Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.
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PMID:Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients. 1117 Sep 83

Our previous study demonstrated formation of T cell-dendritic cell (DC) clusters in inflamed dermis of intraorally autotransplanted skin flaps. Such T cell-DC clusters are supposed to be important for close interactions between T cells and DCs including the specific antigen presentation. Here we show the involvement of the macrophage-derived chemokine (MDC/CCL22) and its specific receptor CC chemokine receptor 4 (CCR4) in the formation of T cell-DC clusters. Reverse transcriptase-polymerase chain reaction analysis revealed high levels of mRNA expression for MDC and CCR4 in inflamed skin and neck lymph nodes (LNs), but not in normal skin. Immunohistochemically, MDC(+) cells and CCR4(+) cells were mainly located within the T cell-DC clusters both in the dermis of inflamed skin and the T cell area of LNs. MDC(+) cells were identified to be DCs both in inflamed skin and LNs. The majority of CCR4(+) cells were CD4(+) T cells, accounting for approximately one-third of total CD4(+) T cells in the inflamed skin. Our data suggest that the MDC-CCR4 system plays an important role in the formation of T cell-DC clusters both in inflamed skin and LNs.
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PMID:Macrophage-derived chemokine (MDC/CCL22) and CCR4 are involved in the formation of T lymphocyte-dendritic cell clusters in human inflamed skin and secondary lymphoid tissue. 1129 May 44

We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reaching significance, was observed for patients with HIV strains with the reverse transcriptase codon 215 mutation (P = 0.07), but this trend disappeared after adjustment for initial CD4 cell counts. During the first 3 months on didanosine therapy, the increase in CD4 cell counts was greater in patients who were wild type at codon 215 than in those with the mutation at codon 215 (P = 0.03). These data suggest that there was a better initial CD4 response to didanosine therapy in patients with HIV without the mutation at codon 215, but that this response did not translate into increased survival.
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PMID:Predictive value of codon 215 reverse transcriptase mutation on the efficacy of didanosine in HIV-infected, zidovudine-experienced patients. 1132 50

The Inter-Company Collaboration for AIDS Drug Development (ICC) is now enrolling for its first series of clinical trials for HIV infection for patients with CD4 (T-helper) counts between 200 and 500, who have not previously taken AZT. Each 48-week trial will assign 75 volunteers to three different treatment arms. In the first trial (ICC 001), everyone will receive AZT (Retrovir) and ddC (HIVID). As the third drug, one group will receive nevirapine (an experimental non-nucleoside reverse-transcriptase inhibitor); another group will receive saquinavir (Indirase); and the third treatment group will receive the placebo. In the second trial (ICC 002), everyone will receive AZT and ddI. One group will receive nevirapine as the third drug; another group will receive 3TC as the third drug. For information on how to enroll, volunteers may call the coordinating center at PAREXEL International Corporation (800-925-AIDS). Or volunteers can call directly to the office of the physician in their city (listed in the article).
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PMID:ICC Trials -- first study enrolling. 1136 34

DuPont Merck announced an expanded access program for Sustiva, a non-nucleoside transcriptase prohibitor. The once-daily drug in combination with Crixivan is effective in reducing viral load and increasing CD4 cell counts. The drug is well tolerated and shows no serious side effects. The manufacturer is submitting its application for approval to the Food and Drug Administration (FDA) in the second quarter of 1998.
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PMID:Broadened access to Sustiva. 1136 7

Combinations of cytokines are known to reactivate transcription and replication of latent human immunodeficiency virus type 1 (HIV-1) proviruses in resting CD4(+) T lymphocytes isolated from infected individuals. Transcription of the HIV-1 provirus by RNA polymerase II is strongly stimulated by the viral Tat protein. Tat function is mediated by a cellular protein kinase known as TAK (cyclin T1/P-TEFb) that is composed of Cdk9 and cyclin T1. We have found that treatment of peripheral blood lymphocytes and purified resting CD4(+) T lymphocytes with the combination of interleukin-2 (IL-2), IL-6, and tumor necrosis factor alpha resulted in an increase in Cdk9 and cyclin T1 protein levels and an increase in TAK enzymatic activity. The cytokine induction of TAK in resting CD4(+) T lymphocytes did not appear to require proliferation of lymphocytes. These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4(+) T lymphocytes harboring a latent provirus.
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PMID:Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. 1168 14

The Patient Medication Adherence Questionnaire Version 1.0 (PMAQ-V1.0) is a patient-reported adherence instrument to assess medication-taking behaviors and identify barriers to adherence with antiretroviral therapy. To assess the correlation between adherence and virologic outcome, the PMAQ-V1.0 was administered to 194 antiretroviral-experienced adults with HIV infection enrolled in a 16-week evaluation of protease inhibitor-containing regimens featuring a lamivudine/zidovudine combination tablet. At baseline, plasma HIV-1 RNA levels were less than 10,000 copies/mL and CD4(+)-cell counts were equal to or greater than 300 x 10(6)/L; patients had been receiving a conventional regimen of lamivudine + zidovudine (separately) plus a protease inhibitor for at least 10 weeks immediately prior to the study. Forty-eight percent of patients who reported missing at least one dose of a nucleoside reverse-transcriptase inhibitor (NRTI) during the study had detectable plasma HIV-1 RNA, compared with 26% of patients who reported no missed doses (P = .002). Patients who missed at least one dose of an NRTI or protease inhibitor were 2.5 times more likely to have quantifiable HIV-1 RNA than those who reported no missed doses. Patients who reported fewer barriers and more motivators to adherence had better virologic outcomes (P = .001). Several dimensions of the PMAQ-V1.0 did not function as well as hypothesized. In this study, self-reported adherence derived from the PMAQ-V1.0 predicted virologic outcomes, but further refinement of the dimensions appears warranted.
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PMID:Correlation between self-reported adherence to highly active antiretroviral therapy (HAART) and virologic outcome. 1169 19

Plasmablastic lymphoma is a relatively new entity that is considered to be a diffuse large B-cell lymphoma with an unique immunophenotype and a predilection for the oral cavity. We present a 50 year-old HIV-positive, bisexual, white male with a CD4 count 300/mm(3) and a viral HIV-RNA polymerase chain reaction (PCR) load of 237 copies/ml, who developed a painful, purple-red mass in the edentulous area of the maxillary right first molar. Erythematous gingival enlargements of the interdental papillae were seen in three of the dental quadrants. In addition, the patient was being managed with antiretroviral therapy and liposomal doxorubicin for recurrent cutaneous Kaposi's sarcoma (KS). Although oral KS was suspected, the gingival lesions were biopsied because they were refractory to chemotherapy and a lymphoma could not be excluded. Histopathologic examination revealed a lymphoid malignant neoplasm, consistent with a plasmablastic lymphoma. Immunoreactivity with vs38c, CD79a, kappa light chain, and IgG was readily identified in tumor cells; while only focal cells expressed CD20 and LCA (CD45RB). CD56, CD3, lambda light chain, and EMA were non-reactive. EBV was detected in the tumor by Southern hybridization, PCR amplification, in situ hybridization for EBER-1 DNA, and immunohistochemistry for latent membrane protein-1. The same tumor was negative for HHV-8 by PCR. Recognition of plasmablastic lymphoma is important, because it represents an HIV-associated malignancy that predominantly involves the oral cavity, may mimic KS and has a poor prognosis.
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PMID:Plasmablastic lymphoma: an HIV-associated entity with primary oral manifestations. 1175 27

Highly active antiretroviral therapies (HAARTs) that contain human immunodeficiency virus (HIV) protease inhibitors (PIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were compared for their effect on secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. In therapy-naive HIV-positive subjects, oral Sap was detected in 11, 6, 3, 0, and 0 of 15 subjects treated with PI-HAART and in 7, 7, 9, 6, and 5 of 15 subjects treated with NNRTI-HAART, on days 0, 14, 30, 90, and 180 of treatment, respectively. In another 30 subjects, Sap was detected in 0 and 7 of 15 subjects after 1 year of treatment with PI-HAART or NNRTI-HAART, respectively. The anti-Sap effect of PI-HAART was associated with clinical resolution of oral candidiasis but not with late and inconstant recovery of anticandidal cellular immunity. In all subjects, the 2 therapeutic regimens compared well in increasing CD4(+) cell count and abating viremia. Thus, PIs exert an early, immune reconstitution-independent effect on Candida virulence in the oral cavities of HIV-positive subjects.
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PMID:Antiretroviral therapy with protease inhibitors has an early, immune reconstitution-independent beneficial effect on Candida virulence and oral candidiasis in human immunodeficiency virus-infected subjects. 1180 92

A common dilemma for HIV-positive pregnant women is the issue of continuation or cessation of antiretroviral therapy (ART) postpartum. Current guidelines for ART during pregnancy offer no specific recommendations for postpartum ART care. The objective of this study was to ascertain characteristics that would predict cessation or continuation of ART postpartum. In this study, prenatal and medical clinic records were reviewed retrospectively for a cohort of 29 HIV-infected pregnant women who were seen in the Temple University High Risk obstetrics practice from 1997 to 1998. All women took ART during pregnancy, except for one who received i.v. AZT and nevirapine during labor. HIV-specific medical care was provided concurrently during the time of the woman's obstetrics visit by a nurse practitioner and a clinical nurse specialist in consultation with the physician. Factors that were included for review included race, age, use of ART at the time of pregnancy diagnosis, type of ART during pregnancy, CD4 count, HIV-1 ribonucleic acid polymerase chain reaction (RNA PCR) levels, current substance use, disclosure of HIV status to current partner, years of HIV infection, prior HIV infected child, and whether this was a first pregnancy. The two groups of women were divided between those who discontinued ART postpartum and those who continued ART. The data were analyzed with the Kruskal-Wallis test for two groups, or calculations of risk ratios with Fisher's exact test. Study results indicated that 15 out of 29 women (51%) continued ART postpartum. The significant factors for continuation included Latina ethnicity (risk ratio = 0.24, confidence interval = 0.06-0.87), CD4 < 200 mm3 (p = .04), and a greater number of drugs in the antiretroviral regimen 3 versus 2 (p = .05). This study showed that postpartum continuation of ART was associated with identified Latina ethnicity, lower CD4 counts, and a greater number of drugs in the pregnancy regimen. Further study is recommended to understand the clinical impact of intermittent ART, the strategies for postpartum therapy adherence, and clinical follow-up.
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PMID:Continuation of postpartum antiretroviral therapy in a cohort of women infected with human immunodeficiency virus. 1182 60


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