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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We isolated a revertant virus after prolonged culturing of a replication-impaired human immunodeficiency virus type 1 (HIV-1) mutant of which the Rev open reading frame was inactivated by mutation of the AUG translation initiation codon. Sequencing of the tat-rev region of this revertant virus identified a second-site mutation in tat that restored virus replication in the mutant background. This mutation activated a cryptic 5' splice site (ss) that, when used in conjunction with the regular HIV 3' ss #5, fuses the tat and rev reading frames to encode a novel T-Rev fusion protein that rescues Rev function. We also demonstrate an alternative route to indirectly activate this cryptic 5' ss by mutational inactivation of an adjacent exon splicing silencer element.
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PMID:Repair of a Rev-minus human immunodeficiency virus type 1 mutant by activation of a cryptic splice site. 1123 79

Previous analyses of retroviral nucleotide sequences, suggest a so-called "scrambled duplicative stepwise molecular evolution" (many sectors with successive duplications/deletions of short and longer motifs) that could have stemmed from one or several starter tandemly repeated short sequence(s). In the present report, we tested this hypothesis by focusing on the long terminal repeats (LTRs) (and flanking sequences) of 24 human and 3 simian immunodeficiency viruses. By using a calculation strategy applicable to short sequences, we found consensus overrepresented motifs (often containing CTG or CAG) that were congruent with the previously defined "retroviral signature." We also show many local repetition patterns that are significant when compared with simply shuffled sequences. First- and second-order Markov chain analyses demonstrate that a major portion of the overrepresented oligonucleotides can be predicted from the dinucleotide compositions of the sequences, but by no means can biological mechanisms be deduced from these results: some of the listed local repetitions remain significant against dinucleotide-conserving shuffled sequences; together with previous results, this suggests that interspersed and/or local mononucleotide and oligonucleotide repetitions could have biased the dinucleotide compositions of the sequences. We searched for suggestive evolutionary patterns by scrutinizing a reliable multiple alignment of the 27 sequences. A manually constructed alignment based on homology blocks was in good agreement with the polypeptide alignment in the coding sectors and has been exhaustively assessed by using a multiplied alphabet obtained by the promising mathematical strategy called the N-block presentation (taking into account the environment of each nucleotide in a sequence). Sector by sector, we hypothesize many successive duplication/deletion scenarios that fit our previous evolutionary hypotheses. This suggests an important duplication/deletion role for the reverse transcriptase, particularly in inducing stuttering cryptic simplicity patterns.
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PMID:HIV-1 and HIV-2 LTR nucleotide sequences: assessment of the alignment by N-block presentation, "retroviral signatures" of overrepeated oligonucleotides, and a probable important role of scrambled stepwise duplications/deletions in molecular evolution. 1142 Mar 63

Highly active antiretroviral therapy (HAART) has led to profound decreases in morbidity and mortality rates in human immunodeficiency virus type 1 (HIV-1)-infected persons, at least in the developed world. Many infected persons have plasma levels of HIV-1 RNA that are less than the limits of detection of most clinical assays as a result of combination antiretroviral therapy. Nonetheless, HIV-1 has not been eradicated by HAART. This has been shown to be because of latent HIV-1 replication-competent provirus in resting CD4+ T lymphocytes, cryptic viral replication below the limits of detection of most clinical assays, and, possibly, the presence of viral sanctuary sites. An understanding of these reservoirs for HIV-1 in the setting of virally suppressive HAART will be critical for the development of new approaches to induce HIV-1 remissions and for the exploration of the possibility of viral eradication in the future.
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PMID:Reservoirs of human immunodeficiency virus type 1: the main obstacles to viral eradication. 1173 50

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.
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PMID:Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. 1240 55

Highly active antiretroviral therapy (HAART) has dramatically altered the human immunodeficiency virus type 1 (HIV-1) pandemic in the developed world. Most patients treated with HAART will maintain clinically undetectable plasma virus loads with concomitant dramatic decreases in mortality and morbidity. Nevertheless, HAART does not eradicate HIV-1 infection on the basis of persistent low-level or cryptic viral replication and, of importance, latent provirus in resting CD4+ T lymphocytes. New approaches are now being developed for stimulation of "HAART-persistent" reservoirs. Immune activation therapy (IAT) has begun to be used in attempts to stimulate the HIV-1 latent reservoir. These studies and new approaches to activating latent virus in resting CD4+ T cells are reviewed and critically analyzed in the present report. Development of novel IAT may lead to long-term remission or viral eradication in the future.
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PMID:Approaching eradication of highly active antiretroviral therapy-persistent human immunodeficiency virus type 1 reservoirs with immune activation therapy. 1247 72

The conserved surfaces of the human immunodeficiency virus (HIV)-1 envelope involved in receptor binding represent potential targets for the development of entry inhibitors and neutralizing antibodies. Using structural information on a CD4-gp120-17b antibody complex, we have designed a 27-amino acid CD4 mimic, CD4M33, that presents optimal interactions with gp120 and binds to viral particles and diverse HIV-1 envelopes with CD4-like affinity. This mini-CD4 inhibits infection of both immortalized and primary cells by HIV-1, including primary patient isolates that are generally resistant to inhibition by soluble CD4. Furthermore, CD4M33 possesses functional properties of CD4, including the ability to unmask conserved neutralization epitopes of gp120 that are cryptic on the unbound glycoprotein. CD4M33 is a prototype of inhibitors of HIV-1 entry and, in complex with envelope proteins, a potential component of vaccine formulations, or a molecular target in phage display technology to develop broad-spectrum neutralizing antibodies.
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PMID:Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes. 1248 21

Three of five virally suppressed human immunodeficiency virus type I (HIV-1)-infected patients treated with highly active antiretroviral therapy and followed intensively with a supersensitive reverse transcriptase PCR assay with a lower limit of quantitation of 5 copies/ml showed statistically significant viral load decays below 50 copies/ml, with half-lives of 5 to 8 months and a mean of 6 months. This range of half-lives is consistent with the estimated half-life of the latent HIV-1 reservoir in the peripheral blood. Those patients without decay of viral load in plasma may have significant cryptic HIV-1 residual replication.
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PMID:In a subset of subjects on highly active antiretroviral therapy, human immunodeficiency virus type 1 RNA in plasma decays from 50 to <5 copies per milliliter, with a half-life of 6 months. 1252 64

Highly active antiretroviral therapy (HAART) has profoundly decreased morbidity and mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals, at least in the developed world. Many infected individuals have plasma levels of HIV-1 RNA below the limits of detection of most clinical assays due to combination antiretroviral therapy. Nonetheless, HIV-1 has not been eradicated by HAART. This has been shown recently to be due to latent HIV-1 replication-competent provirus in resting CD4+ T-lymphocytes, cryptic viral replication below the limits of detection of most clinical assays, and viral sanctuary sites. An understanding of these sanctuaries and reservoirs for HIV-1 in the setting of virally suppressive HAART will be critical in developing new approaches to induce HIV-1 remissions or the possibility of viral eradication in the future.
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PMID:Reservoirs, sanctuaries, and residual disease: the hiding spots of HIV-1. 1267 82

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by immunodeficiency, eczema, and thrombocytopenia with small platelets. A wide spectrum of mutations in the Wiskott-Aldrich syndrome protein ( WASP) gene have been identified as causative of the disease. In the present paper, we report on a family with a boy affected by WAS, with a splice-site mutation caused by a T to G substitution in the +2 position of intron 6 (IVS6+2T>G). Expression studies performed in COS-7 and U-937 cells showed that the mutation affected the normal splicing process. As a consequence, an abnormally long transcript of 38 nucleotides is generated. Such missplicing is probably due to the activation of a cryptic splice donor site located 38 nt downstream of exon 6. The translation of such aberrant mRNA will produce a truncated protein with a premature stop at codon 190. Thus, a novel splice-site mutation is reported in a patient with a mild WAS phenotype.
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PMID:Identification and characterization of a novel splice-site mutation in a patient with Wiskott-Aldrich syndrome. 1456 84

Extrachromosomal forms of human immunodeficiency virus (HIV)-1 can be detected in peripheral blood mononuclear cell (PBMC) from HIV-infected patients in the absence of detectable viral replication and are thought to be a sign of active but cryptic virus replication. No information, however, are available on whether these forms are also present in animal models for acquired immunodeficiency syndrome (AIDS) and on their relation with other methods of detection of virus replication. To this aim, a polymerase chain reaction (PCR) approach was used to detect and analyze unintegrated circular 2-LTR-containing forms in PBMC of simian human immunodeficiency virus (SHIV)89.6P infected cynomolgus monkeys with RNA levels ranging between 1.8 x 10(6) and less than 50 copies/ml of plasma. 2-LTR forms were detected in 96.5% of monkeys' samples above 50 copies/ml of plasma, whereas they were present in 75.8% of monkeys' samples below 50 copies/ml of plasma. Persistence of unintegrated viral DNA in monkeys with undetectable plasma RNA could indicate either stability in non-dividing cells or ongoing low levels of viral replication in dividing cells.
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PMID:Circular viral DNA detection and junction sequence analysis from PBMC of SHIV-infected cynomolgus monkeys with undetectable virus plasma RNA. 1520 38


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