content of polynuclear aromatic compounds and mutagenic effects. Two so-called biodiesel fuels, rapeseed oil methylesters (RME) and soybean oil methylesters (SME), were compared directly with two fossil diesel fuels with the normal (DF) and a low sulfur content (LS-DF). Diesel exhaust particles were sampled on filters from the diluted and cooled exhaust of a test engine at five different speeds and loads. Filters were weighed for total particulate matter, Soxhlet extracted with dichloromethane and the content of insoluble material determined. The soluble organic fraction was analysed for polynuclear aromatic compounds. Mutagenicity was determined using the Salmonella typhimurium/mammalian microsome assay with strains TA98 and TA100. Compared with DF, the exhaust particles of LS-DF, RME and SME contained less insoluble material, which consisted mainly of the carbon cores of diesel exhaust particles. The concentrations of individual polynuclear aromatic compounds varied widely among the different exhaust extracts, but total concentrations of the compounds were approximately double for DF and SME compared with LS-DF and RME. In TA98 significant increases in mutation rates were obtained for the soluble organic fractions of all fuels for engines running at full speed (load modes A and D), but for DF revertants were 2- to 10-fold more frequent as compared with LS-DF, RME and SME. Revertant frequencies for DF and partly for LS-DF were also elevated in TA100, while RME and SME gave no significant increase in mutations. The results indicate that diesel exhaust particles from RME, SME and LS-DF contain less black carbon and total polynuclear aromatic compounds and are significantly less mutagenic in comparison with DF. A high sulfur content of the fuel and high engine speeds (rated power) and loads are associated with an increase in mutagenicity of diesel exhaust particles.

Chromatography, High Pressure Liquid↗

PubMed1997

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors.

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.

Adult↗

PubMed2006

Antiretroviral activity of didanosine in patients with different clusters of reverse transcriptase mutations.

Patterns of mutations associated with didanosine (ddI) resistance are still a controversial issue. The correlation between different clusters of reverse transcriptase mutations with the short-term virological activity of ddI when added to a failing regimen was examined in 40 patients. The median fall in plasma viral load at week 4 was 0.67 log10 copies/ml. There was good correlation between the median fall in plasma HIV RNA levels and the number of nucleoside-associated (P = 0.0152) or thymidine-associated (P = 0.0142) mutations. In conclusion, ddI retained substantial antiretroviral activity when the number of nucleoside-associated or thymidine-associated mutations was less than four.

Didanosine↗