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Biomedical subjects

H Agut

Publications and source records attributed to H Agut.

At least 37 records · Page 2Linked to original sources
PubMed2000

Human herpesvirus-6 and human herpesvirus-7 in the bone marrow from healthy subjects.

BACKGROUND: Human herpesviruses (HHVs) 6 and 7 are recently discovered betaherpesviruses. Although HHV-6 has been associated with disordered hematopoiesis in bone marrow transplant recipients, little information is available on the presence of both viruses in the bone marrow from healthy subjects. METHODS: We detected HHV-6 and HHV-7 DNA by means of polymerase chain reaction in bone marrow and peripheral blood samples from 18 healthy subjects who underwent total hip arthroplasty. RESULTS: Genomic HHV-6 and HHV-7 DNA were detected in 11% and 67% of the blood samples, respectively, and in 28% and 50% of the bone marrow samples, respectively. CONCLUSIONS: Both viruses may be present in the bone marrow without hematopoiesis disorder and can be transmitted through bone marrow infusion. Therefore, the causative role of these two viruses in some bone marrow diseases cannot be inferred simply from the detection of their genome in bone marrow by means of polymerase chain reaction.

Adult↗
PubMed2000

Acyclovir-resistant bilateral keratitis associated with mutations in the HSV-1 thymidine kinase gene.

PURPOSE: To evaluate the contribution of molecular methods for the diagnosis of an acyclovir-resistant HSV-1 bilateral keratitis in an AIDS patient and to report a new point mutation in the nucleotide sequence of the thymidine kinase (tk) gene involved. METHODS: A 31 year old HIV-positive female presented with severe, active, bilateral and sight-threatening keratitis of 6 months duration, which was treated unsuccessfully with acyclovir. After corneal biopsy, samples were analysed by standard virological procedures, in situ hybridization, and PCR. The tk gene was cloned and subsequently sequenced. RESULTS: Conventional virological methods remained inconclusive. However, in situ hybridization and PCR rapidly confirmed the diagnosis of HSV-1 keratitis. The tk gene sequence revealed the presence of five variations previously described in two reference strains, but also a new point mutation at nucleotide position 431 which leads to an amino-acid change at position 144 that supported the hypothesis of a putatively altered functional form of the enzyme. Intravenous foscarnet treatment in an induction regimen was effective and cicatrization occurred within 3 weeks. CONCLUSIONS: PCR and in situ hybridization are effective and powerful techniques when other virological procedures are non-contributive, particularly in immunocompromised patients previously treated with antiviral drugs. The new point mutation identified in the tk gene may be associated with resistance to acyclovir.

AIDS-Related Opportunistic Infections↗
PubMed2000

Comparative analysis of translation efficiencies of hepatitis C virus 5' untranslated regions among intraindividual quasispecies present in chronic infection: opposite behaviors depending on cell type.

Hepatitis C virus (HCV) RNA translation initiation is dependent on the presence of an internal ribosome entry site (IRES) that is found mostly in its 5' untranslated region (5' UTR). While exhibiting the most highly conserved sequence within the genome, the 5' UTR accumulates small differences, which may be of biological and clinical importance. In this study, using a bicistronic dual luciferase expression system, we have examined the sequence of 5' UTRs from quasispecies characterized in the serum of a patient chronically infected with HCV genotype 1a and its corresponding translational activity. Sequence heterogeneity between IRES elements led to important changes in their translation efficiency both in vitro and in different cell cultures lines, implying that interactions of RNA with related transacting factors may vary according to cell type. These data suggest that variants occasionally carried by the serum prior to reinfection could be selected toward different compartments of the same infected organism, thus favoring the hypothesis of HCV multiple tropism.

5' Untranslated Regions↗
PubMed2000

[Conditions of "thymidine analog mutations" (TAMs) in naive patients treated with different combinations of d4T].

Recently, d4T/ddI combination has been associated with the selection of thymidine analogue mutations (TAMs) in 50% of patients with a detectable viral load after 6 to 12 months of this bi-therapy (ALBI, STADI and BMS A1460 tests). We evaluated the rate of selection of the TAMs in naive patients with a viral load of > 200 copies/mL after: 6 months to 1 year of d4T/3TC bi-therapy (group 1); 1 year or more of a treatment including d4T/3TC (group 2); and more than 6 months of tri-therapy including d4T/ddI (group 3). The reverse transcriptase gene has ben studied in 33 patients in group 1, 17 patients in group 2 and ten patients in group 3. For the latter patients, the tri-therapies were as follows: d4T/ddI/PI (n = 5), d4T/ddI/NNRTI (n = 4), d4T/ddI/NRTI (n = 1). For the group 1 patients, at baseline, two patients already had TAMs. At M6, all the patients acquired the 3TC-associated mutations, M184V. Only one patient selected a MDR mutation profile (F116Y, Q151M). At M12, 26 of 33 plasmas were analysed. Only one patient selected one TAM (T215Y). For the group 2 patients, only three patients selected TAMs after more than 30 months of treatment. For the group 3 patients, at baseline, only one patient already harbored TAMs. None of the other patients had selected TAMs. In patients who received d4T/ddI/3TC, only the M184V, the 3TC-associated mutation, was selected. In conclusion, stavudine in association with 3TC selected a low rate of TAMs; in patients receiving a treatment including d4T/3TC, time of exposure to stavudine seemed to be an important parameter for the selection of TAMs; and in contrast to results obtained on d4T/ddI, tri-therapies including d4T/ddI did not select any TAMs, whatever the combination (NRTI, NNRTI, PI).

Anti-HIV Agents↗
PubMed1999

Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen.

OBJECTIVES: We evaluated the parameters influencing CD4 cell reconstitution after the introduction of highly active antiretroviral therapies in real life, as well as the frequency and the determinants of the discrepancies occurring between virus and CD4 cell count evolution. DESIGN AND METHODS: A total of 317 pre-treated patients starting a protease inhibitor (PI)-containing regimen were prospectively followed for 2 years on an intent-to-treat basis for CD4 cell counts and viral loads. RESULTS: The CD4 cell counts rapidly increased from baseline (50/mm3) by a median of 50/mm3 at month 2 (+0.72 CD4 cells/mm3/day) and up to 137/mm3 at the last follow-up (second slope: +0.16 CD4 cells/mm3/day). Two independent major factors among five parameters tested significantly affected the first phase, which was negatively correlated to the slope of CD4 cell decline before PI initiation, and was positively correlated to baseline CD4 cell counts (P = 0.0001); the second phase was mostly affected by the mean viral load reduction over time (P = 0.0001). Paradoxical CD4 cell reconstitution (15% of cases) was defined by a rapid or slow CD4 cell increase contrasting with a minor or strong viral reduction, respectively. The role of previous CD4 cell decline and the low effect of viral load reduction during the first 2 months explain the early paradoxical CD4 cell responses. The major influence of viral load reduction on the long-term reconstitution, however, reduces such paradoxical responses at 2 years. CONCLUSIONS: Early paradoxical CD4 cell reconstitution after the introduction of a PI are explained by the major influence of previous disease progression on the early CD4 cell increase, whereas the magnitude of viral load reduction over time reduces such paradoxical evolutions in the long term.

Adult↗
PubMed1999

HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. Comet Study Group.

BACKGROUND: Potent antiretroviral therapy (ART) with a protease inhibitor-based regimen is commonly used to treat HIV-1-infected patients. Transient treatment interruptions because of drug intolerance or other reasons are not uncommon. HIV-1 dynamics during therapy interruption and its consequences for the subsequent reinitiation of therapy have not been properly studied. METHODS: Ten antiretroviral-naive, HIV-1-infected subjects (mean baseline CD4 cell count of 414 cells/mm3 and plasma viral load of 4.8 log10 copies/ml) were treated with the triple drug ART regimen indinavir/zidovudine/lamivudine for 28 days. Therapy was then interrupted for 28 days, after which the same ART regimen was re-started. RESULTS: HIV-1 in plasma declined during the first 7 days of therapy with T1/2 of 1.5 days, and during days 7-28 with T1/2 of 8.9 days. Once therapy was interrupted, a delay of 4-7 days was observed in all subjects, preceding a rapid viral rebound with a mean doubling time of 1.6 days. Mean viral load after 28 days of interruption was 96% of baseline. Upon reinitiation of the same ART regimen, viral load declined at rates similar to those observed during the initial therapy (T1/2 of 1.6 and 8.0 days, respectively). No resistance-conferring mutations were observed in the HIV-1 reverse transcriptase (RT) and protease regions after the interruption of therapy. Plasma viral loads were maintained below 200 copies/ml in subjects continuing therapy for 4 (n = 9) to 12 (n = 5) months, with a mean CD4 cell count increase of 145 cells/mm3. CONCLUSIONS: The reintroduction of efficient ART therapy after a 1 month interruption shows viral kinetics similar to that of naive patients, and is not associated with the development of resistance. No deleterious effect on the reinitiated therapy was observed in patients who temporarily discontinued ART therapy. Nevertheless, because viral load rebounds back to baseline during treatment interruption, viral suppression is in effect put off by that period of time.

Anti-HIV Agents↗
PubMed1999

[Immunologic reconstruction after antiretroviral treatment].

DATA FAVORING IMMUNE RECONSTITUTION: Multiple drug therapies for HIV infection have enabled a major reduction in the viral load, higher CD4 counts, and a lower incidence of opportunistic infections and tumor formations, and subsequently lower hospitalization rates and mortality. TWO STAGES OF CD4 RECONSTITUTION: In HIV-positive patients with advanced stage disease treated with a protease inhibitor associated with 2 nucleoside analog reverse transcriptase inhibitors and followed prospectively, it has been observed that CD4 counts rise considerably, with a rapid increase during the first 2 months followed by a slower but still positive slope over a period of 18 months. Discordant results have however also been observed suggesting an ineffective anti-viral effect or a retarded immune reconstitution. SEVERAL MECHANISMS: The lymphocyte amplification observed during the early phase corresponds to re-circulation of CD4 and CD8 lymphocytes which had been sequestered in lymphoid organs; most of these CD4 lymphocytes are memory cells. A second phase corresponds to a more moderate and progressive rise in naive CD4 cells which originate from an unknown source. This biphasic reconstitution of CD4 lymphocytes is associated with a correction of the chronic lymphocyte overactivation. PARTIAL IMMUNE RECONSTITUTION: With treatment, the capacity to respond to known antigens reappears. This restored capacity is secondary to the amplification of CD4 memory cells and appears prior to the expansion phase of naive cells. The response remains moderate and is only observed against antigens from microorganisms highly prevalent during advanced stage infection.

Antiviral Agents↗
PubMed1999

Polymorphism of the human immunodeficiency virus type 1 (HIV-1) protease gene and response of HIV-1-infected patients to a protease inhibitor.

In order to analyze the impact of protease gene polymorphism on response to regimens containing a protease inhibitor, the entire protease coding domain from 58 human immunodeficiency virus type 1 (HIV-1)-infected patients who were protease inhibitor naive was sequenced before therapy was started. Plasma HIV-1 RNA levels were measured at baseline and at month 3 and month 6 after treatment. All patients were treated with a combination of two reverse transcriptase inhibitors and a protease inhibitor (saquinavir EOF [n = 28], ritonavir [n = 16], or indinavir [n = 14]). Before treatment, 30 different positions whose codons differed from the subtype B consensus sequence were observed. Major mutations associated with protease inhibitor resistance were not observed. No statistical correlation between the number of amino acid differences and the treatment efficacy at month 3 (-2.4 log) or month 6 (-2.7 log) was observed. At baseline, genotypic analysis of the HIV-1 protease gene of patients who have never received a protease inhibitor does not allow prediction of the efficacy of regimens containing a protease inhibitor.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Hepatitis B virus (HBV) mutations associated with resistance to lamivudine in patients coinfected with HBV and human immunodeficiency virus.

Mutations associated with hepatitis B virus (HBV) resistance to lamivudine have not been extensively addressed in human immunodeficiency virus (HIV)-HBV coinfection. We have studied the HBV polymerase sequences from nine coinfected patients who experienced HBV recurrence while under lamivudine treatment. In seven of these nine patients, Met(550), belonging to the highly conserved YMDD motif, was mutated to Val and was associated with a substitution of Met for Leu(526) in each case. In the two remaining patients, we found a Met(550)-to-Ile change that was associated in only one case with a Leu(526)-to-Met mutation. No mutation was observed in three control patients not receiving lamivudine. This study demonstrates the emergence of particular genetic profiles in HBV-HIV-coinfected patients experiencing a loss of control of HBV infection despite high doses of lamivudine.

Anti-HIV Agents↗
PubMed1999

Preferential associations of alleles of three distinct genes argue for the existence of two prototype variants of human herpesvirus 7.

We had previously described six distinct alleles of the glycoprotein B (gB) gene of human herpesvirus 7 (HHV-7). The genetic changes corresponding to these alleles did not affect gB gene transcription or translation in in vitro assays. The study of distinct HHV-7-positive human samples showed preferential associations of some gB alleles with some alleles of two other genes, distantly located on the HHV-7 genome, coding for the phosphoprotein p100 (p100) and the major capsid protein (MCP). Two allele combinations, corresponding to 44 and 31% of the samples studied, respectively, were interpreted as the genetic signatures of two major prototype HHV-7 variants.

Alleles↗
PubMed1999

[Polymorphism of protease genes in patients infected with HIV-1 and response to therapy including a protease inhibitor].

Protease inhibitors (PIs) are recently introduced drugs that have improved the survival of HIV-infected patients when given in combination with two reverse transcriptase inhibitors. The HIV-1 protease gene is naturally highly polymorphic. Selection pressure due to IP use can result in major or minor resistance-associated mutations (RAMs). This study investigated whether presence before IP therapy of minor RAMs on the protease gene predicts the virological response. Of the 58 PI-naive patients included in the study, 12 had received two nucleoside reverse transcriptor inhibitors, 14 had received indinavir, 16 ritonavir, and 28 saquinavir-SGC. Viral load was measured on D0 (prior to PI initiation) and at M3 and M6 (Roche Monitor 1.5 with 200 and 20 copies/ml as the thresholds). The protease gene was fully sequenced on D0 using the ABI 377 automatic sequencer after RNA amplification by nested RT-PCR. None of the viral strains exhibited major mutations, but 57 of 58 (98%) had at least one minor mutation (median number of substitutions, 4), 60% had 1 to 4 substitutions, and 40% had 5 to 9 substitutions. Substitutions seen with a prevalence > 20% were located at codons 15, 35, 37, 41, 63, and 77. Numbers of substitutions at M3 and M6 were not correlated with viral load or the nature of the PI used, and neither were they significantly different between patients with more or fewer than 20 copies/ml. These data suggest that the protease genotype at PI initiation does not predict the efficacy of a regimen including a PI and is of no assistance in deciding whether or not to include a PI in a triple combination regimen.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with virus replication properties and cell tropism. French ALT Study Group.

Qualitative and quantitative virological parameters were investigated in 68 long-term nonprogressor (LTNP) HIV-1-infected patients and 9 slow-progressor controls. LTNP status was defined as an asymptomatic HIV infection for at least 8 years, a stability of CD4+ cell counts > or =600 cells/mm3 and no antiretroviral therapy. LTNP subjects exhibited a lower median plasma RNA load than controls (6,000 vs. 40,000 RNA copies/ ml) despite a wide range of values in both groups. When compared to the control group, LTNP subjects also exhibited a lower virus isolation rate (65% vs. 100%) and cell-associated viremia (0.75 vs. 56.8 number of infectious unit/ million cells) when CD8-depleted CD4+ cells were tested. By contrast, no major differences in virus replication properties or cell tropism were observed. After 1 year of follow-up, no major overall changes in the virological parameters was observed in the 50 LTNP subjects evaluated at this time. However, nine patients had started antiretroviral therapy, and six others had increased viral loads. Despite the progression observed during the first year of follow-up, the hypothesis that there is a specific subgroup of LTNP patients who will not develop disease cannot be ruled out as yet.

CD4-Positive T-Lymphocytes↗
PubMed1999

[Antiretroviral therapy and immune reconstitution].

The course of the HIV infection has been dramatically modified since the introduction of highly active antiretroviral therapy (HAART) combining inhibitors of the HIV-1 reverse transcriptase and protease. Despite some controversies about the extent to which the immune system can normalize, it is generally admitted nowadays that a numerical and functional CD4 cell profile more akin to asymptomatic HIV-infected individuals can be restored in AIDS patients and can confer host protection against opportunistic events. The best hallmark of such immune restoration is the massive decline in the mortality and morbidity related to AIDS that have been registered in all industrialized countries. These changes involve a recirculation of mature peripheral T cells, a regeneration of naive T cells from thymic origin and a restoration of memory CD4 T cell réactivities. Although these recent advances warrant increased optimism, HAART by reducing the virus burden is unable to restore immunity against HIV itself, except when introduced at the very early stage after virus inoculation. The single condition required for immune reconstitution is an efficient and durable inhibition of virus replication. These positive effects can be obtained at late stages of the disease even when the patients have been heavily pre-treated. They also demonstrate that HIV does not definitively alter the lymphoid tissues nor the immune defenses, even aller years of infection and severe immune suppression, except for HIV-specific CD4 T helper cells.

CD4 Lymphocyte Count↗
PubMed1998

Yellow fever 5' noncoding region as a potential element to improve hepatitis C virus production through modification of translational control.

The lengthy 5' noncoding region (5' NCR) of hepatitis C virus (HCV) RNA forms a highly ordered secondary structure, very conserved among different strains. It includes an internal ribosome entry site (IRES) element, responsible for the cap-independent translation initiation of HCV RNA. Similarly to the IRES of hepatitis A virus (HAV), another human hepatitis virus, HCV IRES, activity in internal initiation of translation is weak. Furthermore, both viruses exhibit a poor growth phenotype that may result at least partially from an inhibitory control of translation. To enhance HCV translation, as a preliminary step in designing constructs for improvement in viral production, we sought to evaluate a chimeric construct containing the yellow fever virus (YFV) 5' NCR fused to the initiation codon of the HCV coding sequence. YF viral RNA, as the majority of eukaryotic messenger RNAs, is translated by a ribosome scanning mechanism in a cap-dependent manner. The efficiency of translation initiation of the parental HCV construct was compared in vitro in rabbit reticulocyte lysates with that of the chimeric construct containing YFV 5' NCR. Surprisingly, the related distanced YFV 5' NCR was fivefold more active than was the wild-type HCV IRES in directing that function. Furthermore, chimeric transcripts were shown to be effective in vivo after transfection of eukaryotic cells. Taken together, these results raise the following question: why has the HCV genus evolved to the acquisition of an IRES element within its 5' NCR among the Flaviviridae family?

5' Untranslated Regions↗
PubMed1998

Efficacy and tolerability of stavudine plus lamivudine in treatment-naive and treatment-experienced patients with HIV-1 infection.

BACKGROUND: A combination of two nucleoside analogues is currently the core of any antiretroviral regimen for HIV-1 infection. Stavudine plus lamivudine has shown an additive effect in vitro, as well as an absence of overlapping toxicity and cross-resistance. OBJECTIVE: To evaluate the antiviral efficacy of stavudine plus lamivudine in treatment-naive patients and in patients previously treated with other nucleoside reverse transcriptase inhibitors. DESIGN: Prospective, open-label pilot study. SETTING: Three urban clinical centers in Paris. PATIENTS: 83 patients with CD4+ cell counts between 50 and 400 cells/mm3 (42 treatment-naive and 41 treatment-experienced patients). INTERVENTIONS: Stavudine, 40 mg twice daily (30 mg twice daily in patients with a body weight < or = 60 kg), and lamivudine, 150 mg twice daily. MEASUREMENTS: Primary end points for efficacy included changes in plasma viral load and CD4+ cell count at 24 weeks compared with baseline. RESULTS: Therapy with stavudine plus lamivudine resulted in a median decrease of 1.66 log10 (10(1.66)) (range, -3.04 to -0.79 log10) in plasma HIV-1 RNA; the median increase in CD4+ cell count was 108 cells/mm3 (range, -58 to 406 cells/mm3) at week 24 in treatment-naive patients. In treatment-experienced patients, the median reduction in plasma HIV-1 RNA was 0.55 log10 (range, -2.86 to 0.52 log10), and the median increase in CD4+ cell count was 46 cells/mm3 (range, -188 to 311 cells/mm3). The percentages of patients with less than 3000 HIV-1 RNA copies/mL and less than 400 copies/mL at 24 weeks were, respectively, 57% (95% CI, 41% to 72%) and 26% (CI, 12% to 40%) among treatment-naive patients and 22% (CI, 10% to 38%) and 5% (CI, 1% to 17%) among treatment-experienced patients. Of 82 patients, 14 (17%) experienced grade 3 or 4 toxicity and 2 discontinued therapy because of intolerance toward treatment. CONCLUSION: Stavudine plus lamivudine seems to have a potent antiviral effect in treatment-naive and treatment-experienced patients. No major drug-limiting toxicity was found. This two-nucleoside combination should be considered in multidrug therapy for HIV.

Adult↗
PubMed1998

Human herpesvirus-6 meningoencephalitis in a recipient of an unrelated allogeneic bone marrow transplantation.

BACKGROUND: Human herpesvirus-6 (HHV-6) has been implicated in bone marrow suppression, interstitial pneumonitis, and fatal meningoencephalitis in bone marrow transplant (BMT) recipients. METHODS: We describe the case of a woman with acute myeloid leukemia in second remission who developed febrile meningoencephalitis 8 months after a second unrelated BMT. RESULTS: Computed tomography and magnetic resonance images of the brain were nonspecific. Analysis of cerebrospinal fluid (CSF) revealed lymphocytosis and an increased protein level. Using polymerase chain reaction methods, HHV-6 was the only pathogen detected in CSF, peripheral blood mononuclear cells, and bone marrow. The patient was treated with ganciclovir and foscarnet for 3 months. All clinical manifestations resolved and HHV-6 polymerase chain reaction analysis of CSF became negative 40 days after the beginning of antiviral treatment. CONCLUSIONS: This observation strongly suggests that HHV-6 should be sought in BMT patients with neurological complications and that HHV-6 meningoencephalitis may respond to ganciclovir and foscarnet therapy.

Acute Disease↗