Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The termini of integrated retroviral DNAs are characterized by highly conserved dinucleotide sequences: 5'TG...//...CA3'. For the avian and murine C-type retroviruses, the dinucleotide sequences reside two deoxynucleotides (usually AA and TT) from the LTR ends of unintegrated viral DNA (5' AATG...//...CATT3'). The number and identity of terminal deoxynucleotides in unintegrated HIV-1 linear DNA that extend beyond the conserved dinucleotides have not been determined. However, they had been presumed to consist of a single nucleotide (5'CTG...//...CAG3') on each end, based on inspection of the nucleotide sequence between the end of the supposed primer sites for retroviral DNA synthesis and the conserved proviral termini. We have utilized the polymerase chain reaction (PCR) to amplify segments representing the joined ends of linear DNA present in covalently closed circular HIV-1 DNA molecules isolated from infected T cells. These fragments were cloned and the nucleotide sequence of the LTR-LTR circle junction of several independent clones determined. Based upon the results, we predict that, like the avian and murine viruses, HIV-1 linear DNA contains two nucleotides beyond the conserved dinucleotides: 5'ACTG...//...CAGT3'. Models for the origin of these termini and other observed junction sequences are proposed.
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PMID:Terminal nucleotides of the preintegrative linear form of HIV-1 DNA deduced from the sequence of circular DNA junctions. 238 63

The recently published Protocol 076 study (ACTG 076/ANRS 024) showed that zidovudine significantly decreased the relative risk of maternal HIV transmission by 71.5% compared with placebo. Oral zidovudine 100 mg five times daily until the onset of labour, followed by intravenous zidovudine 2 mg/kg over 1 hour then 1 mg/kg.h until delivery, or an identical placebo regimen were administered to HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ counts > 200 cells/microliters. 400 babies born to these women received zidovudine syrup 2 mg/kg or placebo administered 6-hourly for 6 weeks. The zidovudine regimens were well tolerated by both mothers and infants. Further studies should aim to determine the mechanism by which zidovudine reduces the risk of maternal HIV transmission, the timing of HIV transmission, the efficacy of zidovudine in women not meeting the entry criteria for Protocol 076 and the long term effects of zidovudine during pregnancy on both mother and infant, and should examine the possibility of developing a simplified zidovudine regimen. Following recent guidelines from the US and French public health services, the full Protocol 076 regimen should be given to all women fulfilling that study's entry criteria. This regimen should also be considered in women with more severe disease or in later stages of gestation. Clinical efficacy of zidovudine should be monitored closely in women and infants, who should also be followed up for long term adverse effects. Unblinded screening for HIV in pregnant women in the USA is facing extreme opposition; nevertheless, guidelines on HIV counselling and HIV testing of pregnant women are currently being developed there in light of the Protocol 076 findings.
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PMID:Prevention of maternal HIV transmission. Practical guidelines. 761 98

Proviral DNAs from 3 laboratory strains and 21 clinical isolates of HIV-1 were extracted from infected cells after proteinase K digestion and the protease gene was PCR amplified and sequenced directly by the Sanger method. In vitro susceptibilities of the virus isolates to protease inhibitors were determined by the ACTG/DoD consensus assay. Four different HIV protease inhibitors were tested including P9941, a C2 symmetrical diol (Du Pont-Merck); A80987, an asymmetric mono-ol (Abbott); XM323, a cyclic urea (Du Pont-Merck); and Ro31-8959, an asymmetric hydroxyethylene isostere (Roche). Maximum sequence variation was 10% at both the nucleic and amino acid levels. Purine-purine substitutions were most common. Five noncontiguous regions were conserved across all isolates and corresponded to amino acids 1-9 (amino terminal), 21-32 (catalytic site), 47-56 ("flap" region), 78-88 (substrate-binding region), and 94-99 (carboxy terminal). All clinical isolates demonstrated in vitro susceptibility to the protease inhibitors. There was no significant difference between the susceptibility of the reference strains and the clinical isolates. These data suggest that the variable regions of protease do not contain sites that are important for interactions with the inhibitors tested.
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PMID:Limited sequence diversity of the HIV type 1 protease gene from clinical isolates and in vitro susceptibility to HIV protease inhibitors. 773 83

Data about the virology and pathogenesis of HIV disease suggest that early therapeutic intervention, perhaps even before the CD4+ cell count has fallen substantially, would be a theoretically sound approach. A limited number of large clinical studies address early therapy with zidovudine. A European-Australian study, which enrolled patients with CD4+ cell counts > 400 cells/microliters, found a benefit of zidovudine therapy compared to placebo in delaying minor HIV manifestations and CD4+ cell loss after a 2-year follow-up period. The results of the Concorde study, which enrolled > 1700 asymptomatic patients and followed them for an average of 3 years, have created controversy about the results of ACTG protocol 019, which had led to widespread zidovudine use for patients with CD4+ cells < 500/microliters. Although there was a favorable change in CD4+ cell count in the Concorde study patients assigned to immediate zidovudine treatment compared with those assigned to deferred treatment, there were no significant differences in progression to AIDS or survival. Preliminary results from follow-up of ACTG 019 patients enrolled with CD4+ cell counts of 300-500/microliters suggest that the duration of benefit of zidovudine may be longer than in patients with CD4+ cell counts less than 300 cells/microliters. Finally, the impact of antiretroviral therapy on quality-of-life measures is now recognized as an important issue and should be incorporated into treatment decisions. The available data from several large studies of patients with asymptomatic HIV infection are concordant, in that they suggest that zidovudine has a limited duration of efficacy but does not prolong survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early intervention in HIV infection: where are we? 781 39

The clinical significance of the reduced in vitro susceptibility of HIV to antiretroviral agents has been difficult to elucidate for nucleoside analogs such as zidovudine. However, the virological significance of resistance to nevirapine and other HIV-1-specific reverse transcriptase inhibitors has been established. With antiretroviral therapy, disease progression is not equivalent to drug failure, which is not equivalent to drug resistance. Clinical disease progression is only indirectly linked to HIV replication. Drug resistance is complex, and combining drugs does not appear to delay emergence of resistant strains of HIV although it may affect the specific amino acid substitutions. Drug resistance does appear to contribute to drug failure. The clinical trial ACTG 116B/117 found that the duration of prior zidovudine therapy was not related to the relative benefit of switching to didanosine. Preliminary results of analysis of resistant strains of HIV isolated from ACTG 116B/117 patients revealed that the relative hazard of progression was about threefold higher for patients with high-level resistance to zidovudine, syncytium-inducing biological phenotype, and an AIDS diagnosis at baseline. This study showed clearly that acquisition of an HIV strain with high-level resistance to zidovudine was a poor prognostic factor. Although nevirapine resistance emerges rapidly, preliminary data suggest that high dosages may be active against HIV even in the presence of resistant HIV strains. At the present time, viral resistance and biological phenotype are not useful in the management of individual patients.
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PMID:Resistance, drug failure, and disease progression. 781 40

The rationale for combining anti-HIV-1 agents is to provide more complete viral suppression, to limit the emergence of drug resistance during chronic viral replication, and to provide more effective antiretroviral treatment even when mixtures of drug-resistant and drug-sensitive strains are present. In vitro experiments reveal increased suppression with multiple-drug therapy, but viral breakthrough occurs after prolonged time in culture even during triple-drug therapy. Clinical results available to date indicate that drugs should be given simultaneously for optimal benefit. There appears to be a rationale for early initiation of combination therapy before the onset of increased viral burden and the emergence of syncytium-inducing viral variants. The results of ACTG protocol 155 revealed benefit of zidovudine and zalcitabine over monotherapy with either agent in patients with CD4+ cell counts > or = 150 cells/mm3. However, further clinical studies will be necessary before firm recommendations can be made about the indications for combination antiretroviral therapy in HIV-1-infected individuals at different stages of disease. Ultimately, we need better drugs, in combination, which significantly impact on HIV-1 burden to achieve more complete viral suppression and to reduce selection of drug-resistant viral variants.
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PMID:Combination therapy: more effective control of HIV type 1? 781 41

Management of women with HIV infection or AIDS should follow the established guidelines for antiretroviral therapy and prevention and treatment of opportunistic complications of HIV infection. Gynecological manifestations of HIV are primarily cervical dysplasia and cancer associated with human papillomavirus (HPV) infection and vaginal and mucocutaneous candidiasis. Human papillomavirus-associated cervical dysplasia/neoplasia is more common in women with advanced rather than early HIV disease, and monitoring with Pap smears should probably increase to every 6 months in patients with CD4+ cell counts < 500 cells/microliter (and certainly when this value falls below 200), with positive Pap smears confirmed by colposcopy and biopsy. For patients with CD4+ cell counts > 350 cells/microliter, cryotherapy is probably adequate, but therapy should be increasingly aggressive at lower CD4+ cell counts. Results of ongoing studies should be available soon to guide therapy. Optimal treatment of candidiasis in HIV-infected women includes prevention of recurrence with a combination of topical and systemic antifungal agents. Women with child-bearing potential should be treated as medically indicated for other HIV-infected patients, including during pregnancy. In fact, preliminary results of ACTG 076 indicated that zidovudine therapy during pregnancy reduces vertical transmission of HIV about threefold.
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PMID:Management of the female HIV-infected patient. 781 46

In 1990 the results of a placebo-controlled study conducted within the AIDS Clinical Trials Group (ACTG 019) showed that in the short term, zidovudine was effective in slowing progression to advanced disease in HIV-infected asymptomatic patients with low CD4 cell counts. More recently, the preliminary results of the Concorde Trial suggested that while the data at 1 year agreed with those of ACTG 019, no sustained clinical benefit was detectable at 3 years for early versus deferred therapy. Therefore, the length of the clinical usefulness of zidovudine in this population is still to be determined. We evaluated the 2-year outcome of zidovudine therapy in asymptomatic patients through the prospective follow-up of a cohort of 936 subjects with low CD4+ (< 500/mm3) counts who strictly satisfied, at enrollment, the inclusion and exclusion criteria of the ACTG 019 trial. The clinical end point of the analysis was the development of AIDS. The majority (72.2%) of the individuals in the cohort acquired HIV infection through intravenous drug use; 26.6% were women. The median baseline CD4 cell count was 308/mm3. At 55 weeks of mean follow-up, the progression rate to AIDS (3.2 events per hundred person-years) appears to be comparable to that already reported at the same mean follow-up time for the ACTG 019 zidovudine-treated asymptomatic patients. After 124 weeks of mean follow-up, the overall rate of progression to AIDS was 5.2 per hundred person-years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term follow-up of zidovudine therapy in asymptomatic HIV infection: results of a multicenter cohort study. The Italian Zidovudine Evaluation Group. 790 80

Genetic variation of human immunodeficiency virus (HIV) over time is an important consideration in long-term antiretroviral therapy, in all likelihood affecting the course of HIV disease and its response to antiretroviral therapy. Viral replication persists throughout HIV disease, and viral burden is correlated with disease stage. CD4+ T-helper cells, a prime target for HIV, appear responsible for direct cellular and humoral responses to infection. HIV can be divided into three groups: nonsyncytium-inducing (NSI) isolates with low replicative capacity; high-replicative-capacity NSI isolates; and high-replicative-capacity, syncytium-inducing (SI) isolates. The SI phenotype also is associated with T-helper-cell tropism, rapid CD4+ cell count decline, and rapid HIV disease progression. In some HIV-infected individuals, SI variants evolve from NSI variants at approximate mean CD4+ cell counts of 400 to 500 cells/microliters. Appearance of SI variants may be a useful prognostic marker for decline in cell counts and more rapid progression to AIDS. However, SI variants are not required for HIV disease progression. Only about one-half of AIDS patients harbor SI variants, indicating that HIV that remains NSI can cause AIDS and death. Zidovudine resistance has been found (in ACTG 116B/117) to be an independent predictor of HIV disease progression. Zidovudine resistance and SI phenotype together are closely associated with rapid HIV disease progression.
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PMID:Pathogenicity and diversity of HIV and implications for clinical management: a review. 796 48

CD4 lymphocyte and survival data from two completed trials, a double-blind placebo-controlled trial of zidovudine in patients with advanced human immunodeficiency virus type 1 (HIV) disease (BW-02 study) and a randomized trial of two different doses of zidovudine in patients with advanced HIV disease (ACTG-002 study) were used to determine the degree to which CD4 lymphocyte counts reflect zidovudine-associated survival benefit. Proportional hazards models were used, and CD4 lymphocyte counts were smoothed by using empirical Bayes estimates. The geometric mean of the CD4 lymphocyte counts increased by 71 and 46 cells/mm3 for patients in the BW-02 and ACTG-002 studies, respectively, followed by a progressive decline. Higher pretreatment CD4 lymphocyte counts (p = 0.001), greater increases in CD4 lymphocytes at 8 weeks (p = 0.1), and smaller declines in the slope (p = 0.001) were associated with a lower risk of death. The most current CD4 lymphocyte count was most prognostic of death (p = 0.001). The risk of death was greater for patients with lower CD4 lymphocytes and this risk increased sharply when the CD4 lymphocyte counts fell below 50 cells/mm3. The hazard of death was higher for placebo recipients at all levels of CD4 lymphocytes compared with zidovudine recipients. Although higher CD4 lymphocyte counts are associated with improved survival, these increases account for only a small proportion of the survival benefit of zidovudine in these two studies.
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PMID:Modeling the relationship between survival and CD4 lymphocytes in patients with AIDS and AIDS-related complex. 809 80


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